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Objective: Investigating whether mechanosensitive lncRNA H19 can directly target miR-148a to alleviate cartilage damage in post-traumatic osteoarthritis (PTOA). Methods: Thirty-two female rats were randomly divided into four groups: Sham-operated group (Sham group, n = 8), treadmill running group (R group, n = 8), anterior cruciate ligament transection (ACLT) group (ACLT group, n = 8), and ACLT + treadmill running group (ACLT + R group, n = 8). Histological evaluation was performed to observe the pathological changes in the cartilage of the rat knee. Micro-CT was performed to detect the bone morphological changes in the subchondral bone. RT-qPCR and Western-Blot were performed to detect changes in mRNA and protein levels of metabolic and inflammatory factors as well as changes in the expression of lncRNA H19 and miR-148a in cartilage. The Flexcell 5000™ Tension System was used to further validate that lncRNA H19 has mechanosensitivity in vitro. Finally, cell transfection techniques were used to knock down the expression of lncRNA H19 in chondrocytes to validate the regulatory role of lncRNA H19/miR-148a in cartilage metabolism. Results: ACLT combined with treadmill running aggravated the abnormal hyperplasia of subchondral bone in the lateral tibial plateau of the rat knee joint, disturbed the balance of cartilage metabolism, induced cartilage inflammatory response and chondrocyte pyroptosis, which eventually led to cartilage damage and PTOA. Importantly, we found that the expression of lncRNA H19 was significantly downregulated in the cartilage of the ACLT + R group. Bioinformatics analysis revealed that miR-148a may be a direct target of lncRNA H19. Subsequently, we focused on the mechanosensitive of lncRNA H19. Subsequently, moderate-intensity mechanical tension stress reversed the expression of lncRNA H19 and autophagy-related factors in inflammatory chondrocytes, while miR-148a showed an opposite expression trend, demonstrating that mechanosensitive lncRNA H19 may be involved in regulating the chondrocyte inflammatory response by targeting miR-148a and activating autophagy. Cell transfection experiments revealed that lncRNA H19 knockdown upregulated miR-148a expression and significantly inhibited the autophagy level of chondrocytes without significant alteration of chondrocyte pyroptosis, which in turn exacerbated the inflammatory response of chondrocytes. Conclusions: Mechanosensitive lncRNA H19 can promote chondrocyte autophagy rather than pyroptosis by targeting miR-148a, thus alleviating cartilage damage in PTOA. LncRNA H19 may be a potential therapeutic target for PTOA.

O-GlcNAcylation, as a post-translational modification, can modulate cellular activities such as kinase activity, transcription-translation, protein degradation, and insulin signaling by affecting the function of the protein substrate, including cellular localization of proteins, protein stability, and protein/protein interactions. Accumulating evidence suggests that dysregulation of O-GlcNAcylation is associated with disease progression such as cancer, neurodegeneration, and diabetes. Recent studies suggest that O-GlcNAcylation is also involved in the regulation of osteoblast, osteoclast and chondrocyte differentiation, which is closely related to the initiation and development of bone metabolic diseases such as osteoporosis, arthritis and osteosarcoma. However, the potential mechanisms by which O-GlcNAcylation regulates bone metabolism are not fully understood. In this paper, the literature related to the regulation of bone metabolism by O-GlcNAcylation was summarized to provide new potential therapeutic strategies for the treatment of orthopedic diseases such as arthritis and osteoporosis.

Periodontal disease is one of the most common oral diseases with the highest incidence world-wide. In particular, the treatment of periodontal bone defects caused by periodontitis has attracted extensive attention. Guided bone regeneration (GBR) has been recognized as advanced treatment techniques for periodontal bone defects. GBR technique relies on the application of barrier membranes to protect the bone defects. The commonly used GBR membranes are resorbable and non-resorbable. Resorbable GBR membranes are divided into natural polymer resorbable membranes and synthetic polymer resorbable membranes. Each has its advantages and disadvantages. The current research focuses on exploring and improving its preparation and application. This review summarizes the recent literature on the application of GBR membranes to promote the regeneration of periodontal bone defects, elaborates on GBR development strategies, specific applications, and the progress of inducing periodontal bone regeneration to provide a theoretical basis and ideas for the future application of GBR membranes to promote the repair of periodontal bone defects.

