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Lead (Pb(II)) is a pervasive heavy metal toxin with many well-established negative effects on human health. Lead toxicity arises from cumulative, repeated environmental exposures. Thus, prophylactic strategies to protect against the bioaccumulation of lead could reduce lead-associated human pathologies. Here we show that DNA and RNA aptamers protect C. elegans from toxic phenotypes caused by lead. Reproductive toxicity, as measured by brood size assays, is prevented by co-feeding of animals with DNA or RNA aptamers. Similarly, lead-induced neurotoxicity, measured by behavioral assays, are also normalized by aptamer feeding. Further, cultured human HEK293 and primary murine osteoblasts are protected from lead toxicity by transfection with DNA aptamers. The osteogenic development, which is decreased by lead exposure, is maintained by prior transfection of lead-binding DNA aptamers. Aptamers may be an effective strategy for the protection of human health in the face of increasing environmental toxicants. • Lead toxicity remains a pervasive public health problem, with limited interventions available. • Aptamers are short single-stranded nucleic acids that bind targets including proteins, small molecules, and ions. • Lead-binding aptamers applied to C. elegans protect the animals from lead-induced reproductive toxicity and neurotoxicity. • Upon transfection, DNA aptamers protect primary osteoblasts from lead toxicity. • The study represents the first demonstration of the use of an aptamer as a prophylactic to an environmental pollutant. [ABSTRACT FROM AUTHOR]

Osteoporosis becomes a global public health concern due to its rising prevalence and substantial impact on life quality. Salvia miltiorrhiza Bunge (Salviae Miltiorrhizae Radix et Rhizoma, SM) has been firstly recorded in Shen Nong's Herbal Classic, and is frequently prescribed in conjunction with other herbs for the management of osteoporosis. This systematic review aims to comprehensively analyze the recent advances of SM on osteoporosis in traditional Chinese clinical uses and preclinical investigations. Literature encompassing pertinent studies were systematically retrieved across multiple databases, including the PubMed, Web of Science, Chinese National Knowledge Infrastructure, Chinese VIP Database, and Chinese Biomedical Literature Database. Original investigations spanning from February 2014 to March 2024, including traditional Chinese medicine (TCM) clinical trials and preclinical studies, were employed to analyze the effects and actions of SM on osteoporosis. Thirty-eight TCM clinical trials were identified to employ SM in combination with other herbs for the management of primary and secondary osteoporosis. The overall efficacy was between 77% and 96.67%. Forty preclinical studies were identified to investigate the effects and actions of SM and/or its ingredients on osteoporosis. The anti-osteoporosis actions of this herb may be attributed to inhibit osteoclastogenesis/bone resorption and promote osteoblastogenesis/osteogenesis. The ethanol extracts and its ingredients (tanshinones) inhibit osteoclastogenesis/bone resorption by inhibiting the MAPK/NF-κB/NFATc1 signaling pathway and cathepsin K-induced collagen degradation. Both ethanol extracts (tanshinones) and water extracts (Sal B and tanshinol) contribute to osteoblastogenesis by promoting osteogenesis and angiogenesis via activation of the Wnt/β-catenin/VEGF and ERK/TAZ pathways, and eliminating ROS production targeting Nrf2/ARE/HO-1 pathway. In conclusions, SM may offer a novel strategy for osteoporosis management. Well-designed clinical trials are still needed to evaluate the actions of this herb and its ingredients on bone remodeling. [ABSTRACT FROM AUTHOR]

Objective This review provides a comprehensive overview of the underlying mechanism and research findings pertaining to the STING signaling pathway in osteoporosis, aiming to offer novel insights for the therapeutic management of this condition. Methods In November 2023, the first authors searched PubMed and CNKI databases with the terms STING, osteoporosis, osteoblast, osteoclast, IFN-β, NF-kB, and type H vessels. Results A total of 41 papers were cited after screening by reading titles and abstracts. Conclusion The STING pathway provides a new direction for the treatment of osteoporosis. Activation of STING/IFN-β signaling pathway may inhibit osteoclast differentiation and bone resorption. However, STING/NF-KB signaling may lead to an increased bone resorption and a decreased bone formation. In addition, activation of STING signaling inhibits the generation of type H vessels with osteogenic capacity, thereby inhibiting bone formation. Therefore, the STING pathway has a dual regulatory role in the progression of osteoporosis. Regulating different branches of the STING pathway is expected to develop more effective treatments for osteoporosis. [ABSTRACT FROM AUTHOR]

Osteoblasts play an important role in the occurrence of bone metabolic diseases such as osteoporosis. As a natural anti- aging hormone, melatonin can improve oxidative stress, cell differentiation, apoptosis, autophagy and ferroptosis of osteoblasts. The above mechanisms of action are described in detail in this paper, which provides research ideas and basis for further exploring the mechanism of melatonin affecting osteoblasts and the prevention and treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

Glycogen storage disease (GSD) is the most prevalent inherited disorder of glycogen metabolism for which no causal treatment is available. In recent years, thanks to the improved clinical management, the life expectancy of these patients extended, disclosing previously unidentified adverse conditions in other organs. In this study, we evaluated the clinical bone complications and the cellular responses in 20 patients (aged 14.1 ± 3.4 years) affected by GSD type I. Fragility fractures were reported in 35% of the patients, which were older than unfractured patients. They involved appendicular skeletal segments, while no vertebral deformity was detected. 60% of the patients had a bone mineral density (BMD) "below the expected range for age", and lumbar spine (LS) BMD Z-scores positively correlated with muscle strength. Circulating mineral and bone markers showed reduction in the older subjects, with no increase in the pubertal age. Significant correlations could not be detected between circulating markers and LS BMD Z-scores, except for sclerostin levels, which also correlated with muscle strength. The osteoclasts differentiated from patients' peripheral blood mononuclear cells did not show cell-autonomous alterations. However, circulating osteoclast precursors from healthy individuals cultured in the presence of patients' sera exhibited increased osteoclastogenesis compared to control sera suggesting that GSD type I serum factors could affect osteoclast function in a non-autonomous manner. In contrast, circulating osteoprogenitors were unremarkable. [ABSTRACT FROM AUTHOR]

Previous studies have shown that Wnt7b potently stimulates bone formation by promoting osteoblast differentiation and activity. As high-fat feeding leads to obesity and systemic metabolic dysregulation, here we investigate the potential benefit of Wnt7b overexpression in osteoblasts on both bone and whole-body metabolism in mice fed with a high-fat diet (HFD). Wnt7b overexpression elicited massive overgrowth of trabecular and cortical bone but seemed to ameliorate body fat accumulation in mice with prolonged HFD feeding. In addition, Wnt7b overexpression modestly improved glucose tolerance in male mice on HFD. Collectively, the results indicate that targeted overexpression of Wnt7b in osteoblasts not only stimulates bone formation but also improves certain aspects of global metabolism in overnourished mice. Lay Summary: Emerging evidence indicates that increased healthy bone tissue may improve general energy metabolism of the body. Here we test the hypothesis that mice containing excess bone mass may be healthier than usual when overnourished with a high-fat diet. We found that mice with excess bone did not gain as much body fat as the normal mice did. In addition, the male mice with extra bone exhibited better tolerance to glucose injection than their normal counterparts. Thus, the data support the notion that increased bone formation may improve global energy metabolism. [ABSTRACT FROM AUTHOR]

Hippo pathway is an evolutionarily conservative key pathway that regulates organ size and tissue regeneration by regulating cell proliferation, differentiation and apoptosis. Yes-associated protein 1 (YAP)/ WW domain-containing transcription regulator 1 (TAZ) serves as a pivotal transcription factor within the Hippo signaling pathway, which undergoes negative regulation by the Hippo pathway. The expression of YAP/TAZ affects various biological processes, including differentiation of osteoblasts (OB) and osteoclasts (OC), cartilage homeostasis, skeletal muscle development, regeneration and quality maintenance. At the same time, the dysregulation of the Hippo pathway can concurrently contribute to the development of various musculoskeletal disorders, including bone tumors, osteoporosis (OP), osteoarthritis (OA), intervertebral disc degeneration (IDD), muscular dystrophy, and rhabdomyosarcoma (RMS). Therefore, targeting the Hippo pathway has emerged as a promising therapeutic strategy for the treatment of musculoskeletal disorders. The focus of this review is to elucidate the mechanisms by which the Hippo pathway maintains homeostasis in bone, cartilage, and skeletal muscle, while also providing a comprehensive summary of the pivotal role played by core components of this pathway in musculoskeletal diseases. The efficacy and feasibility of Hippo pathway-related drugs for targeted therapy of musculoskeletal diseases are also discussed in our study. These endeavors offer novel insights into the application of Hippo signaling in musculoskeletal disorders, providing effective therapeutic targets and potential drug candidates for treating such conditions. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Material and Methods Results Conclusions The study evaluates three biologically active substances with known bone‐inductive potential on previously decontaminated titanium (Ti) discs.Rough and smooth Ti surfaces were contaminated with a multispecies biofilm and cleaned with a chitosan brush. Discs were treated either with injectable‐platelet‐rich fibrin (i‐PRF), advanced platelet‐rich fibrin (A‐PRF+), or enamel matrix derivatives (EMDs) before osteoblast seeding.Biocompatibility, adhesion, migration, and gene expression of runt‐related transcription factor 2 (RUNX2), collagen Type I Alpha 2 (COL1a2), alkaline phosphatase (ALP), osteocalcin (OC), and osteonectin (ON) were performed. All the tested biologic agents similarly increased cell viability. Specifically, osteoblasts seeded over i‐PRF and EMD‐treated surfaces showed improvement in adhesion and migration and significantly increased ALP, OC, ON, RUNX‐2, and COL1a2 mRNA levels up to 2.8 fold (p < 0.05) with no differences between Ti surfaces.i‐PRF and EMD possess beneficial bioactive properties that enhance tissue healing and promote regeneration on thoroughly sterilized surfaces. Biologically active materials may hold the potential to influence the process of implant re‐osseointegration, which warrants more research since sterilization of the affected surfaces under clinical conditions is still not reliably possible and remains one of the greatest challenges. [ABSTRACT FROM AUTHOR]

