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Purpose: To describe serum irisin and fibroblast growth factor-21 (FGF-21) concentrations in healthy female adolescents with different training activity patterns and their associations with bone mineral properties and metabolic markers. Methods: A total of 62 adolescent girls aged 14–18 years were recruited: 22 rhythmic gymnasts, 20 swimmers, and 20 untrained controls. Bone mineral characteristics by dual-energy X-ray absorptiometry, daily energy intake by dietary recall, serum irisin, FGF-21, undercarboxylated osteocalcin, and C-terminal telopeptide of type I collagen were measured in all girls. Results: Whole body and lumbar spine areal bone mineral density and lumbar spine bone mineral content were higher in the rhythmic gymnasts group compared with swimmers and untrained controls groups (P <.05). Serum irisin, FGF-21, undercarboxylated osteocalcin, and C-terminal telopeptide of type I collagen levels were not significantly different between the groups. In the rhythmic gymnasts group, serum FGF-21 concentration was positively correlated with lumbar spine areal bone mineral density independently of confounding factors (r =.51; P =.027). Conclusions: Serum irisin and FGF-21 levels were not different between adolescent eumenorrheic girls with different training activity patterns. FGF-21 was positively associated with lumbar spine areal bone mineral density, which predominantly consists of trabecular bone in adolescent rhythmic gymnasts. [ABSTRACT FROM AUTHOR]

Assessing bone's response to physical activity interventions is challenging. This randomized controlled trial investigates if changes in bone turnover markers can offer an early evaluation of a physical activity intervention's effectiveness in improving bone mineral density (BMD) in premenopausal women. Participants in the intervention group (n = 27, with 24 completing the trial) were instructed to walk at least 10,000 steps every day on a brisk walk and to execute 60 jumps daily, each surpassing 4g of acceleration, using an accelerometer-based wearable device. Meanwhile, the control group (n = 26, with 18 completing the trial) continued with their usual lifestyle. Bone turnover markers, comprising of C-terminal telopeptide of Type I collagen, procollagen Type 1 N-terminal propeptide, and total osteocalcin (carboxylated and undercarboxylated) were measured at baseline and midway through the intervention (3 months). Dual-energy X-ray absorptiometry scans of the hip and lumbar spine were conducted at baseline and the end of the intervention (6 months) to estimate BMD. Analysis of covariance exhibited significant differences between groups in procollagen Type 1 N-terminal propeptide (−6.74 μg/L, p =.023) and C-terminal telopeptide of Type I collagen (−83 ng/L, p =.043) after 3 months, and in femoral neck BMD (+0.024 g/cm2, p =.016), total hip BMD (+0.036 g/cm2, p =.004), and lumbar spine BMD (+0.026 g/cm2, p =.020) after 6 months. A significant correlation (r = −.73; p <.001) was detected between reductions in C-terminal telopeptide of Type I collagen and increases in femoral neck BMD. In conclusion, this intervention improved BMD in premenopausal women, with bone turnover markers potentially useful for early intervention assessment, though further research is needed. [ABSTRACT FROM AUTHOR]

Bone tissue is constantly regenerated and repaired through a finely balanced process known as bone remodeling. Many miRNAs act as regulators of the signaling pathways involved in bone metabolic processes to maintain tissue homeostasis. This study aimed to assess the circulating levels of MIR21, MIR34a, and MIR155 in human serum and their bone expression, and the expression of bone turnover-related genes which can reflect the bone quality. This prospective study was conducted on 60 patients (30 males and 30 females) indicated for surgical interventions for neural decompression +/- fixation. Relative quantification of expression of MIR21, miR34a, and MIR155 and bone related genes was assayed using PCR. The serum levels of osteocalcin and Serum Bone Alkaline Phosphatase (sBAP) were assayed using a human ELISA kit. The main finding of the present work was the strong positive association between the circulating levels of only miR21 and MIR155 and their bone expression in the population under study and with bone markers and target genes Also, a positive association was found between both bone expression and circulating MIR21 levels with age and sBAP. These results suggest that the circulating levels of these microRNAs as early markers for the predication of bone quality. [ABSTRACT FROM AUTHOR]

This study aims to discover the association between serum osteocalcin, the Chinese visceral adiposity index (CVAI), and atherosclerotic cardiovascular disease (ASCVD) risk, and their impact on arterial stiffness in T2DM patients. We included 639 T2DM patients aged 30 and older who received the assessment of ASCVD risk using the China-PAR equation, Osteocalcin and arterial stiffness in this cross-sectional study. We found that osteocalcin and CVAI as independent risk factors for both medium–high-risk ASCVD (osteocalcin: men, OR,0.96, 95% CI 0.92, 1.00; women, OR, 0.93, 95% CI 0.8, 1.08, respectively)(CVAI: men, OR,1.01,95% CI 1.00,1.02; women: OR, 1.08, 95% CI 1.02,1.14, respectively) and arterial stiffness (osteocalcin: men, OR, 0.98, 95% CI 0.94,1.01; women, OR, 0.98, 95% CI 0.90,1.06, respectively)(CVAI: men, OR,1.0, 95% CI 0.99,1.01; women, OR, 1.02, 95% CI 1.00,1.04, respectively) in both men and women patients with T2DM. Combining osteocalcin levels and CVAI improved the prediction accuracy of arterial stiffness in men patients with T2DM (difference of AUC(Model 4 vs. Model 1):1.5%, NRI: 0.06 [0.0,0.4]). All P-values were < 0.05. The results suggested that osteocalcin levels and CVAI are independent risk factors for ASCVD risk and arterial stiffness in T2DM. Combining osteocalcin and CVAI can enhance the early detection of atherosclerosis through male patients with T2DM. [ABSTRACT FROM AUTHOR]

Objective: Bone incision leads to interrupted and sluggish blood flow in the process of distraction osteogenesis (DO), creating a hypoxia (0–2% oxygen tension) at the center of the bone callus. This hypoxia is critical in the coupling of osteogenesis and angiogenesis during DO. This study aimed to investigate the effect of Uniaxial Static Strain (USS) on osteogenesis in osteoblasts under hypoxic conditions, with a focus on the expression of osteogenic markers and angiogenic factors. Methods: The USS was made by a multi-unit tension compression device.Osteoblasts were subjected to 10% USS made under hypoxic conditions to mimic the process of DO in vitro. The cell proliferation, alkaline phosphatase (ALP) activity, mineralized nodule formation, and expression of osteogenic and angiogenic markers were evaluated by using a CCK-8 assay, alkaline phosphatase (ALP) staining, ALP activity assay, alizarin red S staining, qRT-PCR, Western blotting and ELISA. Results: Hypoxia inhibited osteoblast cell proliferation, ALP activity, mineralized nodule formation, and the expression of runt-related transcription factor 2 (Runx- 2), osteopontin(OPN), osteocalcin (OCN), collagen type I (Col1a1). Conversely, hypoxia upregulated the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF), which are associated with angiogenesis. However, the application of USS enhanced osteoblasts' osteogenic capacity and upregulated angiogenic factors under hypoxic conditions. Conclusion: USS can enhance osteogenesis in osteoblasts under hypoxic conditions. Moreover, it may stimulate angiogenesis by promoting the expression of VEGF, which further contributes to bone formation. This finding provides important implications for understanding the mechanisms involved in bone regeneration and may have clinical applications in optimizing the effectiveness of DO techniques. [ABSTRACT FROM AUTHOR]

Adipocyte enhancer‐binding protein 1 (AEBP1) is closely implicated in osteoblastic differentiation and bone fracture; this research aimed to investigate the effect of AEBP1 on restoring osteoblastic differentiation under dexamethasone (Dex) treatment, and its interaction with the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT) pathway. Pre‐osteoblastic MC3T3‐E1 cells were cultured in osteogenic medium and treated by Dex to mimic steroid‐induced osteonecrosis cellular model. They were then further transfected with control or AEBP1‐overexpressed lentiviral vectors. Finally, cells were treated with the PI3K inhibitor LY294002, with or without AEBP1‐overexpressed lentiviral vectors. AEBP1 expression showed a downward trend in MC3T3‐E1 cells under Dex treatment in a dose‐dependent manner. AEBP1‐overexpressed lentiviral vectors increased relative cell viability, alkaline phosphatase (ALP) staining, Alizarin red staining and osteoblastic differentiation markers including osteocalcin (OCN), osteopontin (OPN), collagen type I alpha 1 (COL1A1), runt‐related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP2), but decreased cell apoptosis rate in MC3T3‐E1 cells under Dex treatment; besides, AEBP1‐overexpressed lentiviral vectors positively regulated p‐PI3K and p‐AKT expressions. Furthermore, LY294002 treatment decreased relative cell viability, Alizarin red staining, osteoblastic differentiation markers including OCN, OPN, RUNX2 and BMP, increased cell apoptosis rate and did not affect ALP staining in MC3T3‐E1 cells under Dex treatment; meanwhile, LY294002 treatment weakened the effect of AEBP1 overexpression vectors on the above cell functions. AEBP1 restores osteoblastic differentiation under Dex treatment by activating the PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