Bone metabolic homeostasis is dependent on coupled bone formation dominated by osteoblasts and bone resorption dominated by osteoclasts, which is a process of dynamic balance between bone formation and bone resorption. Notably, the formation of bone relies on the development of bone vasculature. Previous studies have shown that oxidative stress caused by disturbances in the antioxidant system of the whole organism is an important factor affecting bone metabolism. The increase in intracellular reactive oxygen species can lead to disturbances in bone metabolism, which can initiate multiple bone diseases, such as osteoporosis and osteoarthritis. Traditional Chinese medicine is considered to be an effective antioxidant. Cumulative evidence shows that the traditional Chinese medicine can alleviate oxidative stress-mediated bone metabolic disorders by modulating multiple signaling pathways, such as Nrf2/HO-1 signaling, PI3K/Akt signaling, Wnt/β-catenin signaling, NF-κB signaling, and MAPK signaling. In this paper, the potential mechanisms of traditional Chinese medicine to regulate bone me-tabolism through oxidative stress is summarized to provide direction and theoretical basis for future research related to the treatment of bone diseases with traditional Chinese medicine.

Osteoporosis (OP) is a chronic bone disease characterized by decreased bone mass, destroyed bone microstructure, and increased bone fragility. Accumulative evidence shows that extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) (MSC-EVs), especially exosomes (Exos), exhibit great potential in the treatment of OP. However, the research on MSC-EVs in the treatment of OP is still in the initial stage. The potential mechanism has not been fully clarified. Therefore, by reviewing the relevant literature of MSC-EVs and OP in recent years, we summarized the latest application of bone targeted MSC-EVs in the treatment of OP and further elaborated the potential mechanism of MSC-EVs in regulating bone formation, bone resorption, bone angiogenesis, and immune regulation through internal bioactive molecules to alleviate OP, providing a theoretical basis for the related research of MSC-EVs in the treatment of OP.

This study aimed to explore the possible relationship between the expression of Micro RNA-214 (miR-214) and the pathogenesis and recovery in mice with post-traumatic osteoarthritis (PTOA). In this study, 40 male C57BL/6 mice were randomly divided into five groups: model control (MC) group, model (M) group, rehabilitation control (RC) group, model + rehabilitation (M + R) group, and model + convalescent (M + C) group. Four weeks of high-intensity treadmill exercise (HITE) and 4 weeks of moderate-intensity treadmill exercise (MITE) were implemented for PTOA modeling and rehabilitation, respectively. In vitro, 10% elongation mechanical strain was used for IL-1β stimulated chondrocytes. We found that compared with the MC group, there was a significant increase in the aspect of inflammation and catabolism while a dramatic fall in miR-214 expression was observed in the M group. After the 4 weeks of MITE, the level of inflammation and metabolism, as well as miR-214 expression, was partially reversed in the M + R group compared with the M + C group. The expression of miR-214 decreased dramatically after chondrocyte stimulation by IL-1β and then increased significantly after 10% strain was applied to IL-1β-treated cells. These results suggest that a suitable mechanical load can increase the expression of miR-214, and that miR-214 may play a chondroprotective effect in the development of OA.

Sarcopenia is a chronic degenerative disease affecting primarily older adults. A growing aging population is gradually increasing the number of patients suffering from sarcopenia, placing increasing financial pressure on patients’ families and society in general. There is a strong link between mitochondrial dysfunction and sarcopenia pathogenesis. As a result, treating sarcopenia by improving mitochondrial dysfunction is an effective strategy. Numerous studies have demonstrated that exercise has a positive effect on mitochondrial dysfunction when treating sarcopenia. Exercise promotes mitochondrial biogenesis and mitochondrial fusion/division to add new mitochondria or improve dysfunctional mitochondria while maintaining mitochondrial calcium homeostasis, mitochondrial antioxidant defense system, and mitochondrial autophagy to promote normal mitochondrial function. Furthermore, exercise can reduce mitochondrial damage caused by aging by inhibiting mitochondrial oxidative stress, mitochondrial DNA damage, and mitochondrial apoptosis. Exercise effectiveness depends on several factors, including exercise duration, exercise intensity, and exercise form. Therefore, Moderate-intensity exercise over 4 weeks potentially mitigates sarcopenia in older adults by ameliorating mitochondrial dysfunction. HIIT has demonstrated potential as a viable approach to addressing sarcopenia in aged rats. However, further investigation is required to validate its efficacy in treating sarcopenia in older adults.