BACKGROUND: Careful regulation of bone immune response during repair of bone scaffold is important for bone regeneration. OBJECTIVE: To review the influence of bone immune response on bone repair and the design of bone tissue engineering scaffold with regulating bone immune function and its application in bone repair. METHODS: Relevant articles published from 1973 to 2023 were retrieved from Science Direct, PubMed, Web of Science, and CNKI databases. English search terms were “osteoimmunology, macrophages, bone repair materials, bone scaffold, bone defects, bone regeneration”. Chinese search terms were “bone immunity, macrophages, bone repair material, bone stent, bone defect, bone regeneration”. Totally 80 articles of the latest research progress in this field were summarized and analyzed. RESULTS AND CONCLUSION: (1) A detailed review was conducted on the important time points in the origin and development process of bone immunity, and it was explained that macrophages, as important members of the bone immune regulatory system, can be divided into two phenotypes: M1 (pro-inflammatory) and M2 (anti-inflammatory), and play a key role in different stages of bone regeneration. During the inflammatory phase, M1 type macrophages can activate osteoclasts, initiate tissue repair processes, and participate in the reconstruction of bone microvascular networks. On the other hand, during the bone tissue regeneration process in the later stages of inflammation, sustained high expression of M1 type macrophages can hinder the formation of new bones. During the repair phase, M2 macrophages can secrete osteogenic cytokines, stimulate osteogenic differentiation and mineralization of bone marrow mesenchymal stem cells, and promote bone formation. On the other hand, long-term activation of M2 macrophages can increase the secretion of fibrogenic molecules, leading to excessive formation of scar tissue and delaying the healing process. Therefore, regulating macrophages to undergo phenotype transformation at appropriate stages and constructing an immune microenvironment beneficial for osteogenesis has great significance for bone regeneration. (2) In the process of designing bone scaffolds with bone immune regulation characteristics, the physical and chemical properties such as scaffold roughness, pore structure, stiffness, hydrophilicity, surface charge, and surface functional groups can be changed to affect non-specific protein and cell adhesion, thereby affecting the interaction between bone scaffolds and the immune system. By designing surface functional coatings of bioactive substances such as hydroxyapatite, bioactive glass, metal ions, extracellular matrix, drugs, cytokines, and exosomes, the immune microenvironment can be actively regulated by releasing bioactive substances after implantation into the body, affecting macrophage polarization and crosstalk between macrophages and bone cells, and promoting more M2 polarization of macrophages, so as to build a bone immune microenvironment that is conducive to bone regeneration. (3) Based on the research and development of bone tissue engineering scaffolds, in addition to focusing on the direct regulatory factors of stem cell osteogenic differentiation, this article also proposes that attention should be paid to the management of the immune microenvironment of stem cell differentiation. By regulating the appropriate bone immune microenvironment, more stem cell osteogenic differentiation can be induced; the osteogenic efficiency of the scaffold can be enhanced, and the concept of “bone immune regulatory characteristics” can be condensed; deeply elucidated the multi-directional regulatory role of the bone immune microenvironment and introduced the existing strategies for changing the physicochemical properties and surface functional coating of scaffolds to endow them with bone immune regulatory potential, providing new ideas for guiding the development of a new generation of bone tissue engineering scaffolds with bone immune regulatory characteristics. However, the bone immune microenvironment is a dynamic equilibrium state, and most of the existing regulatory strategies do not consider the dynamic matching of regulation. Therefore, the research and development of intelligent bone immune regulatory scaffolds with efficient and targeted regulation of the immune microenvironment will be a key focus of attention for scholars in future. [ABSTRACT FROM AUTHOR]

Osteoporosis becomes a global public health concern due to its rising prevalence and substantial impact on life quality. Salvia miltiorrhiza Bunge (Salviae Miltiorrhizae Radix et Rhizoma, SM) has been firstly recorded in Shen Nong's Herbal Classic, and is frequently prescribed in conjunction with other herbs for the management of osteoporosis. This systematic review aims to comprehensively analyze the recent advances of SM on osteoporosis in traditional Chinese clinical uses and preclinical investigations. Literature encompassing pertinent studies were systematically retrieved across multiple databases, including the PubMed, Web of Science, Chinese National Knowledge Infrastructure, Chinese VIP Database, and Chinese Biomedical Literature Database. Original investigations spanning from February 2014 to March 2024, including traditional Chinese medicine (TCM) clinical trials and preclinical studies, were employed to analyze the effects and actions of SM on osteoporosis. Thirtyeight TCM clinical trials were identified to employ SM in combination with other herbs for the management of primary and secondary osteoporosis. The overall efficacy was between 77% and 96.67%. Forty preclinical studies were identified to investigate the effects and actions of SM and/or its ingredients on osteoporosis. The anti-osteoporosis actions of this herb may be attributed to inhibit osteoclastogenesis/bone resorption and promote osteoblastogenesis/osteogenesis. The ethanol extracts and its ingredients (tanshinones) inhibit osteoclastogenesis/bone resorption by inhibiting the MAPK/NF-B/NFATc1 signaling pathway and cathepsin K-induced collagen degradation. Both ethanol extracts (tanshinones) and water extracts (Sal B and tanshinol) contribute to osteoblastogenesis by promoting osteogenesis and angiogenesis via activation of the Wnt/ß-catenin/VEGF and ERK/TAZ pathways, and eliminating ROS production targeting Nrf2/ARE/HO-1 pathway. In conclusions, SM may offer a novel strategy for osteoporosis management. Well-designed clinical trials are still needed to evaluate the actions of this herb and its ingredients on bone remodeling. [ABSTRACT FROM AUTHOR]

BACKGROUND: The pathogenesis of osteoporosis is complex, and its essence is the weakening of bone formation and the enhancement of bone absorption caused by various reasons, resulting in the imbalance of bone metabolism. In recent years, N6-methyladenosine has been found (N6-methyladenosine, m6A) methylation can prevent and treat osteoporosis by regulating bone metabolism. OBJECTIVE: Taking the regulation of bone metabolism by m6A methylation as an entry point, to systematically sort out and summarize the research progress of m6A methylation in osteoporosis, so as to provide certain theoretical reference bases for the search of new therapeutic targets for osteoporosis. METHODS: CNKI, WanFang, VIP, PubMed, MEDLINE, Nature, and Cochrane databases were retrieved for relevant literature published from database inception to 2023. The keywords were “osteoporosis, m6A methylation, bone metabolism, bone marrow mesenchymal stem cells, osteoblasts, osteoclasts” in Chinese and English. Duplicates and obsolete non-referenced documents were excluded, and a total of 73 standard papers were included for further review. RESULTS AND CONCLUSION: m6A methylation can affect the activity and differentiation of bone marrow mesenchymal stem cells, osteoblasts, and osteoclasts through various pathways to regulate bone metabolism and prevent osteoporosis. The regulatory process of m6A methylation is extremely complex, and its related proteins play different roles in different cells. Even in the same kind of cells, the same type of proteins may have radically different roles, regulating different physiological and pathological processes. [ABSTRACT FROM AUTHOR]

Although mesenchymal stem cells (MSCs) insertion has gained recent attention as a joint-preserving procedure, no study has conducted direct intralesional implantation of human umbilical cord-derived MSCs (hUCMSCs) in patients with ONFH. This is a protocol for a phase 1 clinical trial designed to assess the safety and exploratory efficacy of human umbilical cord-derived osteoblasts (hUC-Os), osteogenic differentiation-induced cells from hUCMSCs, in patients with early-stage ONFH. Nine patients with Association Research Circulation Osseous (ARCO) stage 1 or 2 will be assigned to a low-dose (1 × 107 hUC-O cells, n = 3), medium-dose (2 × 107 cells, n = 3), and high-dose group (4 × 107 cells, n = 3) in the order of their arrival at the facility, and, depending on the occurrence of dose-limiting toxicity, up to 18 patients can be enrolled by applying the 3 + 3 escalation method. We will perform hUC-O (CF-M801) transplantation combined with core decompression and follow-up for 12 weeks according to the study protocol. Safety will be determined through adverse event assessment, laboratory tests including a panel reactive antibody test, vital sign assessment, physical examination, and electrocardiogram. Efficacy will be explored through the change in pain visual analog scale, Harris hip score, Western Ontario and McMaster Universities Osteoarthritis Index, ARCO stage, and also size and location of necrotic lesion according to Japanese Investigation Committee classification before and after the procedure. Joint preservation is important, particularly in younger, active patients with ONFH. Confirmation of the safety and efficacy of hUC-Os will lead to a further strategy to preserve joints for those suffering from ONFH and improve our current knowledge of cell therapy. [ABSTRACT FROM AUTHOR]

Background: The prevention and treatment of bone loss and osteoporotic fractures is a public health challenge. Combined with normobaric hypoxia, whole-body vibration has a high clinic potential in bone health and body composition. The effect of this therapy may be mediated by its action on bone marrow mesenchymal stem cells (MSCs). Objectives: Evaluate the effects of cyclic low-vibration stimuli and/or hypoxia on bone marrow-derived human MSC differentiation. Methods: MSCs were exposed four days per week, two hours/day, to hypoxia (3% O2) and/or vibration before they were induced to differentiate or during differentiation into osteoblasts or adipocytes. Gene and protein expression of osteoblastic, adipogenic, and cytoskeletal markers were studied, as well as extracellular matrix mineralization and lipid accumulation. Results: early osteoblastic markers increased in undifferentiated MSCs, pretreated in hypoxia and vibration. This pretreatment also increased mRNA levels of osteoblastic genes and beta-catenin protein in the early stages of differentiation into osteoblasts without increasing mineralization. When MSCs were exposed to vibration under hypoxia or normoxia during osteoblastic differentiation, mineralization increased with respect to cultures without vibrational stimuli. In MSCs differentiated into adipocytes, both in those pretreated as well as exposed to different conditions during differentiation, lipid formation decreased. Changes in adipogenic gene expression and increased beta-catenin protein were observed in cultures treated during differentiation. Conclusions: Exposure to cyclic hypoxia in combination with low-intensity vibratory stimuli had positive effects on osteoblastic differentiation and negative ones on adipogenesis of bone marrow-derived MSCs. These results suggest that in elderly or frail people with difficulty performing physical activity, exposure to normobaric cyclic hypoxia and low-density vibratory stimuli could improve bone metabolism and health. [ABSTRACT FROM AUTHOR]

Since Teleostei fins have a strong regenerative capacity, further research was conducted on the regulation of gene expression during fin regeneration. This research focuses on miRNA, which is a key post-transcriptional regulatory molecule. In this study, a miRNA library for the fin regeneration of zebrafish was constructed to reveal the differential expression of miRNA during fin regeneration and to explore the regulatory pathway for fin regeneration. Following the injection of miRNA agomir into zebrafish, the proliferation of blastema cells and the overall fin regeneration area were significantly reduced. It was observed that the miRNAs impaired blastocyte formation by affecting fin regeneration through the inhibition of the expressions of genes and proteins associated with blastocyte formation (including yap1 and Smad1/5/9), which is an effect associated with the Hippo pathway. Furthermore, it has been demonstrated that miRNAs can impair the patterns and mineralization of newly formed fin rays. The miRNAs influenced fin regeneration by inhibiting the expression of a range of bone-related genes and proteins in osteoblast lineages, including sp7, runx2a, and runx2b. This study provides a valuable reference for the further exploration of morphological bone reconstruction in aquatic vertebrates. [ABSTRACT FROM AUTHOR]