Osteochondral tissue engineering using layered scaffolds is a promising approach for treating osteochondral defects as an alternative to microfracture procedure, autologous chondrocyte implantation, and cartilage-bone grafting. The team previously investigated the chondrogenesis of mesenchymal stem cells (MSCs) on a polycaprolactone (PCL)/acetylated hyaluronic acid scaffold. The present study first focused on fabricating a novel osteoconductive scaffold utilizing bismuth-nanohydroxyapatite/reduced graphene oxide (Bi-nHAp/rGO) nanocomposite and electrospun PCL. The osteoconductive ability of the scaffold was investigated by evaluating the alkaline phosphatase (ALP) activity and the osteogenic genes expression in the adipose-derived MSCs. The expression of Runx2, collagen I, ALP, and osteocalcin as well as the result of ALP activity indicated the osteoconductive potential of the Bi-nHA-rGO/PCL scaffold. In the next step, a bilayer scaffold containing Bi-nHAp/rGO/PCL as an osteogenic layer and acetylated hyaluronic acid/PCL as a chondrogenic layer was prepared by the electrospinning technique and transplanted into osteochondral defects of rats. The chondrogenic and osteogenic markers corresponding to the surrounding tissues of the transplanted scaffold were surveyed 60 days later by real-time polymerase chain reaction (PCR) and immunohistochemistry methods. The results showed increased chondrogenic (Sox9 and collagen II) and osteogenic (osteocalcin and ALP) gene expression and augmented secretion of collagens II and X after transplantation. The results strongly support the efficacy of this constructed cell-free bilayer scaffold to induce osteochondral defect regeneration. • Bi-nHA/rGO nanocomposite and PCL were used to create an osteogenic scaffold. • A bilayer scaffold consisting of Bi-nHA/rGO/PCL (osteogenic) and Ac-HA/PCL (chondrogenic) was fabricated. • The bilayer scaffold was implanted in rat knee defects. • Chondrogenic and osteogenic markers were assessed using real-time PCR and immunohistochemistry. • Increased osteogenic and chondrogenic markers indicated osteochondral defect regeneration. [ABSTRACT FROM AUTHOR]

Objective: The aim was to investigate the mediating role of inflammatory biomarkers in the causal effect of body composition on glycaemic traits and type 2 diabetes. Methods: A retrospective observational study and a Mendelian randomization (MR) study were used. Observational analyses were performed using data from 4717 Chinese children and adolescents aged 6–18 years who underwent dual‐energy X‐ray absorptiometry for body composition. MR analyses were based on summary statistics from UK Biobank, deCODE2021, Meta‐Analysis of Glucose and Insulin‐Related Traits Consortium (MAGIC) and other large consortiums. Inflammatory biomarkers included leptin, adiponectin, osteocalcin, fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH). Results: In a retrospective observational study, increased fat mass had a positive effect on homeostasis model assessment of insulin resistance (HOMA‐IR) and homeostasis model assessment of pancreatic beta cell function (HOMA‐β) through FGF23, whereas fat‐free mass produced the opposite effects. PTH and osteocalcin played significant roles in the association of fat mass and fat‐free mass with fasting glucose, fasting insulin and HOMA‐IR (all p < 0.05). Mediation MR results indicated that childhood body mass index affected glycaemic traits through leptin and adiponectin. There existed a causal effect of fat‐free mass on type 2 diabetes via FGF23 (indirect effect: OR [odds ratio]: 1.14 [95% CI, confidence interval: 1.01–1.28]) and adiponectin (OR: 0.85 [95% CI: 0.77–0.93]). Leptin mediated the causal association of fat mass (indirect effect: β: −0.05 [95% CI: −0.07, −0.02]) and fat‐free mass (β: 0.03 [95% CI: 0.01, 0.04]) with fasting glucose. Conclusions: Our findings suggest that different body compositions have differential influences on glycaemic traits and type 2 diabetes through distinct inflammatory biomarkers. The findings may be helpful in tailoring management of body composition based on inflammatory biomarkers with different glycaemic statuses. [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]

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]

Aim: To evaluate the suitability of serum osteocalcin (OC) as a marker to distinguish between rapidly and non‐rapidly progressive central precocious puberty (RP‐CPP and NRP‐CPP), as well as its potential to assess growth rates following treatment with gonadotropin‐releasing hormone agonist (GnRHa). Methods: Serum levels of OC were measured using enzyme‐linked immunosorbent assays in girls diagnosed with either RP‐CPP or NRP‐CPP as well as in normal control subjects. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut‐off value for OC. Multivariate linear regression analysis was used to analyse the main influencing factors associated with OC. Results: Serum OC levels were higher in the CPP girls when compared to normal controls (110.76 ± 43.69 vs 55.97 ± 20.96 ng/mL, P < 0.001). The level in the RP‐CPP group was higher than the NRP‐CPP group (153.28 ± 33.89 vs 88.33 ± 29.26 ng/mL, P < 0.001). The cut‐off value of OC levels for distinguishing between RP‐CPP and NRP‐CPP was 107.05 ng/mL, the sensitivity was 94.7% and the specificity was 77.8%, which was superior to using the basal luteinising hormone (B‐LH) levels, and the area under ROC curve (AUC) were 0.933 versus 0.695, respectively. Following 1–2 years of treatment with GnRHa for girls with CPP, both OC levels and the growth rates decreased to pre‐pubertal values. B‐LH levels, bone age and body weight were also significant factors, which affected OC levels. Conclusions: Serum OC levels may be a useful marker for distinguishing RP‐CPP from NRP‐CPP. In addition, it was also found to be a useful predictor for growth rate during GnRHa treatment. [ABSTRACT FROM AUTHOR]

Objective: To determine whether combining cross‐linked (CL) collagen‐integrated xenogeneic bone blocks stabilized with the fixation of resorbable collagen membranes (CM) can enhance guided bone regeneration (GBR) in the overaugmented calvarial defect model. Materials and Methods: Four circular defects with a diameter of 8 mm were prepared in the calvarium of 13 rabbits. Defects were randomly assigned to receive one of the following treatments: (i) non‐cross‐linked (NCL) porcine‐derived collagen‐embedded bone block covered by a CM without fixation (NCL + unfix group); (ii) NCL bone block covered by CM with fixation using bone‐tack (NCL + fix group); (iii) cross‐linked (CL) porcine‐derived collagen‐embedded bone block covered by CM without fixation (CL + unfix group); and (iv) CL bone block covered by CM with fixation using bone‐tack fixation (CL + fix group). The efficacy of GBR was assessed through histological and molecular analyses after 2 and 8 weeks. Results: At 2 weeks, there were no significant differences in histologically measured areas of newly formed bone among the groups. At 8 weeks, however, the CL + fix group exhibited a larger area of new bone (5.08 ± 1.09 mm2, mean ± standard deviation) compared to the NCL + unfix (1.62 ± 0.42 mm2; p <.0083), NCL + fix (3.97 ± 1.39 mm2) and CL + unfix (2.55 ± 1.04 mm2) groups. Additionally, the expression levels of tumour necrosis factor‐alpha, fibroblast growth factor‐2, vascular endothelial growth factor, osteocalcin and calcitonin receptor were significantly higher in the CL + fix group compared to the other three groups (p <.0083). Conclusion: Cross‐linked bone blocks stabilized with collagen membrane fixation can significantly enhance GBR. [ABSTRACT FROM AUTHOR]

Background and Aim: Bone as an endocrine organ regulates metabolic processes independently of mineral metabolism through the production/release of proteins collectively named 'osteokines'. Relevant connections were reported between the insulin/glucose system, calcification of the atherosclerotic plaque, and several osteokines. We aimed to test the hypothesis that the osteokine network could be involved in beta‐cell function, insulin sensitivity, and vascular damage in a cohort of people with newly diagnosed type 2 diabetes (T2D). Subjects and Methods: In 794 drug‐naive, GADA‐negative, newly‐diagnosed T2D patients (mean ± SD age: 59 ± 9.8 years; BMI: 29.3 ± 5.3 kg/m2; HbA1c: 6.6 ± 1.3%) we assessed: plasma concentration of osteocalcin (OCN), osteopontin (OPN), RANKL, and its putative decoy receptor osteoprotegerin (OPG); insulin sensitivity (SI) by hyperinsulinemic euglycemic clamp; beta cell function (BCF), estimated by OGTT minimal modelling and expressed as derivative (DC) and proportional (PC) control. Echo‐doppler of carotid and lower limb arteries were also performed in 708 and 701 subjects, respectively. Results: OCN, RANKL and OPG were significantly associated with PC (p < 0.02); OCN was positively related to DC (p = 0.018). OPG was associated with lower IS (p < 0.001). Finally, the higher RANKL levels, the greater was the severity of atherosclerosis in common carotid artery (p < 0.001). Increased OPG and OPN concentrations were related to subclinical atherosclerosis in peripheral arteries of lower limbs (p = 0.023 and p = 0.047, respectively). Conclusion: These data suggest that, in patients with newly diagnosed T2D, the osteokine network crosstalks with the glucose/insulin system and may play a role in modulating the atherosclerotic process. [ABSTRACT FROM AUTHOR]

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In recent years, systemic inflammation has emerged as a pivotal player in the development and progression of various degenerative diseases. This complex, chronic inflammatory state, often undetected, can have far‐reaching consequences for the body's physiology. At the molecular level, markers such as C‐reactive protein, cytokines and other inflammatory mediators serve as indicators of systemic inflammation and often act as predictors of numerous musculoskeletal diseases and even certain forms of cancer. The concept of 'meta‐inflammation', specifically referring to metabolically triggered inflammation, allows healthcare professionals to understand inflammatory responses in patients with metabolic syndrome. Driven by nutrient excess and the expansion of adipose tissue, meta‐inflammation is closely associated with insulin resistance, further propagating the metabolic dysfunction observed in many Western societies. Wound persistence, on the other hand, exacerbates the detrimental effects of prolonged inflammation at the local level. Acute inflammation is a beneficial and essential process for wound healing and infection control. However, when inflammation fails to resolve, it can impede the healing process, leading to chronic wounds, excessive scarring and even the activation of fibrotic pathways. This approach significantly reduces the efficacy of regenerative biological therapies. Our review focuses on the vital role of proteins, vitamins and minerals in collagen synthesis and cell proliferation for tissue healing. We also examine hormonal influences on regeneration, noting the negative effects of imbalances, and emphasize glucose regulation's importance in creating a stable environment for chronic wound healing. [ABSTRACT FROM AUTHOR]