Background: Lactic acid, previously regarded only as an endpoint of glycolysis, has emerged as a major regulator of tumor invasion, growth, and the tumor microenvironment. In this study, we aimed to explore the reprogramming of lactic acid metabolism relevant to osteosarcoma (OS) microenvironment by decoding the underlying lactic acid metabolic landscape of OS cells and intercellular signaling alterations. Methods: The landscape of OS metabolism was evaluated using single-cell gene expression data, lactic acid metabolism clustering, and screening of the hub genes in lactic acid metabolism of OS samples using transcriptome data. The role of the hub gene NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 6 (NDUFAF6) was validated with in vitro studies and patient experiments. Results: Single-cell RNA sequencing data validated a lactic acid metabolismhigh subcluster in OS. Further investigation of intercellular communications revealed a unique metabolic communication pattern between the lactic acid metabolismhigh subcluster and other subclusters. Next, two lactic acid metabolic reprogramming phenotypes were defined, and six lactic acid metabolism-related genes (LRGs), including the biomarker NDUFAF6, were screened in OS. In vitro studies and patient experiments confirmed that NDUFAF6 is a crucial lactic acid metabolism-associated gene in OS. Conclusions: The patterns of lactic acid metabolism in OS suggested metabolic reprogramming phenotypes relevant to the tumor microenvironment (TME) and identified NDUFAF6 as an LRG prognostic biomarker.

Abstract Background The purpose of this study was to explore whether moderate-intensity exercise can alleviate motion-induced post-traumatic osteoarthritis (PTOA) and the expression change of lncRNA H19 during this progression. Methods Twenty-week-old male C57BL/6 mice were randomly divided into five groups: model control group (MC group, n = 6), treadmill model group (M group, n = 6), rehabilitation control group (RC group, n = 6), treadmill model + rehabilitation training group (M + R group, n = 6) and treadmill model + convalescent group (M + C group, n = 6). Paraffin sections were used to observe the pathological changes in the mouse knee joint in each group. A micro-CT was used to scan the knee joint to obtain the morphological indexes of the tibial plateau bone. Real-time PCR was used to detect the mRNA levels of inflammatory factors, synthetic and catabolic factors in cartilage. Results After high-intensity exercise for 4 weeks, the inflammation and catabolism of the mouse knee cartilage were enhanced, and the anabolism was weakened. Further study showed that these results were partially reversed after 4-week moderate-intensity training. The results of hematoxylin–eosin staining confirmed this finding. Meanwhile, high-intensity exercise reduced the expression of lncRNA H19 in cartilage, while the expression of lncRNA H19 increased after 4 weeks of moderate-intensity exercise. Conclusion High-intensity treadmill running can cause injury to the knee cartilage in C57BL/6 mice which leads to PTOA and a decrease of lncRNA H19 expression in cartilage. Moderate-intensity exercise can relieve PTOA and partially reverse lncRNA H19 expression.