Objectives: To explore the role of fibrocytes in the recurrence and calcification of fibrous epulides. Methods: Different subtypes of fibrous epulides and normal gingival tissue specimens were first collected for histological and immunofluorescence analyses to see if fibrocytes were present and whether they differentiated into myofibroblasts and osteoblasts upon stimulated by transforming growth factor‐β1 (TGF‐β1). Electron microscopy and elemental analysis were used to characterize the extracellular microenvironment in different subtypes of fibrous epulides. Human peripheral blood mononuclear cells (PBMCs) were subsequently isolated from in vitro models to mimic the microenvironment in fibrous epulides to identify whether TGF‐β1 as well as the calcium and phosphorus ion concentration in the extracellular matrix (ECM) of a fibrous epulis trigger fibrocyte differentiation. Results: Fibrous epulides contain fibrocytes that accumulate in the local inflammatory environment and have the ability to differentiate into myofibroblasts or osteoblasts. TGF‐β1 promotes fibrocytes differentiation into myofibroblasts in a concentration‐dependent manner, while TGF‐β1 stimulates the fibrocytes to differentiate into osteoblasts when combined with a high calcium and phosphorus environment. Conclusions: Our study revealed fibrocytes play an important role in the fibrogenesis and osteogenesis in fibrous epulis, and might serve as a therapeutic target for the inhibition of recurrence of fibrous epulides. [ABSTRACT FROM AUTHOR]

In this study, the interaction of pure Mg and WE43 alloy under the presence of osteoblast (OB) and osteoclast (OC) cells and their influence on the degradation of materials have been deeply analyzed. Since OB and OC interaction has an important role in bone remodeling, we examined the surface morphology and dynamic changes in the chemical composition and thickness of the corrosion layers formed on pure Mg and WE43 alloy by direct monoculture and coculture of pre-differentiated OB and OC cells in vitro. Electrochemical techniques examined the corrosion performance. The corrosion products were characterized using a combination of the focused ion beam (FIB), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDX). Cell viability and morphology were assessed by fluorescent microscopy and SEM. Our findings demonstrate cell spread and attachment variations, which differ depending on the Mg substrates. It was clearly shown that cell culture groups delayed degradation processes with the lowest corrosion rate observed in the presence of OBOC coculture for the WE43 substrate. Ca-P enrichment was observed in the outer-middle region of the corrosion layer but only after 7 days of OBOC coculture on WE43 and after 14 days on the pure Mg specimens. Magnesium metallic materials that can degrade over time provide distinct opportunities for orthopedic application. However, there is still a lack, especially in elucidating cell-material interface characterization. This study investigated the influence of osteoblast-osteoclast coculture in direct Mg-material contact. Our findings demonstrated that pre-differentiated osteoblasts and osteoclasts cocultured on Mg substrates influenced the chemistry of the corrosion layers. The cell spread and attachment were Mg substrate-dependent. The findings of coculturing bone cells directly on Mg materials within an in vitro model provide an effective approach for studying the dynamic degradation processes of Mg alloys while also elucidating cell behavior and their potential contribution to the degradation of these alloys. [Display omitted] [ABSTRACT FROM AUTHOR]

Coupling, the mechanism that controls the sequence of events in bone remodeling, is a fundamental theory for understanding the way the skeleton changes throughout life. This review is an adapted version of the Louis V Avioli lecture, delivered at the Annual Scientific Meeting of the American Society of Bone and Mineral Research in 2023. It outlines the history of the coupling concept, details how coupling is thought to occur within trabecular and cortical bone, and describes its multiple contexts and the many mechanisms suggested to couple bone-forming osteoblasts to the prior action of osteoclasts on the same bone surface. These mechanisms include signals produced at each stage of the remodeling sequence (resorption, reversal, and formation), such as factors released by osteoclasts through their resorptive action and through protein synthesis, molecules deposited in the cement line during the reversal phase, and potential signals from osteocytes within the local bone environment. The review highlights two examples of coupling factors (Cardiotrophin 1 and EphrinB2:EphB4) to illustrate the limited data available, the need to integrate the many functions of these factors within the basic multicellular unit (BMU), and the multiple origins of these factors, including the other cell types present during the remodeling sequence (such as osteocytes, macrophages, endothelial cells, and T-cells). Lay Summary: Coupling is a fundamental process by which bone-resorbing cells (osteoclasts) are followed by bone-forming cells (osteoblasts) on the same surface during the process of bone remodeling. This review outlines the history, basic concepts, and mechanisms proposed, and suggests directions for further research into the way this sequence of events is controlled in bone maintenance, development, and healing. [ABSTRACT FROM AUTHOR]

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BACKGROUND: Recent studies have shown that the occurrence and prevention of osteoporosis often focus on the cellular molecular level, and the mechanism of related signaling pathways is an important way to further understand osteoporosis. At present, traditional Chinese medicine has been proved to play a significant role in alleviating osteoporosis. Kaempferol as an emerging Chinese herbal extract has become the focus of clinical and basic research due to its antiosteoporosis effectiveness and mechanism of action. OBJECTIVE: To further understand the mechanism underlying the anti-osteoporosis effect of kaempferol active monomer through regulation of related signaling pathways by analyzing and collating domestic and foreign literature. METHODS: “Kaempferol, osteoporosis, osteoblasts, osteoclasts, bone marrow mesenchymal stem cells, signaling pathways” were used as Chinese and English search terms to search CNKI, WanFang, VIP, PubMed, Web of Science and Embase databases for relevant literature published from database inception to February 2023. RESULTS AND CONCLUSION: Kaempferol affects the occurrence and progression of osteoporosis to varying degrees by participating in the regulation of differentiation, proliferation and apoptosis of bone marrow mesenchymal stem cells, osteoblasts and osteoclasts. Kaempferol can prevent and treat osteoporosis by regulating various signaling pathways. Kaempferol can promote the proliferation and differentiation of osteoblasts and inhibit the formation of osteoclasts by interfering with the Wnt/β-catenin signaling pathway to regulate β-catenin protein counting and the formation of β-catenin-TCf/LEF complex. Kaempferol interferes with the RANK/RANKL pathway to maintain the dynamic balance of osteoclasts and bone homeostasis. Kaempferol can promote bone formation by intervening with the PI3K/Akt signaling pathway to upregulate the levels of related osteogenic factors Runx2 and Osterix and promote bone cell calcification. Kaempferol interferes with osteoclast differentiation and inhibits reactive oxygen species activity by regulating the ER/ERK pathway. Kaempferol inhibits the expression of ERK, JNK, p38/MAPK and decreases reactive oxygen species production by interfering with the MAPK pathway, thus protecting osteogenesis. Kaempferol enhances the expression of osteogenic factors, bone morphogenetic protein-2, p-Smad1/5/8, β-catenin and Runx2, inhibits the expression of Peroxisome proliferation-activated receptor, and promotes the differentiation and proliferation of osteoblasts through the BMP/Smad pathway. [ABSTRACT FROM AUTHOR]

BACKGROUND: Upregulation of hedgehog protein signaling can increase the expression of osteoarthritis markers, Runx2, a disintegrin and metalloproteinase with thrombospondin motifs, collagen type X alpha 1, and matrix metalloproteinase 13, while inhibition of hedgehog proteins attenuates the severity of osteoarthritis. It is speculated that osteoarthritic chondrocytes can influence bone formation by affecting osteoblasts through the Indian hedgehog protein (IHH) signaling pathway. OBJECTIVE: To investigate the effect of human osteoarthritic chondrocytes on subchondral osteoblasts. METHODS: Tibial plateau specimens from patients with osteoarthritis were collected. Chondrocytes were extracted using enzymatic digestion, and osteoblasts were extracted using enzymatic pre-digestion + bone block method. Chondrocytes were identified by toluidine blue staining and immunofluorescence and osteoblasts were identified by alkaline phosphatase staining and immunofluorescence. Chondrocytes were cultured in sodium alginate beads to maintain chondrocyte phenotype and co-cultured with osteoblasts. The co-culture system was added with IHH signaling pathway inhibitor (cyclopamine, 10 nmol/L) and activator (purmorphamine, 10 nmol/L) separately. After 48 hours of co-culture, osteoblasts from each group were collected, mRNA expressions of Gli1, osteoprotegerin, Runx2, parathyroid hormone-related peptide, alkaline phosphatase, receptor activator of nuclear factor-kB ligand (RANKL) and osteocalcin were detected by qRT-PCR, and protein expressions of GLi1, oseoprotegerin and RANKL in osteoblasts were detected by western blot. RESULTS AND CONCLUSION: The mRNA expression levels of GLi1, osteoprotegerin and RUNX2 in osteoblasts were significantly increased, while the mRNA expression levels of parathyroid hormone-related peptide were decreased (P < 0.05) when co-cultured with human osteoarthritic chondrocytes. The mRNA and protein levels of Gli1 were significantly decreased after the addition of IHH signaling pathway inhibitor (cyclopamine) (P < 0.05), and the mRNA and protein levels of Gli1 were significantly increased after the addition of IHH signaling pathway activator (purmorphamine) (P < 0.05). Osteoprotegerin showed the same trend as Gli1 in the experiment. The osteoprotegerin/RANKL ratio followed the same trend as osteoprotegerin. To conclude, human osteoarthritic chondrocytes can promote the expression of Gli1, osteoprotegerin, Runx2 and other proteins in osteoblasts. The upregulation of osteoprotegerin is related to the IHH signaling pathway. Osteoarthritic chondrocytes can up-regulate the expression of osteoprotegerin in osteoblasts through the IHH signaling pathway and thus up-regulate the osteoprotegerin/RANKL ratio, which will contribute to bone formation in subchondral bone. [ABSTRACT FROM AUTHOR]

BACKGROUND: Punicalagin has a wide range of effects and high safety, but its effect on osteoblasts and postmenopausal osteoporosis is unknown. OBJECTIVE: To investigate the effect of punicalagin on osteoblasts and postmenopausal osteoporosis. METHODS: The effect of punicalagin on the proliferation of MC3T3-E1 cells was detected. Punicalagin was added to the osteogenic induction medium to detect its effect on osteogenic differentiation. Punicalagin was used to treat ovariectomized rats and Micro CT scan and serum procollagen type 1 N-terminal propeptide test were performed after 3 months to detect the therapeutic effect. RESULTS AND CONCLUSION: Cell counting kit-8 assay showed that punicalagin could promote the proliferation of osteoblasts (P < 0.05). The results of qRTPCR and western blot showed that punicalagin could promote the mRNA and protein expressions of alkaline phosphatase and Runx2 in osteoblasts (P < 0.05). The results of Micro CT scan and serological test showed that punicalagin could improve bone mineral density, bone volume fraction, trabecular thickness, trabecular number and procollagen type 1 N-terminal propeptide level of ovariectomized rats. To conclude, punicalagin can promote osteoblast proliferation and differentiation, and have therapeutic effects in postmenopausal osteoporosis rats [ABSTRACT FROM AUTHOR]