Aim: The present study aimed to investigate the histomorphometric and immunohistochemical impacts of vitamin K2 on guided bone regeneration (GBR) in calvarial critical‐size defects (CSDs) in diabetic rats. Methods: A total of 30 rats were used in this study, comprising 12 non‐diabetic (control) rats and 18 with streptozotocin‐nicotinamide‐induced experimental Diabetes mellitus (DM). In all rats, two calvarial CSDs were created: one defect was left empty (E), the other was treated with bovine‐derived bone graft and collagen‐based resorbable membrane (GM). Study groups were as follows: control rats administered saline (n = 6, C‐E and C‐GM groups) or vitamin K2 (n = 6, CK‐E and CK‐GM groups) and diabetic rats administered saline (n = 6, DM‐E and DM‐GM groups) or vitamin K2 (n = 6, DMK‐E and DMK‐GM groups). After 4 weeks of saline or vitamin K2 administration, the rats were euthanized. Bone defect healing and new bone formation were assessed histomorphometrically, and osteocalcin and osteopontin levels were examined immunohistochemically. Results: Percentage of new bone formation was greater in CK‐GM vs. CK‐E and in DMK‐GM vs. DMK‐E [d = 3.86 (95% CI = 16.38–28.61), d = 1.86, (95% CI = 10.74–38.58), respectively, p <.05]. Bone defect healing scores were higher in CK‐GM vs. CK‐E and in DMK‐GM vs. DMK‐E [d = 2.69 (95% CI = ‐2.12 to −0.87), d = 3.28 (95% CI = 0.98–1.91), respectively, p <.05]. Osteocalcin expression levels were elevated in CK‐GM vs. CK‐E, in DMK‐GM vs. DMK‐E [d = 1.19 (95% CI = 0.08–1.41), d = 1.10 (95% CI = 0.02–1.22), respectively p <.05]. Vitamin K2 enhanced osteocalcin expression levels in DMK‐E vs. DM‐E [d = 2.78, (95% CI = 0.56–1.53), p <.05] and in DMK‐GM vs. DM‐GM [d = 2.43, (95% CI = 0.65–2.10), p <.05]. Osteopontin expression was enhanced in defects treated with GM vs. E defects [C‐GM vs. C‐E, d = 1.56 (95% CI = 0.38–2.01); CK‐GM vs. CK‐E, d = 1.91 (95% CI = 0.49–1.72); DM‐GM vs. DM‐E, d = 2.34 (95% CI = ‐1.12 to −0.50); DMK‐GM vs. DMK‐E, d = 2.00 (95% CI = 0.58–1.91), p <.05]. Conclusion: The research findings suggest that administering vitamin K2 in GBR for rats with DM favorably impacts bone healing in CSDs, presenting an adjunctive strategy for bone regeneration. [ABSTRACT FROM AUTHOR]

Percutaneous implants osseointegrated into the residuum of a person with limb amputation need to provide mechanical stability and protection against infections. Although significant progress has been made in the biointegration of percutaneous implants, the problem of forming a reliable natural barrier at the level of the surface of the implant and the skin and bone tissues remains unresolved. The use of a microporous implant structure incorporated into the Skin and Bone Integrated Pylon (SBIP) should address the issue by allowing soft and bone tissues to grow directly into the implant structure itself, which, in turn, should form a reliable barrier to infections and support strong osseointegration. To evaluate biological interactions between dermal fibroblasts and MC3T3-E1 osteoblasts in vitro, small titanium discs (with varying pore sizes and volume fractions to achieve deep porosity) were fabricated via 3D printing and sintering. The cell viability MTT assay demonstrated low cytotoxicity for cells co-cultured in the pores of the 3D-printed and sintered Ti samples during the 14-day follow-up period. A subsequent Quantitative Real-Time Polymerase Chain Reaction (RT-PCR) analysis of the relative gene expression of biomarkers that are associated with cell adhesion (α2, α5, αV, and β1 integrins) and extracellular matrix components (fibronectin, vitronectin, type I collagen) demonstrated that micropore sizes ranging from 200 to 500 µm of the 3D printed and sintered Ti discs were favorable for dermal fibroblast adhesion. For example, for representative 3D-printed Ti sample S6 at 72 h the values were 4.71 ± 0.08 (α2 integrin), 4.96 ± 0.08 (α5 integrin), 4.71 ± 0.08 (αV integrin), and 1.87 ± 0.12 (β1 integrin). In contrast, Ti discs with pore sizes ranging from 400 to 800 µm demonstrated the best results (in terms of marker expression related to osteogenic differentiation, including osteopontin, osteonectin, osteocalcin, TGF-β1, and SMAD4) for MC3T3-E1 cells. For example, for the representative 3D sample S4 on day 14, the marker levels were 11.19 ± 0.77 (osteopontin), 7.15 ± 0.29 (osteonectin), and 6.08 ± 0.12 (osteocalcin), while for sintered samples the levels of markers constituted 5.85 ± 0.4 (osteopontin), 4.45 ± 0.36 (osteonectin), and 4.46 ± 0.3 (osteocalcin). In conclusion, the data obtained show the high biointegrative properties of porous titanium structures, while the ability to implement several pore options in one structure using 3D printing makes it possible to create personalized implants for the best one-time integration with both skin and bone tissues. [ABSTRACT FROM AUTHOR]

Runx2 (runt related transcription factor 2) and Sp7 (Sp7 transcription factor 7) are crucial transcription factors for bone development. The cotranscription factor Cbfb (core binding factor beta), which enhances the DNA-binding capacity of Runx2 and stabilizes the Runx2 protein, is necessary for bone development. Runx2 is essential for chondrocyte maturation, and Sp7 is partly involved. Runx2 induces the commitment of multipotent mesenchymal cells to osteoblast lineage cells and enhances the proliferation of osteoprogenitors. Reciprocal regulation between Runx2 and the Hedgehog, fibroblast growth factor (Fgf), Wnt, and parathyroid hormone-like hormone (Pthlh) signaling pathways and Dlx5 (distal-less homeobox 5) plays an important role in these processes. The induction of Fgfr2 (Fgf receptor 2) and Fgfr3 expression by Runx2 is important for the proliferation of osteoblast lineage cells. Runx2 induces Sp7 expression, and Runx2+ osteoprogenitors become Runx2+Sp7+ preosteoblasts. Sp7 induces the differentiation of preosteoblasts into osteoblasts without enhancing their proliferation. In osteoblasts, Runx2 is required for bone formation by inducing the expression of major bone matrix protein genes, including Col1a1 (collagen type I alpha 1), Col1a2, Spp1 (secreted phosphoprotein 1), Ibsp (integrin binding sialoprotein), and Bglap (bone gamma carboxyglutamate protein)/Bglap2. Bglap/Bglap2 (osteocalcin) regulates the alignment of apatite crystals parallel to collagen fibrils but does not function as a hormone that regulates glucose metabolism, testosterone synthesis, and muscle mass. Sp7 is also involved in Co1a1 expression and regulates osteoblast/osteocyte process formation, which is necessary for the survival of osteocytes and the prevention of cortical porosity. SP7 mutations cause osteogenesis imperfecta in rare cases. Runx2 is an important pathogenic factor, while Runx1, Runx3, and Cbfb are protective factors in osteoarthritis development. [ABSTRACT FROM AUTHOR]

Endochondral ossification is the process by which cartilage is mineralized into bone, and is essential for the development of long bones. Osteocalcin (OCN), a protein abundant in bone matrix, also exhibits high expression in chondrocytes, especially hypertrophic chondrocytes, while its role in endochondral ossification remains unclear. Utilizing a new CRISPR/Cas9-mediated bglap–bglap2 deficiency (OCNem) mouse model generated in our laboratory, we provide the first evidence of OCN's regulatory function in chondrocyte differentiation and endochondral ossification. The OCNem mice exhibited significant delays in primary and secondary ossification centers compared to wild-type mice, along with increased cartilage length in growth plates and hypertrophic zones during neonatal and adolescent stages. These anomalies indicated that OCN deficiency disturbed endochondral ossification during embryonic and postnatal periods. Mechanism wise, OCN deficiency was found to increase chondrocyte differentiation and postpone vascularization process. Furthermore, bone marrow mesenchymal stromal cells (BMSCs) from OCNem mice demonstrated an increased capacity for chondrogenic differentiation. Transcriptional network analysis implicated that BMP and TGF-β signaling pathways were highly affected in OCNem BMSCs, which is closely associated with cartilage development and maintenance. This elucidation of OCN's function in chondrocyte differentiation and endochondral ossification contributes to a more comprehensive understanding of its impact on skeletal development and homeostasis. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis results from decreased bone mass and disturbed bone structure. Human bone marrow mesenchymal stem cells (hBMSCs) demonstrate robust osteogenic differentiation, a critical process for bone formation. This research was designed to examine the functions of LINC01133 in osteogenic differentiation. Methods: Differentially expressed lncRNAs affecting osteogenic differentiation in hBMSCs were identified from the GEO database. A total of 74 osteoporosis patients and 70 controls were enrolled. hBMSCs were stimulated to undergo osteogenic differentiation using an osteogenic differentiation medium (OM). RT-qPCR was performed to evaluate LINC01133 levels and osteogenesis-related genes such as osteocalcin, osteopontin, and RUNX2. An alkaline phosphates (ALP) activity assay was conducted to assess osteogenic differentiation. Cell apoptosis was detected using flow cytometry. Dual luciferase reporter assay and RIP assay were employed to investigate the association between miR-214-3p and LINC01133 or CTNNB1. Loss or gain of function assays were conducted to elucidate the impact of LINC01133 and miR-214-3p on osteogenic differentiation of hBMSCs. Results: LINC01133 and CTNNB1 expression decreased in osteoporotic patients but increased in OM-cultured hBMSCs, whereas miR-214-3p showed an opposite trend. Depletion of LINC01133 suppressed the expression of genes associated with bone formation and ALP activity triggered by OM in hBMSCs, leading to increased cell apoptosis. Nevertheless, this suppression was partially counteracted by the reduced miR-214-3p levels. Mechanistically, LINC01133 and CTNNB1 were identified as direct targets of miR-214-3p. Conclusions: Our study highlights the role of LINC01133 in positively regulating CTNNB1 expression by inhibiting miR-214-3p, thereby promoting osteogenic differentiation of BMSCs. These findings may provide valuable insights into bone regeneration in osteoporosis. [ABSTRACT FROM AUTHOR]