Purpose: To explore the effect of blood flow restriction training (BFRT) on the recovery of knee function in patients after arthroscopic partial meniscectomy (APM).Methods: Forty patients undergoing APM surgery were included in this parallel group, two-arm, single-assessor blinded, randomized clinical trial. The subjects were randomly divided into two groups: routine rehabilitation group (RR Group, n = 20) and routine rehabilitation + blood flow restriction training group (RR + BFRT Group, n = 20). One subject in each group dropped out during the experiment. All patients received 8 weeks of routine rehabilitation starting from the second day after APM. In addition, patients in the RR + BFRT group required additional BFRT twice a week. Visual analogue scale (VAS) score, range of motion (ROM), one-leg standing test (OLST) score, Lysholm knee score, quadriceps muscle strength, quadriceps thickness, and thigh circumference were evaluated at preoperative, postoperative, 4 and 8 weeks after surgery. SPSS 25.0 software was used for statistical analysis of the data. Repeated measures ANOVA was used if the data were normally distributed and had homogeneity of variance. Generalized estimating equations were chosen if the data were not normally distributed or had homogeneity of variance.Results: There were no significant differences in VAS score, ROM, OLST score, Lysholm knee score, quadriceps muscle strength, quadriceps thickness, and thigh circumference between the two groups before surgery (p > 0.05). Compared with postoperative, VAS score, ROM, OLST score, Lysholm knee score, and thigh circumference were significantly improved in the RR group (p < 0.05), while quadriceps muscle strength and quadriceps thickness were not significantly enhanced at 8 weeks postoperatively (p > 0.05). However, VAS score, ROM, OLST score, Lysholm knee score, quadriceps muscle strength, quadriceps thickness, and thigh circumference were all significantly improved in the RR + BFRT group at 8 weeks postoperatively (p < 0.05). Furthermore, compared with the RR group, VAS score (50% vs. 86%), ROM (7.9% vs. 16.0%), OLST score (57.3% vs. 130.1%), Lysholm knee score (38.4% vs. 55.7%), relative peak torque (11.0% vs. 84.7%), mean power (20.6% vs. 88.1%), rectus femoris thickness (0.40% vs. 13.0%), vastus medialis (0.29% vs. 5.32%), vastus lateralis (0% vs. 6.2%), vastus internus (0% vs. 5.8%), and thigh circumference (2.7% vs. 5.8%) in the RR + BFRT group were significantly improved at 4 and 8 weeks postoperatively (p < 0.05).Conclusion: BFRT combined with routine rehabilitation training can better promote the recovery of knee joint function in patients after APM, especially the improvement of quadriceps muscle strength and thickness.

The study aims to explore the medical prospect of melatonin (MLT) and the underlying therapeutic mechanism of MLT-mediated macrophage (Mφ) polarization on the function of nucleus pulposus (NP) in intervertebral disc degeneration (IDD). RAW 264.7 Mφs were induced by lipopolysaccharide (LPS) to simulate Mφ polarization and the inflammatory reaction of Mφs with or without MLT were detected. Conditioned medium (CM) collected from these activated Mφs with or without MLT treatment were further used to incubate NP cells. The oxidative stress, inflammation and extracellular matrix (ECM) metabolism in NP cells were determined. Then, the changes in SIRT1/Notch signaling were detected. The agonist (SRT1720) and inhibitor (EX527) of SIRT1 were used to further explore the association among MLT. The interaction between SIRT1 and NICD was detected by immunoprecipitation (IP). Finally, puncture-induced rat IDD models were established and IDD degrees were clarified by X-ray, MRI, H&E staining and immunofluorescence (IF). The results of flow cytometry and inflammation detection indicated that LPS could induce M1-type Mφ polarization with pro-inflammatory properties. MLT significantly inhibited the aforementioned process and inhibited M1-type Mφ polarization, accompanied by the alleviation of inflammation. Compared with those without MLT, the levels of oxidative stress, pro-inflammatory cytokines and ECM catabolism in NP cells exposed to CM with MLT were markedly downregulated in a dose-dependent manner. The inhibition of SIRT1 and the enhancement of Notch were observed in activated Mφs and they can be reversed after MLT treatment. This prediction was further confirmed by using the SRT1720 and EX527 to activate or inhibit the signaling. The interaction between SIRT1 and NICD was verified by IP. In vivo study, the results of MRI, Pfirrmann grade scores and H&E staining demonstrated the degree of disc degeneration was significantly lower in the MLT-treated groups when compared with the IDD control group. The IF data showed M1-type Mφ polarization decreased after MLT treatment. MLT could inhibit M1-type Mφ polarization and ameliorate the NP cell injury caused by inflammation in vitro and vivo, which is of great significance for the remission of IDD. The SIRT1/Notch signaling pathway is a promising target for MLT to mediate Mφ polarization.

Over-activation of Toll-like receptor 4 (TLR4) is the key mechanism in Gram-negative bacterial infection-induced sepsis. SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) inhibits multiple viruses, but whether it plays a role during bacterial invasion remains unelucidated. Monocyte-macrophage specific Samhd1 knockout (Samhd1−/−) mice and Samhd1−/− macrophage cell line RAW264.7 were constructed and used as research models to evaluate the role of SAMHD1 in TLR4-activated inflammation. In vivo, LPS-challenged Samhd1−/− mice showed higher serum inflammatory factors, accompanied with more severe inflammation infiltration and lower survival rate. In vitro, Samhd1−/− peritoneal macrophages had more activated TLR4 pathway upon LPS-stimulation, accompanied with mitochondrial depolarization and dysfunction and a higher tendency to be M1-polarized. These results could be rescued by overexpressing full-length wild-type SAMHD1 or its phospho-mimetic T634D mutant into Samhd1−/− RAW264.7 cells, whereas the mutants, dNTP hydrolase-function-deprived H238A and phospho-ablative T634A, did not exert the same effect. Lastly, co-IP and immunofluorescence assays confirmed that SAMHD1 interacted with an outer mitochondrial membrane-localized protein, voltage-dependent anion channel-1 (VDAC1). SAMHD1 inhibits TLR4-induced acute inflammation and M1 polarization of macrophages by interacting with VDAC1 and maintaining mitochondria function, which outlines a novel regulatory mechanism of TLR signaling upon LPS stimulation.