Oxytocin (OT) is a posterior pituitary hormone that, in addition to its role in regulating childbirth and lactation, also exerts direct regulatory effects on the skeleton through peripheral OT and oxytocin receptor (OTR). Bone marrow mesenchymal stem cells (BMSCs), osteoblasts (OB), osteoclasts (OC), chondrocytes, and adipocytes all express OT and OTR. OT upregulates RUNX2, BMP2, ALP, and OCN, thereby enhancing the activity of BMSCs and promoting their differentiation towards OB rather than adipocytes. OT also directly regulates OPG/RANKL to inhibit adipocyte generation, increase the expression of SOX9 and COMP, and enhance chondrocyte differentiation. OB can secrete OT, exerting influence on the surrounding environment through autocrine and paracrine mechanisms. OT directly increases OC formation through the NκB/MAP kinase signaling pathway, inhibits osteoclast proliferation by triggering cytoplasmic Ca2+ release and nitric oxide synthesis, and has a dual regulatory effect on OCs. Under the stimulation of estrogen, OB synthesizes OT, amplifying the biological effects of estrogen and OT. Mediated by estrogen, the OT/OTR forms a feedforward loop with OB. Apart from estrogen, OT also interacts with arginine vasopressin (AVP), prostaglandins (PGE2), leptin, and adiponectin to regulate bone metabolism. This review summarizes recent research on the regulation of bone metabolism by OT and OTR, aiming to provide insights into their clinical applications and further research. [ABSTRACT FROM AUTHOR]

BACKGROUND: Heterotopic ossification of skeletal muscle is a clinically serious complication. For heterotopic ossification of skeletal muscles, the cells involved in the process of heterotopic ossification remain unclear. OBJECTIVE: To investigate the involvement of myocytes, fascia cells, and endothelial cells in the process of heterotopic ossification in skeletal muscle and to observe the cell origin of heterotopic ossification in skeletal muscle induced by bone morphogenetic protein 4. METHODS: Both C2C12 cells and the myotubes formed by the C2C12 cells in the induction medium were cultured, and 500 ng/mL bone morphogenetic protein 4 was added to the medium respectively, and whether the C2C12 cells and myotubes continued to proliferate within 10 days under the treatment were observed under a microscope. Myogenic cells (L6, derived from rats) and fibroblast-derived cells (derived from human) were co-cultured. After treatment with 500 ng/mL bone morphogenetic protein 4 and 10 ng/mL transforming growth factor-β, osteogenic and chondrogenic differentiation potential within 21 days were observed using Safranine O staining and Alcian blue staining. Using transgenic animal FVB/N-TgN (TIE2-LacZ) 182Sato mice, 15 μL of adeno-associated virus-bone morphogenetic protein 4 (5 × 1010 PFU/mL) were implanted in the thigh muscle space of genetic mice for 10 and 14 days. X-gal staining was used to observe the formation of new blood vessel endothelium in the differentiated bone. RESULTS AND CONCLUSION: (1) Bone morphogenetic protein 4 caused myotube breakdown and increased C2C12 cell proliferation. Compared with other groups, the pure fibroblast-derived cell group had a higher area of positive alcian blue and safarin O staining (P < 0.05) and a lower area of alkaline phosphatase staining (P < 0.05), while the pure L6 group had a bigger area of alkaline phosphatase staining (P < 0.05) but a smaller area of positive alcian blue and safarin O staining (P < 0.05). (2) Transplantation of adeno-associated virus-bone morphogenetic protein 4-adsorbed gelatin sponge into FVB/N-TgN (TIE2-LacZ)182Sato mice resulted in heterotopic ossification. (3) X-gal staining results demonstrated that there was no obvious staining in chondrocytes and differentiated bones and Tie2+ endothelial cells did not participate in the formation of the alienated bone. (4) These findings verify that fibroblasts are the primary source of osteoblasts during the adeno-associated virus-bone morphogenetic protein 4-induced ectopic endochondral ossification in skeletal muscle, but myogenic cells are the main source of osteoblasts. Tie2+ endothelial cells might not be the cell source for cartilage and bone. [ABSTRACT FROM AUTHOR]

A major fraction of loci identified by genome-wide association studies (GWASs) mediate alternative splicing, but mechanistic interpretation is hindered by the technical limitations of short-read RNA sequencing (RNA-seq), which cannot directly link splicing events to full-length protein isoforms. Long-read RNA-seq represents a powerful tool to characterize transcript isoforms, and recently, infer protein isoform existence. Here, we present an approach that integrates information from GWASs, splicing quantitative trait loci (sQTLs), and PacBio long-read RNA-seq in a disease-relevant model to infer the effects of sQTLs on the ultimate protein isoform products they encode. We demonstrate the utility of our approach using bone mineral density (BMD) GWAS data. We identified 1,863 sQTLs from the Genotype-Tissue Expression (GTEx) project in 732 protein-coding genes that colocalized with BMD associations (H4PP ≥ 0.75). We generated PacBio Iso-Seq data (N = ∼22 million full-length reads) on human osteoblasts, identifying 68,326 protein-coding isoforms, of which 17,375 (25%) were unannotated. By casting the sQTLs onto protein isoforms, we connected 809 sQTLs to 2,029 protein isoforms from 441 genes expressed in osteoblasts. Overall, we found that 74 sQTLs influenced isoforms likely impacted by nonsense-mediated decay and 190 that potentially resulted in the expression of unannotated protein isoforms. Finally, we functionally validated colocalizing sQTLs in TPM2 , in which siRNA-mediated knockdown in osteoblasts showed two TPM2 isoforms with opposing effects on mineralization but exhibited no effect upon knockdown of the entire gene. Our approach should be to generalize across diverse clinical traits and to provide insights into protein isoform activities modulated by GWAS loci. Many GWAS loci are associated with alternative splicing, but the identities and functions of most protein isoform effectors are unknown. We demonstrate how the integration of splicing QTLs (sQTLs) and PacBio long-read RNA-seq data enables the prediction, characterization, and functional prioritization of protein isoforms associated with complex human disease. [ABSTRACT FROM AUTHOR]

Transposable elements (TEs) are mobile genetic modules of viral derivation that have been co-opted to become modulators of mammalian gene expression. TEs are a major source of endogenous dsRNAs, signaling molecules able to coordinate inflammatory responses in various physiological processes. Here, we provide evidence for a positive involvement of TEs in inflammation-driven bone repair and mineralization. In newly fractured mice bone, we observed an early transient upregulation of repeats occurring concurrently with the initiation of the inflammatory stage. In human bone biopsies, analysis revealed a significant correlation between repeats expression, mechanical stress and bone mineral density. We investigated a potential link between LINE-1 (L1) expression and bone mineralization by delivering a synthetic L1 RNA to osteoporotic patient-derived mesenchymal stem cells and observed a dsRNA-triggered protein kinase (PKR)-mediated stress response that led to strongly increased mineralization. This response was associated with a strong and transient inflammation, accompanied by a global translation attenuation induced by eIF2α phosphorylation. We demonstrated that L1 transfection reshaped the secretory profile of osteoblasts, triggering a paracrine activity that stimulated the mineralization of recipient cells. Synopsis: Transposable elements (TEs) are selfish genetic modules that have, in certain contexts, evolved into modulators of mammalian gene expression. This study provides evidence for a role of TEs in promoting an inflammatory response that is required for bone repair and mineralization via dsRNA sensing-dependent PKR activation. In mice, TE expression is transiently upregulated shortly after a bone fracture concurrently with the onset of the inflammatory process. In humans, mechanically loaded bones upregulate TE expression, which correlates with local bone mineral density. Transfection with LINE-1 (L1) TE RNA stimulates mineralization activity in human osteoblasts in vitro. Cytoplasmic L1 RNA accumulation in differentiating osteoblasts triggers PKR-dependent translational shutdown, inflammation, and reshaping of the secretome. The secretome of L1 RNA-primed osteoblasts induces the mineralization activity of recipient osteoblasts. Bone fracture is associated with upregulation of transient transposable element RNA expression triggering bone mineralization via a paracrine, secretome mediated process. [ABSTRACT FROM AUTHOR]

The occurrence of osteoporosis is due to the disruption of the balance between bone formation mediated by osteoblasts and bone resorption mediated by osteoclasts, resulting in abnormal bone homeostasis. MicroRNAs, as epigenetic regulatory factors, play an important role in bone metabolism by regulating the expression of signaling molecules related to osteoblasts and osteoclasts. This article reviews the latest research progress on the role of microRNAs in regulating and maintaining cell differentiation, proliferation, autophagy, and expression of related signaling molecules and pathways in bone microenvironment in osteoporosis, and summarizes the role of microRNAs in bone cell differentiation, highlighting the potential of microRNAs as therapeutic targets in metabolic bone diseases. [ABSTRACT FROM AUTHOR]

Osteoporosis (OP) is a common metabolic disease in clinic. Studies have found that the imbalance between osteoblast-mediated osteogenesis and osteoclast-mediated bone resorption is the key pathological mechanism of the occurrence and development of OP, which involves a series of complex and highly regulated cytokines and signal pathways. According to the various regulation mechanisms of bone homeostasis, calcitonin and bisphosphonate are mainly used to treat OP. However, many drugs have certain side effects or are not suitable for long-term use. OP may be caused by excessive drinking, glucocorticoid abuse, and estrogen deficiency. Experiments have proved that traditional Chinese medicine may treat OP by improving estrogen secretion, trace element metabolism, and regulating immune stress. As unique macromolecular substances in traditional Chinese medicine, polysaccharides have biological activities such as anti-cancer, anti-inflammation, and antioxidant injury. They regulate bone homeostasis by inhibiting osteoblast apoptosis, promoting osteoblast differentiation, inhibiting osteoclast activity, antioxidant stress, and regulating immune inflammation, and effectively curb postmenopausal osteoporosis (POP) and glucocorticoid-induced osteoporosis (GIOP). It provides a new idea for the clinical treatment of OP. Therefore, by searching the relevant Chinese and English literature, this paper systematically reviews the imbalance between osteoblast and osteoclast homeostasis leading to OP. Traditional Chinese medicine polysaccharides regulate bone tissue homeostasis and treat OP through the above ways. This provides a scientific basis for the intervention with traditional Chinese medicine polysaccharides in OP. [ABSTRACT FROM AUTHOR]