Background. Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) are an intriguing class of antihyperglycemic drugs for type 2 diabetes mellitus (T2DM). Such drugs not only play a primary role in regulating blood glucose levels but also exhibit additional pleiotropic effects, including potential impacts on bone metabolism and fracture risk. However, the mechanism of such drugs is unclear. The purpose of this study was to evaluate the effect of GLP‐1 RAs on bone metabolism in T2DM. Methods. From database inception to May 1, 2023, the searches were conducted on multiple databases such as Web of Science, Embase, PubMed, CNKI, the Cochrane Library, Wanfang, and VIP. We systematically collected all randomized controlled trials of bone metabolism in patients with T2DM treated with GLP‐1 RAs. The quality evaluation was performed according to the Cochrane Handbook for Systematic Reviews of Interventions. Data extraction was analyzed using Review Manager 5.4 software, and funnel plots were drawn to evaluate publication bias. Results. Twenty‐six randomized controlled trials that met the inclusion criteria were included, involving a total of 2268 participants. In this study, compared to other antidiabetic drugs or placebo, GLP‐1 RAs were found to significantly increase serum calcium (mean difference (MD) = 0.05, 95% confidence interval (CI) (0.01, 0.09), P = 0.002], bone alkaline phosphatase [standardized MD (SMD) = 0.76, 95% CI (0.29, 1.24), and P = 0.001), and osteocalcin (SMD = 2.04, 95% CI (0.99, 3.08), and P = 0.0001) in T2DM. Specifically, liraglutide increased procollagen type 1 N‐terminal propeptide (SMD = 0.45, 95% CI (0.01, 0.89), and P = 0.04). GLP‐1 RAs were also associated with a reduction in cross‐linked C‐terminal telopeptides of type I collagen (SMD = −0.36, 95% CI (−0.70, −0.03), and P = 0.03). In additionally, GLP‐1 RAs increased lumbar spine bone mineral density (BMD) (SMD = 1.04, 95% CI (0.60, 1.48), and P < 0.00001) and femoral neck BMD (SMD = 1.29, 95% CI (0.36, 2.23), and P = 0.007). Conclusions. GLP‐1 RAs can not only improve BMD in the lumbar spine and femoral neck of patients with T2DM but also protect bone health by inhibiting bone resorption and promoting bone formation. Systematic Review Registration. PROSPERO, identifier CRD42023418166. [ABSTRACT FROM AUTHOR]

Ridge preservation is an important technique for maintaining the dimensions of the alveolar bone following tooth extraction, which is crucial for successful tooth rehabilitation. The combination of bovine amniotic membrane and hydroxyapatite has shown promise as a scaffold material containing growth factors that can stimulate osteogenic‐related factors such as bone morphogenetic protein 2 (BMP2), Runt‐related transcription factor 2 (RUNX2), and osteocalcin. This stimulation leads to collagen production and osteoblast proliferation, resulting in new bone formation. In this study, bovine amniotic membrane‐hydroxyapatite (BAM‐HA) composites were prepared using three different ratios of bovine amniotic membrane and hydroxyapatite (2 : 3, 3 : 7, 7 : 13). Thirty Sprague–Dawley rats had their first incisors extracted, and different types of BAM‐HA were applied for ridge preservation. The control group received no treatment, while the positive control group was given xenograft. After 14 and 28 days, the animals were sacrificed, and immunohistochemical analysis was performed to evaluate the expression of BMP2, RUNX2, and osteocalcin. Additionally, a histological examination was conducted to analyse collagen thickness and osteoblast cell proliferation. The results demonstrated that the application of BAM‐HA significantly increased collagen density, osteoblast cell proliferation, and the expression of BMP2, RUNX2, and osteoclacin compared to the control group (p < 0.05) on both days 14 and 28. Furthermore, increasing the hydroxyapatite content in the composite was found to enhance collagen thickness, osteoblast cell proliferation, and the expression of osteogenic‐related factors. These preliminary findings suggest that the combination of BAM‐HA can be used for ridge preservation to prevent further bone resorption following tooth extraction. [ABSTRACT FROM AUTHOR]

Objective: The prevalence of type 2 diabetes mellitus (T2DM) and bone metabolism disorders increase with age. Diabetic kidney disease (DKD) is one of the most serious microvascular complications of T2DM, and bone metabolism disorders are closely linked to the occurrence of DKD. The relationship between bone turnover markers(BTMs) and the kidney disease in elderly patients with T2DM remains unclear. Therefore, this study aims to investigate the association between common BTMs and DKD in a large sample of elderly patients. The goal is to provide a basis for early identification of high-risk individuals for DKD among elderly T2DM patients from a bone metabolism perspective. Methods: In this cross-sectional study, BTMs were collected from a cohort of 2,051 hospitalized Chinese patients. The relationships between 25-hydroxyvitamin D (25-OH-D), β-CrossLaps (β-CTX), osteocalcin (OSTEOC), intact parathyroid hormone (iPTH), and total type I collagen N-terminal propeptide (TP1NP), and DKD, as well as urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were analyzed using regression analysis and restrictive cubic spline (RCS) curves. Results: Higher 25-OH-D levels were independently linked to a lower incidence of DKD and decreased UACR. The RCS curves showed a linear association of 25-OH-D and DKD, approaching the L-shape. β-CTX was independently and positively correlated with UACR. There is an independent positive correlation between OSTEOC and UACR and a negative correlation with eGFR. iPTH is independently and positively correlated with DKD incidence and UACR, and negatively correlated with eGFR. Additionally, the RCS curves showed a non-linear association of OSTEOC and iPTH and DKD, approaching the J-shape, and the point of inflection is 10.875 ng/L and 34.15 pg/mL respectively. There is an independent positive correlation between TP1NP and UACR incidence, and a negative correlation with eGFR. Risk estimates significantly increase with higher TP1NP levels in the RCS model. Conclusion: BTMs are closely associated with kidney disease in elderly patients with T2DM. These discoveries potentially assist clinicians in establishing more preventive measures and targeted treatment strategies for elderly patients with T2DM. [ABSTRACT FROM AUTHOR]

Objective Exploring the Effect of External Application of Warm Meridian Medicinal Wine Combined with Acupuncture on Osteoporosis Rats. Methods Forty SPF grade female rats were selected and divided into normal group, model group, acupuncture group, and combination group, with 10 rats per group. Except for the normal group, osteoporosis (OP) models were established in all other groups. After successful modeling, the normal group and model group were not treated. The acupuncture group was treated with acupoints at Guanyuan, Sanyinjiao (Shuang), Shenshu (Shuang), and Housanli (Shuang), and then connected to an electroacupuncture instrument for 5 days per week, 20 minutes per day, for a total of 12 weeks. On the basis of acupuncture treatment, the combination group applied warm meridian medicinal wine twice a day for a total of 12 weeks. The serum levels of osteocalcin (OC), pyridinol (PYD), and type I procollagen carboxy terminal peptide (PICP) were detected using ELISA. The bone trabecular thickness (Tb. Th), trabecular septa (Tb. Sp), bone density (BMD), and cortical bone area (Ct. Ar) were measured using computed tomography. Osteoblast apoptosis was detected using TUNEL, and pathological changes in femoral tissue were observed using HE staining. Notch1, Notch2, Jagged1, and Jagged2 were measured using Western blot. Results Compared with the normal group, the model group PYD and Tb Sp, increased apoptosis rate of osteoblasts, OC, PICP, Tb Th, BMD, Ct A. Notch1, Notch2, Jagged1, and Jagged2 decreased (P<0.05); Compared with the model group, the acupuncture group had PYD and Tb Sp, decreased apoptosis rate of osteoblasts, OC, PICP, Tb Th, BMD, Ct A. Notch1, Notch2, Jagged1, and Jagged2 increased (P<0.05); Compared with the acupuncture group, the combination group had PYD and Tb Sp, decreased apoptosis rate of osteoblasts, OC, PICP, Tb Th, BMD, Ct A. Notch1, Notch2, Jagged1, and Jagged2 increased (P<0.05); The bone morphology and structure of the normal group rats are good; The model group had severe bone damage; The bone morphology and structure of the acupuncture group and the combination group have improved, with the combination group showing better improvement. Conclusion The combination of external application of Wen Jing Yao Jiu and acupuncture has a good improvement effect on osteocalcin, osteoblast activity, and Notch signaling pathway in osteoporosis rats, and it is recommended to promote its use. [ABSTRACT FROM AUTHOR]