Bone diseases are usually caused by abnormal metabolism and death of cells in bones, including osteoblasts, osteoclasts, osteocytes, chondrocytes, and bone marrow mesenchymal stem cells. Mitochondrial dysfunction, as an important cause of abnormal cell metabolism, is widely involved in the occurrence and progression of multiple bone diseases, including osteoarthritis, intervertebral disc degeneration, osteoporosis, and osteosarcoma. As selective mitochondrial autophagy for damaged or dysfunctional mitochondria, mitophagy is closely related to mitochondrial quality control and homeostasis. Accumulating evidence suggests that mitophagy plays an important regulatory role in bone disease, indicating that regulating the level of mitophagy may be a new strategy for bone-related diseases. Therefore, by reviewing the relevant literature in recent years, this paper reviews the potential mechanism of mitophagy in bone-related diseases, including osteoarthritis, intervertebral disc degeneration, osteoporosis, and osteosarcoma, to provide a theoretical basis for the related research of mitophagy in bone diseases.

Ferroptosis is a new iron-dependent programmed cell death process that is directly mediated by the accumulation of lipid peroxides and reactive oxygen species. Numerous studies have shown that ferroptosis is important in regulating the occurrence and development of bone-related diseases, but the underlying mechanisms are not completely clear. Herein, we review the progress of the mechanism of ferroptosis in bone marrow injury, osteoporosis, osteoarthritis, and osteosarcoma and attempt to deeply understand the regulatory targets of ferroptosis, which will open up a new way for the prevention and treatment of orthopedic diseases.

The repair of critical bone defects is a hotspot of orthopedic research. With the development of bone tissue engineering (BTE), there is increasing evidence showing that the combined application of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) (MSC-EVs), especially exosomes, with hydrogels, scaffolds, and other bioactive materials has made great progress, exhibiting a good potential for bone regeneration. Recent studies have found that miRNAs, proteins, and other cargo loaded in EVs are key factors in promoting osteogenesis and angiogenesis. In BTE, the expression profile of the intrinsic cargo of EVs can be changed by modifying the gene expression of MSCs to obtain EVs with enhanced osteogenic activity and ultimately enhance the osteoinductive ability of bone graft materials. However, the current research on MSC-EVs for repairing bone defects is still in its infancy, and the underlying mechanism remains unclear. Therefore, in this review, the effect of bioactive materials such as hydrogels and scaffolds combined with MSC-EVs in repairing bone defects is summarized, and the mechanism of MSC-EVs promoting bone defect repair by delivering active molecules such as internal miRNAs is further elucidated, which provides a theoretical basis and reference for the clinical application of MSC-EVs in repairing bone defects.

Extracellular vesicles (EVs) are small membrane vesicles that can be secreted by most cells. EVs can be released into the extracellular environment through exocytosis, transporting endogenous cargo (proteins, lipids, RNAs, etc.) to target cells and thereby triggering the release of these biomolecules and participating in various physiological and pathological processes. Among them, EVs derived from bone marrow mesenchymal stem cells (BMSC-EVs) have similar therapeutic effects to BMSCs, including repairing damaged tissues, inhibiting macrophage polarization and promoting angiogenesis. In addition, BMSC-EVs, as efficient and feasible natural nanocarriers for drug delivery, have the advantages of low immunogenicity, no ethical controversy, good stability and easy storage, thus providing a promising therapeutic strategy for many diseases. In particular, BMSC-EVs show great potential in the treatment of bone metabolic diseases. This article reviews the mechanism of BMSC-EVs in bone formation and bone resorption, which provides new insights for future research on therapeutic strategies for bone metabolic diseases.