PANoptosis, also known as panapoptosis, represents a distinctive form of cell demise characterized by the simultaneous occurrence of pyroptosis, apoptosis and necrosis within the same cellular population. This burgeoning field of investigation has garnered considerable scholarly interest due to its fundamental nature as a finely orchestrated and harmoniously balanced program of inflammatory cell death, amalgamating key traits of pyroptosis, apoptosis, and necrosis. The intricate interplay between osteoporosis and the regulation of bone homeostasis, often referring to bone balance, has been particularly associated with the formation of the PANoptosome. The PANoptosome is an indispensable cellular structure whose assembly and activation exhibits a strong correlation with systemic degenerative and inflammatory ailments, notably including osteoporosis. Consequently, this exists an immediate need for a comprehensive understanding of the mechanisms and controls governing PANoptosis, as well as the intricate relationship between PANoptosis and osteoporosis. This article provides a thorough exploration of both the distinctions and parallels between PANoptosis and the three well-established modes of cell demise: pyroptosis, apoptosis, and necrosis. The central focus is directed towards elucidating the molecular mechanisms and regulatory patterns of PANoptosis, with the ultimate goal of advancing further investigations into the regulatory framework of PANoptosis in the context of osteoporosis. [ABSTRACT FROM AUTHOR]

Background: Here, we evaluated whether the histone lysine demethylase 5B (JARID1B), is involved in osteogenic phenotype commitment of periodontal ligament cells (PDLCs), by considering their heterogeneity for osteoblast differentiation. Materials and Methods: Epigenetic, transcriptional, and protein levels of a gene set, involved in the osteogenesis, were investigated by performing genome‐wide DNA (hydroxy)methylation, mRNA expression, and western blotting analysis at basal (without osteogenic induction), and at the 3rd and 10th days of osteogenic stimulus, in vitro, using PDLCs with low (l) and high (h) osteogenic potential as biological models. Results: h‐PDLCs showed reduced levels of JARID1B, compared to l‐PDLCs, with significant inversely proportional correlations between RUNX2 and RUNX2/p57. Epigenetically, a significant reduction in the global H3K4me3 content was observed only in h‐PDLCs. Immunoblotting data reveal a significant reduction in the global H3K4me3 content, at 3 days of induction only in h‐PDLCs, while an increase in the global H3K4me3 content was observed at 10 days for both PDLCs. Additionally, positive correlations were found between global H3K4me3 levels and JARID1B gene expression. Conclusions: Altogether, our results show the crucial role of JARID1B in repressing PDLCs osteogenic phenotype and this claims to pre‐clinical protocols proposing JARID1B as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Diet‐induced obesity is associated with enhanced systemic inflammation that limits bone regeneration. HDAC inhibitors are currently being explored as anti‐inflammatory agents. Prior reports show that myeloid progenitor‐directed Hdac3 ablation enhances intramembranous bone healing in female mice. In this study, we determined if Hdac3 ablation increased intramembranous bone regeneration in mice fed a high‐fat/high‐sugar (HFD) diet. Micro‐CT analyses demonstrated that HFD‐feeding enhanced the formation of periosteal reaction tissue of control littermates, reflective of suboptimal bone healing. We confirmed enhanced bone volume within the defect of Hdac3‐ablated females and showed that Hdac3 ablation reduced the amount of periosteal reaction tissue following HFD feeding. Osteoblasts cultured in a conditioned medium derived from Hdac3‐ablated cells exhibited a four‐fold increase in mineralization and enhanced osteogenic gene expression. We found that Hdac3 ablation elevated the secretion of several chemokines, including CCL2. We then confirmed that Hdac3 deficiency increased the expression of Ccl2. Lastly, we show that the proportion of CCL2‐positve cells within bone defects was significantly higher in Hdac3‐deficient mice and was further enhanced by HFD. Overall, our studies demonstrate that Hdac3 deletion enhances intramembranous bone healing in a setting of diet‐induced obesity, possibly through increased production of CCL2 by macrophages within the defect. [ABSTRACT FROM AUTHOR]

Yang Zhang,1 Minjie Zhang,2 Mengying Li,2 Maomao Miao,2 Dan Shou,2 Peijian Tong1 1Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310053, People’s Republic of China; 2School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of ChinaCorrespondence: Dan Shou; Peijian Tong, Email shoudanok@163.com; peijiantong@zcmu.edu.cnBackground: Infected bone defects pose a challenging clinical issue due to an imbalance of osteoclasts (OC) and osteoblasts (OB). Exosomes are crucial for intercellular signaling of OC and OB in bone repair. Icariin, has been shown to regulate the balance between OC and OB. However, the specific mechanisms by which icariin influences exosomes derived from osteoclasts, and subsequently impacts osteoblast activity, remain unclear. This study aims to investigate the effects of icariin-treated osteoclast-derived exosomes (ICA-OC-Exo) on osteoblast function and bone repair in cases of infected bone defects.Methods: We investigated the exosome profile and localization of multivesicular bodies (MVB) and quantification of intraluminal vesicles (ILVs) in osteoclasts by using transmission electron microscopy. Additionally, the expressions of Rab27A and MITF, which are associated with exosome release, were determined through immunofluorescence staining and Western blot. The profiling of exosomal miRNA expression was conducted via miRNA-sequencing. The effects of ICA-OC-Exo on osteoblast differentiation were determined using RT-qPCR, Western blot, alkaline phosphatase staining. Additionally, ICA-OC-Exo was administered into the localized bone defect of the infected bone rat models, and bone formation was assessed using Micro-CT.Results: Icariin increased the presence of MVBs in the cytoplasm through modulation of the MITF/Rab27A signaling pathway, resulting in higher number of ICA-OC-Exo compared to OC-Exo. Additionally, miR-331-3p expression in ICA-OC-Exo was found to be elevated compared to OC-Exo. ICA-OC-Exo was observed to stimulate osteoblast function by targeting FGF23, reducing DKK1, and subsequently upregulating ALP. In the in vivo study, ICA-OC-Exo exhibited the capacity to enhance bone healing at the site of a local bone defect following anti-infection treatment.Conclusion: Icariin enhanced the quantification of OC-Exo and the expression of miRNA-331-3p in OC-Exo, leading to the regulation of osteoblast function via activation of the miRNA-331-3p/FGF23/DKK1 pathway. ICA-OC-Exo demonstrated potential clinical applicability in bone repair of infected bone defects. Keywords: infected bone defects, icariin, osteoclast, exosomes, osteoblast

Abstract Hippo pathway is an evolutionarily conservative key pathway that regulates organ size and tissue regeneration by regulating cell proliferation, differentiation and apoptosis. Yes-associated protein 1 (YAP)/ WW domain-containing transcription regulator 1 (TAZ) serves as a pivotal transcription factor within the Hippo signaling pathway, which undergoes negative regulation by the Hippo pathway. The expression of YAP/TAZ affects various biological processes, including differentiation of osteoblasts (OB) and osteoclasts (OC), cartilage homeostasis, skeletal muscle development, regeneration and quality maintenance. At the same time, the dysregulation of the Hippo pathway can concurrently contribute to the development of various musculoskeletal disorders, including bone tumors, osteoporosis (OP), osteoarthritis (OA), intervertebral disc degeneration (IDD), muscular dystrophy, and rhabdomyosarcoma (RMS). Therefore, targeting the Hippo pathway has emerged as a promising therapeutic strategy for the treatment of musculoskeletal disorders. The focus of this review is to elucidate the mechanisms by which the Hippo pathway maintains homeostasis in bone, cartilage, and skeletal muscle, while also providing a comprehensive summary of the pivotal role played by core components of this pathway in musculoskeletal diseases. The efficacy and feasibility of Hippo pathway-related drugs for targeted therapy of musculoskeletal diseases are also discussed in our study. These endeavors offer novel insights into the application of Hippo signaling in musculoskeletal disorders, providing effective therapeutic targets and potential drug candidates for treating such conditions.

Bone diseases, such as osteoporosis and osteoarthritis, have emerged as pressing public health concerns requiring immediate attention and resolution. Cellular therapy and tissue engineering techniques are among the most promising therapeutic approaches for such conditions. Human induced pluripotent stem cells (hiPSCs) possess remarkable capacity for indefinite self-renewal in vitro and the ability to differentiate into all somatic cell types originating from the three germ layers, thereby making them a promising source of osteoblasts. Consequently, it is crucial to establish a well-delineated system for osteogenic differentiation of hiPSCs in vitro, with the aim to generate osteoblast-like cells that conform to clinical application standards. Numerous research teams have achieved substantial advancements in both the direct osteogenic differentiation of hiPSCs and the indirect pathway via mesenchymal stem cells. In this article, we provide a comprehensive review of these two osteogenic differentiation pathways and their current applications, with the aim of serving as a valuable reference for bone regeneration technologies. Current research efforts have relied on embryoid body formation and monolayer induction methods utilizing biomaterials to develop a system that facilitates in vitro culture and osteogenic differentiation of hiPSCs. However, the existing research is primarily constrained by unclear system components and low efficiency. Therefore, the development of a stepwise and three-dimensional induction system based on stringent regulation by specific compounds is a primary research direction for the future.

Yu-Chi Wang,1,&ast; Meng-Ting Cai,1,&ast; Ming-Hong Chen,2,3 Fu-I Tung,4,5 Mei-Hsiu Chen,6,7 Tse-Ying Liu1 1Department of Biomedical Engineering, National Yang Ming Chiao Tung University, Taipei, 112304, Taiwan; 2Division of Neurosurgery, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, 220216, Taiwan; 3Department of Electrical Engineering, Yuan Ze University, Taoyuan City, 320315, Taiwan; 4Department of Orthopaedics, Yang-Ming Branch, Taipei City Hospital, Taipei, 111024, Taiwan; 5Department of Health and Welfare, College of City Management, University of Taipei, Taipei, 111036, Taiwan; 6Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, 220216, Taiwan; 7Department of Biomedical Engineering, Ming Chuang University, Taoyuan, 333, Taiwan&ast;These authors contributed equally to this workCorrespondence: Tse-Ying Liu; Mei-Hsiu Chen, Email tyliu5@nycu.edu.tw; michelle8989@gmail.comPurpose: Osteoporosis, characterized by reduced bone mass and structural deterioration, poses a significant healthcare challenge. Traditional treatments, while effective in reducing fracture risks, are often limited by side effects. This study introduces a novel nanocomplex, europium (Eu) ions-doped superparamagnetic iron oxide (SPIO) nanocrystals encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanospheres, abbreviated as SPIO:Eu@PLGA nanospheres, as a potential therapeutic agent for osteoporosis by modulating macrophage polarization, enhancing osteoblast differentiation and inhibiting osteoclastogenesis.Methods: SPIO and SPIO:Eu nanocrystals were synthesized through pyrolysis and encapsulated in PLGA using an emulsification method. To evaluate the impact of SPIO:Eu@PLGA nanospheres on macrophage reprogramming and reactive oxygen species (ROS) production, flow cytometry analysis was conducted. Furthermore, an ovariectomized (OVX) rat model was employed to assess the therapeutic efficacy of SPIO:Eu@PLGA nanospheres in preventing the deterioration of osteoporosis.Results: In vitro, SPIO:Eu@PLGA nanospheres significantly attenuated M1 macrophage activation induced by lipopolysaccharides, promoting a shift towards the M2 phenotype. This action is linked to the modulation of ROS and the NF-κB pathway. Unlike free Eu ions, which do not achieve similar results when not incorporated into the SPIO nanocrystals. SPIO:Eu@PLGA nanospheres enhanced osteoblast differentiation and matrix mineralization while inhibiting RANKL-induced osteoclastogenesis. In vivo studies demonstrated that SPIO:Eu@PLGA nanospheres effectively targeted trabecular bone surfaces in OVX rats under magnetic guidance, preserving their structure and repairing trabecular bone loss by modulating macrophage polarization, thus restoring bone remodeling homeostasis. The study underscores the critical role of Eu doping in boosting the anti-osteoporotic effects of SPIO:Eu@PLGA nanospheres, evident at both cellular and tissue levels in vitro and in vivo.Conclusion: The inclusion of Eu into SPIO matrix suggests a novel approach for developing more effective osteoporosis treatments, particularly for conditions induced by OVX. This research provides essential insights into SPIO:Eu@PLGA nanospheres as an innovative osteoporosis treatment, addressing the limitations of conventional therapies through targeted delivery and macrophage polarization modulation.Keywords: osteoporosis, macrophage polarization, osteoblast, osteoclast, nanocrystals, poly(lactic-co-glycolic acid)