GPRC6A, a member of the Family C G‐protein coupled receptors, regulates energy metabolism and sex hormone production and is activated by diverse ligands, including cations, L‐amino acids, the osteocalcin (Ocn) peptide and the steroid hormone testosterone. We sought a structural framework for the ability of multiple distinct classes of ligands to active GPRC6A. We created a structural model of GPRC6A using Alphafold2. Using this model we explored a putative orthosteric ligand binding site in the bilobed Venus fly trap (VFT) domain of GPRC6A and two positive allosteric modulator (PAM) sites, one in the VFT and the other in the 7 transmembrane (7TM) domain. We provide evidence that Ocn peptides act as a PAM for GPRC6A by binding to a site in the VFT that is distinct from the orthosteric site for calcium and L‐amino acids. In agreement with this prediction, alternatively spliced GPRC6A isoforms 2 and 3, which lack regions of the VFT, and mutations in the computationally predicted Ocn binding site, K352E and H355P, prevent Ocn activation of GPRC6A. These observations explain how dissimilar ligands activate GPRC6A and set the stage to develop novel molecules to activate and inhibit this previously poorly understood receptor. [ABSTRACT FROM AUTHOR]

Background: Bone‐derived protein osteocalcin, which has beneficial effects on brain function, may be a future research direction for neurological disorders. A growing body of evidence suggests a link between osteocalcin and neurological disorders, but the exact relationship is contradictory and unclear. Scope of Review: The aim of this review is to summarize the current research on the interaction between osteocalcin and the central nervous system and to propose some speculative future research directions. Major Conclusions: In the normal central nervous system, osteocalcin is involved in neuronal structure, neuroprotection, and the regulation of cognition and anxiety. Studies on osteocalcin‐related abnormalities in the central nervous system are divided into animal model studies and human studies, depending on the subject. In humans, the link between osteocalcin and brain function is inconsistent. These conflicting data may be due to methodological inconsistencies. By reviewing the related literature on osteocalcin, some comorbidities of the bone and nervous system and future research directions related to osteocalcin are proposed. [ABSTRACT FROM AUTHOR]

Objective: Diabetes mellitus is increasing worldwide. Photobiomodulation (PBM) is proposed as a therapeutic method in various medical concerns. This study aimed to compare the effects of PBM at the wavelengths of 660, 808, or 660 + 808 nm on alveolar bone healing in diabetic rats. Methods: Bilateral maxillary first molars were extracted from diabetic Wistar rats (n = 36). Right-sided sockets were treated by an In-Ga-Al-P laser at 660 nm (7.2 J/cm², 24 s; DM660), Ga-Al-As laser at 808 nm (7 J/cm², 14 s; DM808), or a combination of these two sets (DM-dual) (n = 12). Left sides served as controls. On days 7 or 14, specimens were assigned for histomorphometric or real-time PCR analysis of runt-related transcription factor 2, osteocalcin, collagen I, and vascular endothelial growth factor expression. Results: Irradiated sockets of groups DM-808 and DM-dual showed a significant increase in bone tissue and blood vessel establishment as compared to DM-660. Further, group DM-dual exhibited the least amount of fibrotic tissue as compared to the other groups. Conclusions: Within our study limits, the present experiment suggested PBM at 808 nm, alone or combined with 660 nm irradiation, could promote alveolar bone healing, along withminimal fibrosis induction, in diabetic rats. [ABSTRACT FROM AUTHOR]

Objectives: To clarify changes in serum cytokines, chemokines, and bone-related factors during denosumab treatment in rheumatoid arthritis (RA) patients. Methods: This was a post hoc analysis of a multicentre, open-label, randomised, parallel-group study. Patients were randomly assigned to continue treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) plus receive treatment with denosumab (csDMARDs plus denosumab group) or to continue treatment with csDMARD therapy alone for 12 months. Serum biomarker levels were measured at baseline and at 6 and 12 months. Results: Baseline and 6-month data from the csDMARDs plus denosumab (n = 22) and csDMARD therapy alone (n = 22) groups were analysed. Statistically significant changes from baseline were seen: Dickkopf-related protein 1 decreased at 6 and 12 months (both groups); osteopontin decreased at 6 months in the csDMARDs plus denosumab group; osteopontin and soluble CD40 ligand increased at 6 and 12 months in the csDMARD therapy alone group; osteocalcin decreased at 6 and 12 months, epidermal growth factor decreased at 12 months, and macrophage-derived chemokine decreased at 6 months in the csDMARDs plus denosumab group; and interferon gamma-induced protein-10 increased at 12 months in the csDMARD therapy alone group. Conclusions: Denosumab may inhibit bone destruction by suppressing bone-related factors/chemokines. [ABSTRACT FROM AUTHOR]

Loss of osteogenic differentiation potential of osteoblasts has been associated with the pathogenesis of osteoporosis. Thus, stimulation of osteoblastic differentiation is a therapeutic strategy for osteoporosis. Relaxin‐2 is a peptide hormone with potent biological functions. However, the effects of Relaxin‐2 in osteoblastic differentiation and osteoporosis have not been reported before. Here, we report a novel physiological role of Relaxin‐2 in promoting osteoblastic differentiation and mineralization of MC3T3‐E1 cells. Our results indicate that exposure to Relaxin‐2 upregulated the expression, and elevated the activity of alkaline phosphatase (ALP) when MC3T3‐E1 cells were cultured in osteogenic differentiation medium (OM). Additionally, Relaxin‐2 upregulated the mRNA levels of osteocalcin (ocn), osteopontin (opn), and collagen type I alpha 1 (Col1a1). The alizarin red S staining assay revealed that Relaxin‐2 promoted the mineralization of MC3T3‐E1 cells. We also found that Relaxin‐2 increased the expression of Runx‐2 as well as the epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR). Importantly, silencing of EGF abolished the effects of Relaxin‐2 in osteoblastic differentiation and related gene expression. These findings suggest that Relaxin‐2 stimulates osteogenic differentiation through activating EGF/EGFR signaling. [ABSTRACT FROM AUTHOR]

Objective: To explore the potential of metanephric mesenchymal cells (MMCs) for osteogenesis and naringin's ability to enhance this process and its molecular mechanism. Methods: Porcine MMCs at 70 days of gestation were used as tool cells, cultured in osteogenic induction medium, identified by immunocytochemistry staining. Osteogenic potential of porcine MMCs and naringin's ability to enhance this process was tested by detecting changes in cell viability, alkaline phosphatase (ALP) activity, the expression of runt-related transcription factor 2 (Runx2), osteopontin (OPN) and osteocalcin (OCN), and the formation of mineralized nodules, and the application of the p38 signaling pathway inhibitor SB203580 vitiated the osteogenesis-promoting effect of naringin. Results: Immunocytochemical staining showed that the cells were Vimentin and Six2(+), E-cadherin and CK-18(−). Naringin can activate the p38 signaling pathway to enhance the osteogenesis of porcine MMCs by increasing cell viability, ALP activity, the expressions of Runx2, OPN and OCN, and the formation of mineralized nodules (P<0.05). The application of p38 signaling pathway inhibitor SB203580 vitiated the osteogenesis-promoting effect of naringin, manifested by decreased ALP activity, the expressions of Runx2, OPN and OCN, and the formation of mineralized nodules (P<0.05). Conclusion: Naringin, the active ingredient of Chinese herbal medicine Rhizoma Drynariae for nourishing Shen (Kidney) and strengthening bone, enhances the osteogenic differentiation of renal MMCs through the p38 signaling pathway. [ABSTRACT FROM AUTHOR]

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Abstract Bone tissue is constantly regenerated and repaired through a finely balanced process known as bone remodeling. Many miRNAs act as regulators of the signaling pathways involved in bone metabolic processes to maintain tissue homeostasis. This study aimed to assess the circulating levels of MIR21, MIR34a, and MIR155 in human serum and their bone expression, and the expression of bone turnover-related genes which can reflect the bone quality. This prospective study was conducted on 60 patients (30 males and 30 females) indicated for surgical interventions for neural decompression +/- fixation. Relative quantification of expression of MIR21, miR34a, and MIR155 and bone related genes was assayed using PCR. The serum levels of osteocalcin and Serum Bone Alkaline Phosphatase (sBAP) were assayed using a human ELISA kit. The main finding of the present work was the strong positive association between the circulating levels of only miR21 and MIR155 and their bone expression in the population under study and with bone markers and target genes Also, a positive association was found between both bone expression and circulating MIR21 levels with age and sBAP. These results suggest that the circulating levels of these microRNAs as early markers for the predication of bone quality.