Glucocorticoid-induced bone loss is a severe and toxic effect of long-term therapy with glucocorticoids, which are currently prescribed for millions of people worldwide. Previous studies have uncovered that glucocorticoids reciprocally converted osteoblast lineage cells into endothelial-like cells to cause bone loss and showed that the modulations of Foxc2 and Osterix were the causative factors that drove this harmful transition of osteoblast lineage cells. Here, we find that the inhibition of aurora kinase A halts this transition and prevents glucocorticoid-induced bone loss. We find that aurora A interacts with the glucocorticoid receptor and show that this interaction is required for glucocorticoids to modulate Foxc2 and Osterix. Together, we identify a new potential approach to counteracting unwanted transitions of osteoblast lineage cells in glucocorticoid treatment and may provide a novel strategy for ameliorating glucocorticoid-induced bone loss.

BACKGROUND: Magnetic nanomaterials have biological activities such as promoting osteogenic differentiation of stem cells and inhibiting osteoclast formation, and can effectively promote the healing of injured bone tissue under the synergistic effect of magnetic fields. They have a very broad application prospect in bone injury repair. OBJECTIVE: To review the mechanism of magnetic nanomaterials and magnetic fields promoting bone repair, as well as their research progress in the field of bone injury repair. METHODS: Relevant literature search was conducted in PubMed and Web of Science databases with the search terms "magnetic nanomaterials, magnetic field, bone repair, bone tissue engineering, stem cell, osteoblast, osteoclast." The time limit of literature search was from 2003 to 2023, which was screened and analyzed. Some classic articles were manually retrieved, and 98 articles were finally included for RESULTS AND CONCLUSION: (1) Magnetic nanomaterials have biological effects such as promoting osteoblast differentiation, inhibiting osteoclast formation and regulating the immune microenvironment. In addition, magnetic nanomaterials can regulate the physicochemical properties of tissue engineering scaffolds, such as mechanical properties and surface morphology, and endowed with magnetic properties, which is conducive to the regulation of the adhesion, proliferation and osteogenic differentiation of stem cells. (2) The magnetic field has the ability to regulate multiple cell signaling pathways to promote osteoblast differentiation, inhibit osteoclast formation, stimulate angiogenesis and other biological effects, thus accelerating the healing of damaged bone tissue. (3) The joint application of magnetic nanomaterials and magnetic field accelerates the repair of bone damage by activating mechanotransduction, increasing the content of intracellular magnetic nanoparticles, and enhancing the effect of micro-magnetic field, which provides a new idea for the research of bone tissue engineering. (4) Magnetic field has demonstrated definite efficacy in the treatment of clinical fractures, osteoporosis, and osteoarthritis diseases, which is beneficial for bone tissue growth, reducing bone loss, alleviating pain, and improving the quality of life of patients. (5) Magnetic nanomaterials and magnetic fields have great potential for application in bone damage repair and regeneration, but the interaction mechanism between magnetic nanomaterials, magnetic fields, and cells has not been fully elucidated. Moreover, the key parameters of magnetic fields that regulate intracellular molecular events, including the type, intensity, frequency, duration, and mode of the magnetic field, as well as the precise biological effects of a specific magnetic field on osteoblasts and the underlying mechanisms, have yet to be defined. (6) Further attention needs to be paid to the effects on osteoclasts, nerves, blood vessels, and immune cells in the microenvironment of damaged tissues. Finally, the safety of magnetic materials for human use is yet to be systematically studied in terms of their distribution, metabolism, and acute and chronic toxicities. [ABSTRACT FROM AUTHOR]

BACKGROUND: It has also been confirmed that ferroptosis is closely related to a variety of musculoskeletal diseases, such as rheumatoid arthritis, osteosarcoma, and osteoporosis. The pathophysiological mechanisms of ferroptosis and osteoporosis need to be further studied and elucidated to broaden our understanding of iron metabolism and osteoporosis. It will provide research ideas for the future elucidation of new mechanisms of osteoporosis and the development of new technologies and drugs for the treatment of osteoporosis. OBJECTIVE: To provide an overview of the current status of research on ferroptosis in osteoporosis, to provide a new direction for future research on the specific molecular mechanisms of osteoporosis, and to provide more effective and better options for osteoporosis treatment strategies. METHODS: The first author used the computer to search the literature published from 2000 to 2024 in CNKI, WanFang, VIP, and PubMed databases with search terms “ferroptosis, iron metabolism, osteoporosis, osteoblast, osteoclast, bone metabolism, signal pathway, musculoskeletal, review” in Chinese and English. A total of 68 articles were finally included according to the selection criteria. RESULTS AND CONCLUSION: (1) Ferroptosis is a new type of cell death discovered in recent years, which is usually accompanied by a large amount of iron accumulation and lipid peroxidation during cell death, and its occurrence is iron-dependent. This is distinctly different from several types of cell death that are currently being hotly studied (e.g., cellular pyroptosis, necrotic apoptosis, cuproptosis, and autophagy). (2) Intracellular iron homeostasis is manifested as a balance between iron uptake, export, utilization, and storage. The body’s iron regulatory system includes systemic and intracellular regulation. The main factor of systemic regulation is hepcidin produced by hepatic secretion, and cellular regulation depends on the iron regulatory protein/iron response element system. Of course, intracellular iron homeostasis can be controlled by other factors, such as hypoxia, cytokines, and hormones. (3) Lipid peroxidation causes oxidative damage to biological membranes (plasma membrane and internal organelle membranes), lipoproteins, and other lipid-containing molecules. Polyunsaturated fatty acid-containing phospholipids are important targets of lipid peroxidation. Free polyunsaturated fatty acid is an important substrate for lipid oxidation and can bind to the phospholipid bilayer, leading to over-oxidation and thus triggering lipid apoptosis. (4) Several studies have shown that osteoblasts are overloaded with iron in different ways, resulting in the accumulation of unstable ferrous iron and the generation of reactive oxygen species and lipid peroxides, causing ferroptosis of osteoblasts and ultimately a decrease in bone formation, affecting bone homeostasis and the development of osteoporosis. (5) Osteoclasts are large multinucleated cells formed by the fusion of mononuclear macrophage cell lines or bone marrow mesenchymal stem cells induced by nuclear factor-κB ligand receptor activator, and they have the function of bone resorption. Iron ions can promote osteoclast differentiation and bone resorption through the production of intracellular lipid reactive oxygen species, while iron chelators can inhibit osteoclast formation in vitro and thus affect the occurrence and development of osteoporosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pinoresinol diglucoside promotes bone formation and bone matrix synthesis and accelerates bone tissue repair. However, the mechanism of action and effects of this compound in osteoblasts need to be further explored. OBJECTIVE: To investigate the effect and mechanism of action of pinoresinol diglucoside on dexamethasone-treated osteoblasts based on the Wnt/β-catenin signaling pathway. METHODS: Different concentrations of dexamethasone groups and pinoresinol diglucoside groups were set to treat osteoblasts for 24 hours, and the optimal intervention concentrations were screened. Osteoblasts were treated with dexamethasone, pinoresinol diglucoside and inhibitor XAV-939. Then, control group, dexamethasone group, XVA-939 group, pinoresinol diglucoside group, pinoresinol diglucoside+XVA-939 group were set up. Cell counting kit-8 assay was used to detect cell activity. Alkaline phosphatase activity and caspase3/7 enzyme activity in cells were detected. Annexin V/PI staining and EdU assay were used to detect cell apoptosis and proliferation. Real-time qPCR and western blot were used to detect the mRNA and protein expression levels of Wnt3a, β-catenin, c-myc, osteocalcin, and type I collagen, respectively. RESULTS AND CONCLUSION: After dexamethasone and pinoresinol diglucoside intervened in osteoblasts for 24 hours, 10 μmol/L dexamethasone was found to be the optimal intervention concentration for cell inhibition, and cell proliferation was most pronounced at a concentration of pinoresinol diglucoside of 100 μmol/L. Compared with the dexamethasone group, alkaline phosphatase activity was significantly enhanced (P < 0.05) and caspase3/7 enzyme activity was significantly reduced (P < 0.05) in the pinoresinol diglucoside group. Annexin V/PI staining and cell proliferation assay by EdU method showed that pinoresinol diglucoside inhibited apoptosis and promoted proliferation of osteoblasts after dexamethasone intervention. The mRNA and protein expression levels of Wnt3a, β-catenin, c-myc, osteocalcin, and type I collagen were significantly higher in the pinoresinol diglucoside group and pinoresinol diglucoside+XVA-939 group compared with the dexamethasone and XVA-939 groups (P < 0.05). To conclude, pinoresinol diglucoside can inhibit osteoblast apoptosis after dexamethasone intervention, protect osteoblast activity and promote osteoblast proliferation by activating the Wnt/β-catenin signaling pathway, which may play a role in delaying steroid-induced osteonecrosis of the femoral head . [ABSTRACT FROM AUTHOR]

BACKGROUND: Some studies have found that ferroptosis of osteoblasts can be an important mechanism to induce the occurrence and development of hormone-induced femoral head necrosis. With the development of Chinese medicine, some scholars have found that some Chinese medicine monomer, Chinese medicine compound and Chinese patent medicine can regulate the ferroptosis of osteoblasts through various pathway mechanisms, and finally play a role in the treatment of steroid-induced avascular necrosis of femoral head. OBJECTIVE: To investigate the relationship between ferroptosis and steroid-induced avascular necrosis of femoral head and the mechanism of Chinese medicine regulating ferroptosis of osteoblasts in the treatment of steroid-induced avascular necrosis of femoral head, so as to provide new ideas for the diagnosis and treatment of steroid-induced avascular necrosis of femoral head. METHODS: With “ferroptosis, steroid-induced avascular necrosis of femoral head, osteoblast, Chinese herbal medicine, glucocorticoid, iron metabolism, reactive oxygen species, glutathione peroxidase” as Chinese search terms, and “ferroptosis, hormonal necrosis of the femoral head, osteoblast, Chinese herbal medicine, glucocorticoid, iron metabolism, ROS, GPX4” as English search terms, the search was conducted on CNKI, PubMed, WanFang, VIP and other databases. The relevant articles on osteoblast ferroptosis and steroid-induced avascular necrosis of femoral head and the regulation of Chinese herbal medicine intervention from the establishment of each database to 2023 were screened. Finally, 76 articles were systematically analyzed. RESULTS AND CONCLUSION: (1) Ferroptosis of osteoblasts plays an important role in the pathogenesis of steroid-induced avascular necrosis of femoral head. (2) The occurrence of ferroptosis in osteoblasts is regulated by a variety of mechanisms, such as intracellular iron overload causing ferroptosis. Lipid peroxidation damages cell membrane and causes ferroptosis. Cystine/glutamate reverse transporter induced ferroptosis by influencing glutathione level and glutathione peroxidase 4 activity. Fenton reaction in the cell produces a large number of reactive oxygen species and causes ferroptosis. (3) Chinese medicine monomer icariin, Chinese medicine compound Qinge pills and Chinese patent medicine Bushen Huoxue granules can regulate the occurrence of osteoblast ferroptosis, and help to prevent and treat steroid-induced avascular necrosis of femoral head. (4) The mechanism of ferroptosis in osteoblasts is still unclear. Further investigation on the mechanism of action of both is expected to provide a new choice for clinical treatment of steroid-induced avascular necrosis of femoral head. [ABSTRACT FROM AUTHOR]

BACKGROUND: In recent years, numerous studies have found that long non-coding RNA is involved in the occurrence and development of osteoporosis. p38MAPK signaling pathway is involved in the differentiation of bone marrow mesenchymal stem cells, osteoblasts and osteoclasts, and participates in the development of osteoporosis. LncRNA can directly or indirectly participate in the occurrence and development of osteoporosis by affecting the p38MAPK signaling pathway. OBJECTIVE: To review the effect of long non-coding RNA directly or indirectly on the progression of osteoporosis through the p38MAPK signaling pathway, and to provide a new idea for long non-coding RNA in the prevention and treatment of osteoporosis. METHODS: PubMed, CNKI, and Wanfang databases were searched with “long non-coding RNA, osteoporosis, mesenchymal stem cells, osteoblasts, osteoclasts, p38 signaling pathway” as the Chinese and English search terms. Old, repeated and low-credibility views were excluded. The retrieved literature was summarized, summed up, and analyzed. Seventy-six representative articles were selected. RESULTS AND CONCLUSION: (1) Long non-coding RNA participates in the prevention and treatment of osteoporosis through a variety of ways, including promoting the osteogenic differentiation of bone marrow mesenchymal stem cells, promoting the differentiation and secretion activity of osteoblasts, inhibiting the proliferation and bone resorption of osteoclasts, and regulating the activation or inhibition of osteoblast-related cellular pathways. Activation of p38MAPK signaling pathway can delay the progression of osteoporosis, and inhibition of p38MAPK signaling pathway can inhibit the absorption of osteoclasts, thereby affecting the occurrence and development of osteoporosis. (2) The overexpression or low expression of the corresponding long non-coding RNA can affect the proliferation or differentiation of osteoblasts and osteoclasts through the p38MAPK signaling pathway, regulate the process of bone remodeling, and then affect the occurrence and development of osteoporosis. A large number of basic research results show that long non-coding RNA and p38MAPK signaling pathway may be potential application and clinical translation value in the treatment of osteoporosis. Moreover, the corresponding long non-coding RNA overexpression or low expression lentivirus, transfection plasmid, and the corresponding p38MAPK signaling pathway inhibitor have been confirmed to have targeted regulatory effects in vitro cell experiments and animal models. (3) Therefore, targeting long non-coding RNA and p38MAPK signaling pathways to regulate the differentiation and function of bone marrow mesenchymal stem cells or inhibiting the proliferation and differentiation of osteoclasts may provide an innovative therapeutic strategy to delay the progression of osteoporosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: It has been found that vascular endothelial growth factor 165 and bone morphogenetic proteins interact with each other during hypoxiareoxygenation and are involved in the repair process of osteoblast injury by regulating the activation of intracellular signaling pathways. OBJECTIVE: To further investigate the relationship between vascular endothelial growth factor 165/bone morphogenetic protein and hypoxic-reoxygenated osteoblast injury. METHODS: Osteoblasts were selected and the hypoxic-reoxygenated injury model was established. Vascular endothelial growth factor 165 and bone morphogenetic protein expressions at mRNA and protein levels were detected by real-time PCR and western blot before and after modeling. After modeling, osteoblasts were given different concentrations of vascular endothelial growth factor 165 and bone morphogenetic protein 2 (10, 20, 40 ng/mL). Cell proliferation was detected by cell counting kit-8 method and apoptosis was detected by DAPI at 12, 24, 36, 48, and 72 hours after treatment. RESULTS AND CONCLUSION: Compared with before modeling, the mRNA and protein expressions of vascular endothelial growth factor 165 and bone morphogenetic protein 2 in osteoblasts after modeling were significantly decreased (P < 0.05). The proliferation rate of osteoblasts was significantly increased with the increase of vascular endothelial growth factor 165 concentration (P < 0.05), while the apoptosis rate of osteoblasts decreased significantly with the increase of vascular endothelial growth factor 165 concentration (P < 0.05). The proliferation rate of osteoblast was significantly increased with the increase of bone morphogenetic protein 2 concentration (P < 0.05), while the apoptosis rate of osteoblast decreased significantly with the increase of bone morphogenetic protein 2 concentration (P < 0.05). To conclude, vascular endothelial growth factor 165 and bone morphogenetic protein are lowly expressed in hypoxicreoxygenated osteoblast injury, and treatment with vascular endothelial growth factor 165 and bone morphogenetic protein can reduce the injury of hypoxicreoxygenated osteoblast in a concentration-dependent manner, suggesting that vascular endothelial growth factor 165 and bone morphogenetic protein have a significant protective effect against the injury of hypoxic-reoxygenated osteoblasts. [ABSTRACT FROM AUTHOR]

BACKGROUND: Sepsis-induced systemic inflammation leads to rapid bone mass loss; however, there is a lack of effective treatments. Ulinastatin is an antiinflammatory drug, but its protective effect and mechanism on bone under sepsis-induced systemic inflammation are still unclear. OBJECTIVE: To explore whether ulinastatin can relieve acute bone loss caused by lipopolysaccharide. METHODS: (1) Animal experiment. Thirty male C57BL/6 mice were randomly divided into three groups (n=10 per group): control group, model group and experimental group. The control group was injected intraperitoneally with normal saline, the model group was injected intraperitoneally with lipopolysaccharide, and the experimental group was injected intraperitoneally with lipopolysaccharide and ulinastatin. In the experimental group, ulinastatin was injected continuously for 3 days. After intraperitoneal injection of ulinastatin for 14 days, femoral tissues were taken for CT scanning and pathological observation. (2) Cell experiment. C57BL/6 mouse primary osteoblasts were isolated and divided into three groups: the control group was routinely cultured, lipopolysaccharide was added to the model group, and lipopolysaccharide with ulinastatin was added to the experimental group. Cell proliferation and osteogenic differentiation were detected. C57BL/6 mouse bone marrow mononuclear cells were isolated and divided into three groups: the control group was routinely cultured, lipopolysaccharide was added to the model group, and lipopolysaccharide and ulinastatin were added to the experimental group. Osteoclast differentiation was detected. RESULTS AND CONCLUSION: (1) Animal experiment. CT scanning and hematoxylin-eosin staining showed that bone mass in lipopolysaccharide-treated mice was reduced but increased after treatment with ulinastatin. Tartrate resistant acid phosphatase staining showed that the number of osteoclasts in bone tissue increased in the model group, but significantly decreased in the experimental group compared with the model group. (2) Cell experiment. Cell counting kit-8 assay showed that lipopolysaccharide treatment inhibited the proliferation of osteoblasts, and ulinastatin elevated the proliferation of osteoblasts after lipopolysaccharide treatment. Alkaline phosphatase staining, alizarin red staining and osteogenesis-related gene (alkaline phosphatase, Runx2, osteocalcin, osteoblastin, nuclear factor κB receptor-activating factor ligand, osteoprotegerin) detection showed that lipopolysaccharide treatment inhibited osteogenic differentiation of osteoblasts and elevated the nuclear factor κB receptor-activating factor ligand/osteoprotegerin ratio; ulinastatin did not have any significant effect on the reduction of osteoblast function induced by lipopolysaccharide but decreased the nuclear factor κB receptor-activating factor ligand/osteoprotegerin ratio. Tartrate resistant acid phosphatase staining and osteoclast-related gene (tartrate resistant acid phosphatase and matrix metalloproteinase 9) detection showed that lipopolysaccharide treatment could promote osteoclast differentiation of bone marrow monocytes, while ulinastatin could inhibit lipopolysaccharide-induced osteoclast differentiation of bone marrow monocytes. (3) Overall, ulinastatin can significantly inhibit lipopolysaccharide-induced bone loss, mainly through promoting osteoblast proliferation and directly or indirectly inhibiting osteoclast differentiation to alleviate bone loss and achieve osteoprotective effects. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recent studies have shown that research on naringin anti-osteoporosis mostly stays in in vitro and in vivo experiments. Understanding the mechanism of related signaling pathways and the expression of related proteins and some specific genes is an important way to deeply understand naringin anti-osteoporosis. At present, traditional Chinese medicine has been confirmed to have a significant role in anti-osteoporosis. Naringin is one of the main active ingredients in Rhizoma Drynariae. Its effectiveness and mechanism of action against osteoporosis have been gradually recognized by scholars, and its clinical and basic research has been gradually emphasized. OBJECTIVE: To analyze and summarize the research progress of naringin in anti-osteoporosis in vitro and in vivo, thereby providing some ideas for the next step to study its related mechanism of action. METHODS: The relevant literatures included in CNKI and PubMed database were searched with the Chinese search terms of “naringin, osteoporosis, traditional Chinese medicine compound, pathogenesis, signaling pathway, bone marrow mesenchymal stem cells, osteoblasts, osteoclasts” in Chinese and English, respectively. The corresponding criteria were established according to the research needs, and finally 69 articles were included for review. RESULTS AND CONCLUSION: Naringin blocks the increase in the number of osteoclasts and adipocytes, the decrease in the number of osteocytes and osteocalcin (+) cells induced by fructose-rich diet, and promotes the secretion of Sema3A from osteoblasts and osteocytes, thereby enhancing local bone formation and inhibiting osteoclast production by activating the Wnt/β-catenin pathway. Naringin is an important way to induce autophagy of osteoblasts, but autophagy-related proteins participate in osteoblast differentiation and bone formation. Lack of autophagy in osteoblasts reduces mineralization and leads to an imbalance in the number of osteoblasts and osteoclasts, which results in bone loss and decreased bone density. The composite scaffold loaded with naringin can be used as a necessary carrier for bone defect repair and has excellent bone repair properties. Naringin can also accelerate the growth of new bone tissue by increasing the local contents of bone morphogenetic protein 2 and vascular endothelial growth factor. Naringin can regulate bone metabolism and inhibit oxidative stress via ERK, PI3K/Akt and Wnt signaling pathways to improve osteoporosis, which can play a good role in preventing and controlling the disease. However, the depth and breadth of the relevant research is insufficient. Based on the mechanism of the current study, we should investigate the specific mechanisms by which naringin regulates different pathways and inter-pathway interactions in the future, which will be beneficial to the multifaceted development of naringin used in the treatment of osteoporosis.. [ABSTRACT FROM AUTHOR]