Abstract This study aims to discover the association between serum osteocalcin, the Chinese visceral adiposity index (CVAI), and atherosclerotic cardiovascular disease (ASCVD) risk, and their impact on arterial stiffness in T2DM patients. We included 639 T2DM patients aged 30 and older who received the assessment of ASCVD risk using the China-PAR equation, Osteocalcin and arterial stiffness in this cross-sectional study. We found that osteocalcin and CVAI as independent risk factors for both medium–high-risk ASCVD (osteocalcin: men, OR,0.96, 95% CI 0.92, 1.00; women, OR, 0.93, 95% CI 0.8, 1.08, respectively)(CVAI: men, OR,1.01,95% CI 1.00,1.02; women: OR, 1.08, 95% CI 1.02,1.14, respectively) and arterial stiffness (osteocalcin: men, OR, 0.98, 95% CI 0.94,1.01; women, OR, 0.98, 95% CI 0.90,1.06, respectively)(CVAI: men, OR,1.0, 95% CI 0.99,1.01; women, OR, 1.02, 95% CI 1.00,1.04, respectively) in both men and women patients with T2DM. Combining osteocalcin levels and CVAI improved the prediction accuracy of arterial stiffness in men patients with T2DM (difference of AUC(Model 4 vs. Model 1):1.5%, NRI: 0.06 [0.0,0.4]). All P-values were

Objective To investigate the effect of the Piezo1 channel on tension-side angiogenesis and osteogenic remodeling during orthodontic tooth movement, so as to provide an experimental basis for accelerating orthodontic periodontal tissue remodeling. Methods This study was approved by the Animal Ethics Committee. Sixty healthy male Sprague-Dawley rats with bilateral maxillary incisors as the anchorage were selected, and nickel titanium tension springs were used to apply 0.5 N of force to the right maxillary first molar of the rats and construct an orthodontic tooth movement model. The rats were randomly divided into three groups (n = 20 per group). On Days 0 and 8 of force application, equal volumes of saline (control group), 100 μmol/L Piezo1 channel agonist (Yoda1 group), and 48 μmol/L Piezo1 channel inhibitor (GsMTx4 group) were injected into the buccal and palatal submucosa of the right maxillary first molar. Tooth movement distances were recorded on Days 1, 3, 7, and 14. Five rats from each group were sacrificed at each time point to obtain maxillary tissue samples. Hematoxylin and eosin (HE) staining was performed to observe the histophysiological changes in the tension-side periodontal tissues. Immunohistochemical staining was used to mark and count CD31-positive cells (microvascular quantification) and to detect the expression of osteocalcin (OCN) in the tension side. Results Measurements of tooth movement distance showed that the Yoda1 group exhibited significantly increased tooth movement distances on Days 3, 7, and 14 (0.238 ± 0.008 mm, 0.406 ± 0.011 mm, and 0.746 ± 0.013 mm, respectively) compared to the control group (PPPPPP

Abstract Objective The prevalence of type 2 diabetes mellitus (T2DM) and bone metabolism disorders increase with age. Diabetic kidney disease (DKD) is one of the most serious microvascular complications of T2DM, and bone metabolism disorders are closely linked to the occurrence of DKD. The relationship between bone turnover markers(BTMs) and the kidney disease in elderly patients with T2DM remains unclear. Therefore, this study aims to investigate the association between common BTMs and DKD in a large sample of elderly patients. The goal is to provide a basis for early identification of high-risk individuals for DKD among elderly T2DM patients from a bone metabolism perspective. Methods In this cross-sectional study, BTMs were collected from a cohort of 2,051 hospitalized Chinese patients. The relationships between 25-hydroxyvitamin D (25-OH-D), β-CrossLaps (β-CTX), osteocalcin (OSTEOC), intact parathyroid hormone (iPTH), and total type I collagen N-terminal propeptide (TP1NP), and DKD, as well as urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were analyzed using regression analysis and restrictive cubic spline (RCS) curves. Results Higher 25-OH-D levels were independently linked to a lower incidence of DKD and decreased UACR. The RCS curves showed a linear association of 25-OH-D and DKD, approaching the L-shape. β-CTX was independently and positively correlated with UACR. There is an independent positive correlation between OSTEOC and UACR and a negative correlation with eGFR. iPTH is independently and positively correlated with DKD incidence and UACR, and negatively correlated with eGFR. Additionally, the RCS curves showed a non-linear association of OSTEOC and iPTH and DKD, approaching the J-shape, and the point of inflection is 10.875 ng/L and 34.15 pg/mL respectively. There is an independent positive correlation between TP1NP and UACR incidence, and a negative correlation with eGFR. Risk estimates significantly increase with higher TP1NP levels in the RCS model. Conclusion BTMs are closely associated with kidney disease in elderly patients with T2DM. These discoveries potentially assist clinicians in establishing more preventive measures and targeted treatment strategies for elderly patients with T2DM.

Lijing Huo,1 Xuexin Liu,2 Changmei Wei,1 Fang Yu,1 Luping Ren,3 Yanqing Tie1 1Department of Medical Laboratory, Hebei General Hospital, Shijiazhuang, Hebei Province, People’s Republic of China; 2Health Check-up Centers, Hebei General Hospital, Shijiazhuang, Hebei Province, People’s Republic of China; 3Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei Province, People’s Republic of ChinaCorrespondence: Lijing Huo, Department of Medical Laboratory, Hebei General Hospital, 348 Heping West Road, Xinhua District, Shijiazhuang, Hebei Province, People’s Republic of China, Email huolijing1979@126.comAim: This study was intended to establish the reference intervals of bone turnover markers (BTMs) for healthy populations.Methods: According to the Clinical Laboratory Standards Institute (CLSI) EP28-A3c, we recruited 774 healthy Chinese and investigated their clinical characteristics and relationships among gender, age, season and BTMs. The reference intervals of BTMs for healthy populations in Hebei of China were established through defining the central 95% range of all observations.Results: We found that gender were associated with 25(OH)D, OC, β-CTX, and P1NP (P < 0.05), but not PTH1-84 (P=0.138). All serum BTMs showed differences among different age groups (P < 0.01). The level of 25 (OH) D in winter showed statistical differences with spring, summer, and autumn (P< 0.05). The OC level showed statistical difference between summer and winter (P=0.000). The P1NP levels showed statistical difference between spring and winter (P=0.019), summer and winter (P=0.000), and summer and autumn (P=0.012), respectively. The PTH1-84 levels in winter showed statistical differences with spring, and summer (all P=0.000), while there was no statistically significant difference in β- CTX levels between seasons.Conclusion: We have established the reference intervals of several BTMs for healthy individuals in Hebei of China, which have statistical significance across different age groups and genders, and there are also significant differences between different seasons. Therefore, the Chinese medical laboratories in different locations should group individuals according to gender and age groups in different seasons, and establish corresponding biological reference intervals.Keywords: 25-hydroxyvitamin D, 25(OH)D, osteocalcin, OC, β-carboxy-terminal cross-linking telopeptide of type I collagen, β-CTX, N-terminal procollagen of type I collagen, P1NP, parathyroid hormone 1-84, PTH1-84

on whether ursolic acid has osteogenic effect on human periodontal ligament stem cells. OBJECTIVE: To investigate the effect of ursolic acid on proliferation and osteogenic differentiation of human periodontal ligament stem cells. METHODS: The human periodontal ligament stem cells were isolated and cultured. Passage 3 cells were selected and treated with ordinary medium containing different concentrations (0, 1, 2, 4, 6, 8 μmol/L) of ursolic acid. After intervention for 1, 3, 5, 7 days, the cell proliferation was detected by CCK-8 assay and the appropriate intervention concentration was screened. Passage 3 human periodontal ligament stem cells were treated with osteogenic induction solution containing 0, 1, 2, 4 μmol/L ursolic acid, respectively. After 7 days of intervention, the mRNA expressions of alkaline phosphatase, Runx2, and osteocalcin were detected by qRT-PCR. After 14 days of intervention, the formation of mineralized nodules was observed by alizarin red staining. Passage 3 human periodontal ligament stem cells were taken and the control group was added with osteogenic induction solution; the ursolic acid group and the antagonist group were added with osteogenic induction solution containing ursolic acid (2 μmol/L) and the bone morphogenetic protein signaling pathway antagonist Noggin, respectively. The ursolic acid+antagonist group was added with osteogenic induction solution containing ursolic acid (2 μmol/L) and Noggin, the inhibitor of bone morphogenetic protein signaling pathway, and cultured for 7 days. qRT-PCR and western blot assay were used to detect the mRNA and protein expressions of bone morphogenetic protein 2, Smad1, osteopontin, and Runx2. RESULTS AND CONCLUSION: (1) 1, 2, 4 μmol/L ursolic acid could promote the proliferation of human periodontal ligament stem cells. 6, 8 μmol/L ursolic acid could inhibit the proliferation of human periodontal ligament stem cells, and 1, 2, 4 μmol/L ursolic acid was selected to intervene in subsequent experiments. (2) Compared with 0 μmol/L, 1, 2, 4 μmol/L ursolic acid could promote the expression of alkaline phosphatase, Runx2, and osteocalcin mRNA and the formation of mineralized nodules (P < 0.05), and the effect of 2 μmol/L ursolic acid was the most significant. (3) Compared with the control group, the mRNA and protein expressions of bone morphogenetic protein 2, Smad1, osteopontin, and Runx2 in the ursolic acid group were increased (P < 0.05), while mRNA and protein expressions of the above indexes were decreased in the antagonist group (P < 0.05). Compared with the ursolic acid group, mRNA and protein expressions of above indexes were decreased in ursolic acid+antagonist group (P < 0.05). (4) The results indicate that ursolic acid promotes osteogenic differentiation of human periodontal ligament stem cells through bone morphogenetic protein signaling pathway. [ABSTRACT FROM AUTHOR]

Background: The burgeoning interest in implant and regenerative dental care has led to a notable upsurge in the utilization of regenerative modalities. The intent of the present investigation was to evaluate the osteogenic ability of two different concentrated platelet groups at various concentrations in the human osteosarcoma MG–63 cell line. Materials and Methods: Blood samples from 21 volunteers with chronic periodontitis were collected which were then centrifuged in accordance with the protocols of Choukroun et al. and Miron et al. to produce leukocyte- and platelet-rich fibrin (L-PRF) and injectable platelet-rich fibrin (I-PRF), respectively. Following MG-63 cell culture, the osteogenic ability of 0, 4%, and 20% concentrations of both L-PRF and I-PRF were determined using the real-time polymerase chain reaction assay. Results: The results showed that 20% I-PRF (1.52 ± 0.24) and 4% L-PRF (1.42 ± 0.37) had the highest amount of bone morphogenetic protein 2 and osteocalcin, respectively. Conclusion: I-PRF appears to promote the initial differentiation of cells.

Objectives: Platelet Rich Fibrin (PRF), obtained by centrifuging the peripheral blood sample of the person is an autogenous material and can be affected by systemic and genetic characteristics of the belonging person. This study was undertaken for evaluating the effect of blood group types and the diverse preparation protocols on growth factors and cytokines contained in the PRF. Methods: In total, 192 blood samples were taken from 64 donors, including 16 individuals from each blood group of 4, and from each individual 3 samples were taken for obtaining PRF, titanium platelet‐rich fibrin (T-PRF), and CGF (concentrated growth factors). The platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), angiogenin (Ang), osteocalcin, and osteonectin contents of the PRF were measured with ELISA set. Results: When the relationship between blood groups was examined, the results indicated that there were no statistically significant differences (p>0.05). On the other hand, growth factor content was evaluated to be higher in T-PRF than PRF and CGF (p

Abstract Background Triple negative breast cancer (TNBC) is a type of breast cancer that is negative for oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, is highly malignant and aggressive, lacks of corresponding targeted therapy, and has a relatively poor prognosis. Therefore, understanding the mechanism of TNBC development and formulating effective treatment strategies for inducing cell death are still urgent tasks in the treatment of TNBC. Research has shown that uncarboxylated osteocalcin can promote the proliferation of prostate cancer, lung adenocarcinoma and TNBC cells, but the mechanism by which GluOC affects TNBC growth and metastasis needs further study. Methods MDA-MB-231 breast cancer cells were used for in vitro cell analysis. Key target molecules or pathways were identified by RNA sequencing, and migration ability was detected by scratch assays, Transwell assays, cell adhesion assays and western blot analysis. Fluorescence staining, colony detection, qRT‒PCR and flow cytometry were used to detect apoptosis, oxidative stress, the cell cycle and the stemness of cancer cells, and a xenotransplantation model in BALB/C nude mice was used for in vivo analysis. Results This study demonstrated that GluOC facilitates the migration of MDA-MB-231 breast cancer cells through the ROCK1/MYPT1/MLC2 signalling pathway and promotes the proliferation of TNBC cells via the ROCK1/JAK2/PIK3CA/AKT signalling pathway. Experiments in nude mice demonstrated that GluOC promoted tumour cell proliferation and metastasis in tumour-bearing mice, which further clarified the molecular mechanism of TNBC growth and invasion. Conclusion Our findings highlight the importance of GluOC in driving TNBC progression and its association with poor patient outcomes. This study clarifies the functional effects of GluOC on TNBC growth, providing insight into the molecular basis of TNBC and potentially providing new ideas for developing targeted therapies to improve patient outcomes.

Background. An increase in mortality due to cardiovascular diseases in patients with diabetes mellitus necessitates the search for effective prevention and treatment strategies. Osteocalcin, a proven marker of bone metabolism playing a key role in the pathogenesis of cardiovascular diseases, is considered one of the potential therapeutic targets. The purpose of the study was to reveal possible relationships between the osteocalcin level and severe cardiovascular diseases in patients with type 2 diabetes (T2DM). Materials and methods. Sixty-three patients with T2DM were examined, 40 (63.49 %) men and 23 (36.51 %) women, average age 58.11 ± 1.25 years. Blood osteocalcin, glycated hemoglobin were evaluated, and body mass index was calculated. Two groups were formed: group 1 (n = 30) with a history of cardiovascular diseases, group 2 (n = 33) without the specified conditions in the past. Later, depending on the amount of osteocalcin, the patients of group 2 were further divided into subgroups 2.1 and 2.2, in order to determine the probability of a difference between them in the parameters of the echocardiographic study, which was performed for all patients of group 2. Statistical processing of the results was carried out using the IBM SPSS Statistics 20 program (IBM Corp., USA). The difference was considered significant at p < 0.05. Results. Group 1 patients with a history of cardiovascular diseases (acute myocardial infarction, acute cerebrovascular accident, stenting of coronary or peripheral arteries on the background of T2DM) had lower values of serum osteocalcin compared to the group 2 without specified complications (1.0 [1.0–2.2] vs. 2.4 [1.0–3.5], p = 0.016). Echocardiography revealed that among patients without clinical signs of cardiovascular diseases, low serum osteocalcin values were associated with the occurrence of diastolic dysfunction in the form of delayed relaxation, left ventricular hypertrophy and atherosclerotic lesions of the aortic walls, which were not observed among participants with type 2 diabetes with higher values of the marker (1.0 ng/ml [1.0–2.3] vs. 3.6 ng/ml [3.2–4.4], p < 0.001). Conclusions. The relationship between the osteocalcin level and cardiovascular diseases in patients with T2DM indicates a high potential for the use of serum osteocalcin, namely its low values, as a marker of severe cardiovascular conditions in the future.

Apart from basic roles such as supporting the body, protecting internal organs, and storing calcium, the skeletal system also performs hormonal functions. In recent years, several reports have been published on proteins secreted by bones and their impact on the homeostasis of the entire body. These proteins include fibroblast growth factor 23, sclerostin, lipocalin 2, and osteocalcin. Osteocalcin, the most abundant non-collagenous protein in bone tissue, is routinely measured as a clinical marker for diagnosing bone metabolism disorders. Its molecule undergoes numerous transformations, with decarboxylation being the critical process. Decarboxylation occurs in the acidic environment typical of bone resorption, facilitating the release of the molecule into the bloodstream and enabling its hormonal action. Decarboxylated osteocalcin promotes insulin secretion and stimulates the proliferation of pancreatic islet β-cells. It also plays a role in reducing the accumulation of visceral fat and decreasing fat storage in the liver. Furthermore, decarboxylated osteocalcin levels are inversely correlated with fasting serum glucose levels, total body fat, visceral fat area, and body mass index. Apart from its role in energy metabolism, osteocalcin affects testosterone production and the synthesis of glucagon-like peptide-1. It is also actively involved in muscle-bone crosstalk and influences cognitive function.

Abstract Background Patients with primary hyperparathyroidism (PHPT) are at risk for severe hypocalcemia (SH) following parathyroidectomy (PTX), but limited data exist on the predictors of SH. We aimed to identify risk factors for early postoperative SH after PTX in patients with PHPT and to evaluate the predictive value of clinical parameters. Methods A retrospective review of patients with PHPT who underwent PTX between January 2010 and December 2022 was performed. A total of 46 patients were included in the study, with 15 (32.6%) experiencing postoperative SH, 19 (41.3%) having calculi in the ureter or kidney, and 37 (80.4%) having osteoporosis. Patients were divided into SH and non-SH groups based on postoperative serum calcium levels. Preoperative biochemical indicators, bone turnover markers, and renal function parameters were analyzed and correlated with postoperative SH. Results Statistically significant (P

Background: Medication-related osteonecrosis of the Jaw (MRONJ) is a rare but severe side effect in patients treated with medications such as Bisphosphonates (BPs). Its pathophysiological mechanism needs to be more precise. Establishing preventive measures and treatment standards is necessary. This study aimed to develop a composite hydrogel scaffold constituted by methacrylated gelatin (GelMA), methacrylated heparin (HepMA) and PRF, and investigate its potential application value in the prevention of MRONJ. Methods: GelMA, HepMA, and PRF were prepared using specific ratios for hydrogel scaffolds. Through mechanical properties and biocompatibility analysis, the release rate of growth factors and the ability to promote bone differentiation in vitro were evaluated. To explore the healing-enhancing effects of hydrogels in vivo, the composite hydrogel scaffold was implanted to the MRONJ rat model. Micro-computed tomography (Micro-CT) and histological examination were conducted to evaluate the bone morphology and tissue regeneration. Results: The Hep/GelMA-PRF hydrogel improved the degradation rate and swelling rate. It was also used to control the release rate of growth factors effectively. In vitro, the Hep/GelMA-PRF hydrogel was biocompatible and capable of reversing the inhibitory effect of zoledronic acid (ZOL) on the osteogenic differentiation of MC3T3-E1s. In vivo, the micro-CT analysis and histological evaluation demonstrated that the Hep/GelMA-PRF group exhibited the best tissue reconstruction. Moreover, compared to the ZOL group, the expression of osteogenesis proteins, including osteocalcin (OCN), type collagen I (Col I), and bone morphogenetic protein-2 (BMP-2) in the Hep/GelMA-PRF group were all significantly upregulated (P < 0.05). Conclusions: The Hep/GelMA-PRF hydrogel scaffold could effectively control the release rate of growth factors, induce osteogenic differentiation, reduce inflammation, and keep a stable microenvironment for tissue repair. It has potential application value in the prevention of MRONJ. [ABSTRACT FROM AUTHOR]