BACKGROUND: Fluid shear stress plays an important role in osteoblast proliferation and apoptosis. However, whether Caveolin-1 is involved in the process of fluid shear stress-induced proliferation and apoptosis in osteoblasts is unknown. OBJECTIVE: To explore the role of Caveolin-1 in fluid shear stress-regulated osteoblast proliferation and apoptosis. METHODS: The MC3T3-E1 osteoblasts in good growth status were selected and loaded with fluid shear stress at an intensity of 1.2 Pa for different times (0, 30, 60, 90 minutes). The expression of Caveolin-1 protein was observed and conditions with a time of 60 minutes were screened for the experiment. MC3T3-E1 cells were divided into control group, fluid shear stress group, fluid shear stress+pcDNA 3.1 group (control), fluid shear stress+pcDNA Cav-1 group (plasmid overexpression), and intervened with fluid shear stress and overexpression of Cav-1, respectively. The expression of molecules related to proliferation and apoptosis in MC3T3-E1 cells was detected by qRT-PCR and western blot. In addition, the proliferative activity of MC3T3-E1 cells was detected by cell counting kit-8 and EdU assay; and cell apoptosis was detected by Hoechst 33258 and flow cytometry. RESULTS AND CONCLUSION: The expression of Caveolin-1 in MC3T3-E1 cells was significantly down-regulated after loading fluid shear stress, and the expression level was lowest after 60 minutes. Overexpression of Caveolin-1 attenuated the proliferation-promoting and apoptosis-suppressing effects of fluid shear stress in MC3T3-E1 cells. In conclusion, Caveolin-1 has a vital role in fluid shear stress-regulated osteoblast proliferation and apoptosis, which may offer a potential therapeutic strategy for osteoporosis. [ABSTRACT FROM AUTHOR]

Purpose of Review: Bone homeostasis is balanced between formation and resorption activities and remain in relative equilibrium. Under disease states this process is disrupted, favoring more resorption over formation, leading to significant bone loss and fracture incidence. This aspect is a hallmark for patients with chronic kidney disease mineral and bone disorder (CKD-MBD) affecting a significant portion of the population, both in the United States and worldwide. Further study into the underlying effects of the uremic microenvironment within bone during CKD-MBD are critical as fracture incidence in this patient population not only leads to increased morbidity, but also increased mortality. Lack of bone homeostasis also leads to mineral imbalance contributing to cardiovascular calcifications. One area understudied is the possible involvement of bone marrow adipose tissue (BMAT) during the progression of CKD-MBD. Recent Findings: BMAT accumulation is found during aging and in several disease states, some of which overlap as CKD etiologies. Importantly, research has found presence of BMAT inversely correlates with bone density and volume. Summary: Understanding the underlying molecular mechanisms for BMAT formation and accumulation during CKD-MBD may offer a potential therapeutic avenue to improve bone homeostasis and ultimately mineral metabolism. [ABSTRACT FROM AUTHOR]

Abstract Osteoblasts and osteoclasts play an important role in maintaining the structural integrity of bone tissue, in which osteoclasts degrade bone structure and osteoblasts restore bone tissue. The imbalance of osteoblast and osteoclast function can lead to many bone-related diseases, such as osteoporosis and inflammatory osteolysis. The drug that can both promote bone formation and inhibit bone loss will be able to treat those diseases. In this study, it was found that LMK-235, an selective HDAC4/5 inhibitor, inhibited the differentiation and maturation of osteoclasts by regulating NF-κB and p-Smad2/3 signaling pathways via inhibition of HDAC4. At the same time, we found that LMK-235 promoted osteoblast mineralization by upregulating Runx2 expression via inhibition of HDAC4. In vivo, LMK-235 was able to alleviate lipopolysaccharide (LPS)-induced calvarial osteolysis and promote the repair of bone defects. Taken together, LMK-235 suppresses osteoclast differentiation and promotes osteoblast formation by inhibiting HDAC4. This may provide a valuable treatment for bone diseases caused by abnormal osteoclast bone resorption and osteoblast bone regeneration.

Abstract Objective Delayed fracture healing is a common complication of fractures that significantly impacts human health. This study aimed to explore the role of LINC00339 (lncRNA) in delayed fracture healing to provide new directions for its treatment. Methods This study included 82 patients with fractures healing in a normal manner and 90 patients experiencing delayed fracture healing. Levels of LINC00339, miR-16-5p, and osteogenic marker-related mRNAs were measured using RT-qPCR. The predictive potential of LINC00339 for delayed fracture healing was validated using ROC curve analysis. The interaction between LINC00339 and miR-16-5p was validated using dual-luciferase reporter assays and RIP experiments. CCK-8 was used to assess cell proliferation, and apoptosis rates were measured by flow cytometry. Results LINC00339 was significantly upregulated in delayed fracture healing patients and exhibited strong predictive ability for this condition. Overexpression of LINC00339 inhibited osteoblast proliferation, promoted apoptosis, and reduced mRNA levels of osteogenic markers (P

Ting Liu,1,2 Luxu Wang,1– 3 Tuo Shi,4 Hongrui Liu,1,2 Bo Liu,5 Jie Guo,1,2 Minqi Li1,2,5 1Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, People’s Republic of China; 2Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People’s Republic of China; 3School of Stomatology, Jinzhou Medical University, Jinzhou, People’s Republic of China; 4School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 5School of Clinical Medicine, Jining Medical University, Jining, People’s Republic of ChinaCorrespondence: Bo Liu, School of Clinical Medicine, Jining Medical University, Jining, 272067, People’s Republic of China, Tel +86-0537-6051782, Email liubo7230@mail.jnmc.edu.cn Jie Guo, Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, 250012, People’s Republic of China, Tel +86-0531-88382923, Email kqgj@sdu.edu.cnPurpose: Bone loss is a common complication of type 2 diabetes mellitus (T2DM). Circadian rhythms play a significant role in T2DM and bone remodeling. Eldecalcitol (ED-71), a novel active vitamin D analog, has shown promise in ameliorating T2DM. We aimed to investigate whether the circadian rhythm coregulator BMAL1 mediates the anti-osteoporotic effect of ED-71 in T2DM and its associated mechanisms.Methods: A T2DM mouse model was established using high-fat diet (HDF) and streptozotocin (STZ) injection, and blood glucose levels were monitored weekly. HE staining, Masson staining, and Micro-CT were performed to assess the changes in bone mass. IHC staining and IF staining were used to detect osteoblast status and BMAL1 expression and RT-qPCR was applied to detect the change of oxidative stress factors. In vitro, high glucose (HG) stimulation was used to simulate the cell environment in T2DM. RT-qPCR, Western blot, IF, ALP staining and AR staining were used to detect osteogenic differentiation and SIRT1/GSK3β signaling pathway. DCFH-DA staining was used to detect reactive oxygen species (ROS) levels.Results: ED-71 increased bone mass and promoted osteogenesis in T2DM mice. Moreover, ED-71 inhibited oxidative stress and promoted BMAL1 expression in osteoblasts The addition of STL1267, an agonist of the BMAL1 transcriptional repressor protein REV-ERB, reversed the inhibitory effect of ED-71 on oxidative stress and the promotional effect on osteogenic differentiation. In addition, ED-71 facilitated SIRT1 expression and reduced GSK3β activity. The inhibition of SIRT1 with EX527 partially attenuated ED-71’s effects, whereas the GSK3β inhibitor LiCl further enhanced ED-71’s positive effects on BMAL1 expression.Conclusion: ED-71 ameliorates bone loss in T2DM by upregulating the circadian rhythm coregulator BMAL1 and promoting osteogenesis through inhibition of oxidative stress. The SIRT1/GSK3β signaling pathway is involved in the regulation of BMAL1.Keywords: eldecalcitol, type 2 diabetic mellitus, osteoblast, BMAL1, SIRT1/GSK3β signaling pathway

Objective To investigate the effects of new and traditional non-steroidal anti-inflammatory drugs (NSAIDs) on the proliferation, morphology, adhesion, activity and expression of osteoblast related genes of MG-63 osteoblasts by establishing a osteogenic model of implants. Methods MG-63 cells were implanted on sand-blasted, largegrit, acid-etched titanium plates surface (SLA) to establish a model of osseointegration between implant surface and osteoblasts. The experiments included NO-flurbiprofen group, flurbiprofen group and the control group. Cell proliferation was detected by CCK-8 assay, cell morphology was observed by scanning electron microscopy (SEM), cell adhesion was detected by MTT assay, alkaline phosphatase (ALP) activity was detected by chemical method, calcified nodules was observed after Alizarin red staining, and the expression of bone formation related genes ALP, OCN, Runx-2 was detected by RT-qPCR. Results CCK-8 assay showed that statistical difference was observed in cell proliferation among the groups treated with different drug concentrations (P < 0.01). Cell proliferation was higher in the NO-flurbiprofen group and the flurbiprofen group than the control group, and in the NO-flurbiprofen group than the flurbiprofen group (P < 0.01). SEM displayed that the cells from the NO-flurbiprofen group grew to multiple lays first. Cell adhesion results showed that the number of cell adhesion was lower in the NO-flurbiprofen group than the flurbiprofen group and the control group (P < 0.01). ALP activity of drug groups was lower than the control group (P < 0.01). No typical red deeply stained calcified nodules were observed in neither NO-flurbiprofen group nor flurbiprofen group during the observation period. RT-qPCR indicated that the mRNA expression of OCN in the NO-flurbiprofen group and Runx-2 in the flurbiprofen group was higher than those of the control group, while the mRNA level of ALP was lower than that of the control group (P < 0.01). Conclusion Both NO-flurbiprofen and flurbiprofen effectively promote the proliferation of osteoblasts on the surface of titanium plates and the expression of some osteogenic related genes. The promotion effect of NO-flurbiprofen is more significant.