Objective: To analyse the changes of bone metabolic markers in type 2 diabetes patients with osteoporosis, and analyze the risk factors. Methods: Eighty patients with type 2 diabetes and osteoporosis admitted to our hospital from January 2022 to December 2022 were selected as the research objects, and they were divided into osteoporosis group. Eighty patients with type 2 diabetes and non osteoporosis admitted to our hospital in the same period were selected as the non osteoporosis group, and 80 healthy volunteers who came to our hospital for physical examination in the same period were selected as the control group. The expression level of bone metabolic markers in three groups of subjects was compared, and dual energy X-ray absorptiometry was used as the "gold standard" for the diagnosis of osteoporosis. The ROC curve of subjects was established, and the critical value of related bone metabolic markers for the diagnosis of type 2 diabetes with osteoporosis was analyzed. Finally, the disease risk factors were analyzed. Results: There was no significant difference in the levels of alkaline phosphatase (ALP), blood phosphorus (P), and calcium (Ca) among the three groups of subjects (P＞0.05). However, there were differences in the levels of urinary type 1 collagen C-terminal peptide (CTX-1), osteocalcin, and parathyroid hormone (PTH) among the three groups of subjects. There were also differences in the levels of CTX-1, osteocalcin, and parathyroid hormone (PTH) among the three groups of subjects PTH was higher than that of the non osteoporosis group and control group, while osteocalcin was lower than that of the non osteoporosis group and control group (P＜0.05); The critical value of CTX-1 for the diagnosis of type 2 diabetes with osteoporosis was 525.74 μg/mmoL Cr, the sensitivity was 83.35%, the specificity was 67.95%, the critical value of osteocalcin was 14.12ng/L, the sensitivity was 81.27%, the specificity was 79.46%, and the critical value of PTH was 45.75 pmol/L, the sensitivity was 74.84%, the specificity was 81.36%; There was no difference between the osteoporosis group and the non osteoporosis group in terms of gender, duration of diabetes, combined with other basic diseases, peripheral neuropathy, and fasting blood glucose (P＞0.05). There were differences between the osteoporosis group and the non osteoporosis group in terms of age, BMI, peripheral vascular disease, diabetes nephropathy, retinopathy, glycosylated hemoglobin, CTX-1, osteocalcin, and PTH levels (P＜0.05); Age, diabetes nephropathy, retinopathy, glycosylated hemoglobin, CTX-1, osteocalcin, PTH were independent risk factors for type 2 diabetes with osteoporosis (P＜0.05). Conclusion: The levels of CTX-1 and PTH in type 2 diabetes patients with osteoporosis increase and osteocalcin decreases. The three can provide important reference for the clinical diagnosis of type 2 diabetes patients with osteoporosis. Age, diabetes nephropathy, retinopathy, glycosylated hemoglobin, CTX-1, osteocalcin and PTH are independent risk factors for type 2 diabetes patients with osteoporosis. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to compare the effects of three different training method on bone mineral density(BMD),muscle fitness and musculoskeletal regulatory factors in young men.Methods Thirty-nine young men were randomly assigned to HIIT group,RT group,and CT group.Then they performed exercise intervention for a period of 8 weeks.Before and after 8 weeks of intervention,BMD,body composition,muscle strength,maximal oxygen consumption as well as serum musculoskeletal regulators of irisin and osteocalcin were measured.Results The result showed that all three exercise interventions could significantly increase the lean body weight of young men,but only HIIT(P＜0.01)and CT intervention(P＜0.05)could significantly reduce the body fat rate of young men;Three types of exercise interventions can significantly improve the femoral BMD of young men,butonly HIIT(P＜0.05)and RT(P＜0.05)interventionscansignificantlyimprovethelumbar BMDofyoungmen;RT and CTinterventionscansignificantlyimprovethemaximum strengthofbenchpress,hardpull,rowing,squat(P＜0.01)andthe height of reverse vertical jump(P＜0.01),while HIIT intervention can only significantly improve the maximum strength of squat(P＜0.01);Three types of exercise interventions can significantly increase the serum levels of irisin and osteocalcin in young men.Conclusion Three kinds of exercise intervention could improve the muscle mass,BMD of femur and the levels of serum musculoskeletal regulatory factors irisin and osteocalcin in young men,but the effect of CT on lumbar BMD was less than that of HIIT and RT alone,and the effect of RT and CT on muscle strength and the explosive power were greater than that of HIIT alone. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of microgravity-mediated Notch1 signaling on macrophage polarization on bone homeostasis. Methods: The animal model was constructed by tail-limb suspension （HLS） to simulate the microgravity environment. The animals were grouped into Control group, HLS group, HLS+NC group, HLS+si group, HLS+rhNF-κB group. ELISA was used to detect the content of TNF-α and IL-1β in serum of rats. TUNEL staining was used to detect the apoptosis of bone tissue. Immunofluorescence was used to detect the polarization of macrophages in bone tissue. The rat osteoblast CP-R091 microgravity model was constructed by simulating the microgravity environment with a rotating wall bioreactor. The cell experiments were divided into Control group, HLS group, HLS+NC group, HLS+si group, HLS+rhNF-κB group. CCK-8 test was used to detect the proliferation activity of cells in each group, and AO test was used to test the apoptosis rate of cells in each group. PCR was used to detect the expression of osteogenesis- related genes in bone tissues and cells. Western blot was used to detect the expression of Notch1, hair division-related enhancer-1 （HES-1）, and Notch pathway ligand 1 （Jagged1） in bone tissues and cells of each group. Results: Compared with control group, the contents of TNF-α and IL-1β in the serum of the rats in the HLS group, the apoptosis rate, and the proportion of M1 macrophages were significantly increased. Compared with HLS group, the HLS+si group could obviously partially reverse the change trend of the above parameters, while HLS+rhNF-κB group significantly changed the above parameter values. Compared with control group, the proliferation activity of the cells in the HLS group was significantly reduced, and the apoptosis rate was significantly increased. Compared with HLS group, the HLS+si group could obviously partially reverse the change trend of the above parameters, while the HLS+ rhNF-κB group made the above parameter values worse. The expressions of the osteogenesis-related genes collagen type Ⅰ（COL1）, osteocalcin （OCN） and Runt-related transcription factor 2 （RUNX2） in bone tissues and cells in the microgravity environment were significantly decreased, while the expressions of Notch-1, Hes-1 and Jagged1 were significantly increased, and the differences were statistically significant （all P<0.05）. Conclusion: Microgravity-mediated Notch1 signaling regulates M1/M2 polarization of macrophages, participates in cell proliferation and apoptosis in bone tissue, and affects the progress of bone homeostasis. [ABSTRACT FROM AUTHOR]

Despite their diverse physiologies and roles, the heart, skeletal muscles, and smooth muscles all derive from a common embryonic source as bones. Moreover, bone tissue, skeletal and smooth muscles, and the heart share conserved signaling pathways. The maintenance of skeletal health is precisely regulated by osteocytes, osteoblasts, and osteoclasts through coordinated secretion of bone‐derived factors known as osteokines. Increasing evidence suggests the involvement of osteokines in regulating atherosclerotic vascular disease. Therefore, this review aims to examine the evidence for the role of osteokines in atherosclerosis development and progression comprehensively. Specifically discussed are extensively studied osteokines in atherosclerosis such as osteocalcin, osteopontin, osteoprotegerin, and fibroblast growth factor 23. Additionally, we highlighted the effects of exercise on modulating these key regulators derived from bone tissue metabolism. We believe that gaining an enhanced understanding of how osteocalcin contributes to the process of atherosclerosis will enable us to develop targeted and comprehensive therapeutic strategies against diseases associated with its progression. Significance Statement: Bone is now recognized as an endocrine organ, with numerous studies demonstrating its direct effects on blood vessels and cells, as well as indirect impacts on the process of atherosclerosis. We believe that osteokines hold significant research potential in this area, and understanding their role in atherosclerosis and uncovering underlying mechanisms could lead to new therapeutic targets and improved treatment outcomes. In this review, we summarize four well‐established mechanisms through which osteokines contribute to atherosclerosis, providing valuable insights for future researchers. [ABSTRACT FROM AUTHOR]

Enhancement of orthodontic tooth movement (OTM) through local administration of biofunctional molecules has become increasingly significant, particularly for adult patients seeking esthetic and functional improvements. This comprehensive systematic review analyzes the efficacy of various biofunctional molecules in modulating OTM, focusing on the method of administration and its feasibility, especially considering the potential for topical application. A search across multiple databases yielded 36 original articles of experimental human and animal OTM models, which examined biofunctional molecules capable of interfering with the biochemical reactions that cause tooth movement during orthodontic therapy, accelerating the OTM rate through their influence on bone metabolism (Calcitriol, Prostaglandins, Recombinant human Relaxin, RANKL and RANKL expression plasmid, growth factors, PTH, osteocalcin, vitamin C and E, biocompatible reduced graphene oxide, exogenous thyroxine, sclerostin protein, a specific EP4 agonist (ONO-AE1-329), carrageenan, and herbal extracts). The results indicated a variable efficacy in accelerating OTM, with Calcitriol, Prostaglandins (PGE1 and PGE2), RANKL, growth factors, and PTH, among others, showing promising outcomes. PGE1, PGE2, and Calcitriol experiments had statistically significant outcomes in both human and animal studies and, while other molecules underwent only animal testing, they could be validated in the future for human use. Notably, only one of the animal studies explored topical administration, which also suggests a future research direction. This review concluded that while certain biofunctional molecules demonstrated potential for OTM enhancement, the evidence is not definitive. The development of suitable topical formulations for human use could offer a patient-friendly alternative to injections, emphasizing comfort and cost-effectiveness. Future research should focus on overcoming current methodological limitations and advancing translational research to confirm these biomolecules' efficacy and safety in clinical orthodontic practice. [ABSTRACT FROM AUTHOR]

The aim of the present review is to discuss the roles of vitamin K (phylloquinone or menaquinones) and vitamin K-dependent proteins, and the combined action of the vitamins K and D, for the maintenance of bone health. The most relevant vitamin K-dependent proteins in this respect are osteocalcin and matrix Gla-protein (MGP). When carboxylated, these proteins appear to have the ability to chelate and import calcium from the blood to the bone, thereby reducing the risk of osteoporosis. Carboxylated osteocalcin appears to contribute directly to bone quality and strength. An adequate vitamin K status is required for the carboxylation of MGP and osteocalcin. In addition, vitamin K acts on bone metabolism by other mechanisms, such as menaquinone 4 acting as a ligand for the nuclear steroid and xenobiotic receptor (SXR). In this narrative review, we examine the evidence for increased bone mineralization through the dietary adequacy of vitamin K. Summarizing the evidence for a synergistic effect of vitamin K and vitamin D3, we find that an adequate supply of vitamin K, on top of an optimal vitamin D status, seems to add to the benefit of maintaining bone health. More research related to synergism and the possible mechanisms of vitamins D3 and K interaction in bone health is needed. [ABSTRACT FROM AUTHOR]