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Abstract: Fibroblast growth factor 23 (FGF23) is a new endocrine product discovered in the past decade. In addition to being related to bone diseases, it has also been found to be related to kidney metabolism and parathyroid metabolism, especially as a biomarker and a key factor to be used in kidney diseases. FGF23 is upregulated as early as the second and third stages of chronic kidney disease (CKD) in response to relative phosphorus overload. The early rise of FGF23 has a protective effect on the body and is essential for maintaining phosphate balance. However, with the decline in renal function, eGFR (estimated glomerular filtration rate) declines, and the phosphorus excretion effect caused by FGF23 is weakened. It eventually leads to a variety of complications, such as bone disease (Chronic Kidney Disease-Mineral and Bone Metabolism Disorder), vascular calcification (VC), and more. Monoclonal antibodies against FGF23 are currently used to treat genetic diseases with increased FGF23. CKD is also a state of increased FGF23. This article reviews the current role of FGF23 in CKD and discusses the crosstalk between various organs under CKD conditions and FGF23. Studying the effect of hyperphosphatemia on different organs of CKD is important. The prospect of FGF23 for therapy is also discussed.

Bone marrow contains resident cellular components that are not only involved in bone maintenance but also regulate hematopoiesis and immune responses. The immune system and bone interact with each other, coined osteoimmunology. Hashimoto's thyroiditis (HT) is one of the most common chronic autoimmune diseases which is accompanied by lymphocytic infiltration. It shows elevating thyroid autoantibody levels at an early stage and progresses to thyroid dysfunction ultimately. Different effects exert on bone metabolism during different phases of HT. In this review, we summarized the mechanisms of the long-term effects of HT on bone and the relationship between thyroid autoimmunity and osteoimmunology. For patients with HT, the bone is affected not only by thyroid function and the value of TSH, but also by the setting of the autoimmune background. The autoimmune background implies a breakdown of the mechanisms that control self-reactive system, featuring abnormal immune activation and presence of autoantibodies. The etiology of thyroid autoimmunity and osteoimmunology is complex and involves a number of immune cells, cytokines and chemokines, which regulate the pathogenesis of HT and osteoporosis at the same time, and have potential to affect each other. In addition, vitamin D works as a potent immunomodulator to influence both thyroid immunity and osteoimmunology. We conclude that HT affects bone metabolism at least through endocrine and immune pathways.

Aim: It is well known that alcohol can cause bone loss and that bone mineral density has an inverse relationship with bone marrow adipocyte (BMA). However, little is known about the mechanisms that link alcohol and bone loss, and existing studies lack data on BMA in alcohol-induced bone loss. Here, wild-type (WT) and tumor necrosis factor-alpha knockout (TNF-α KO) mice were used to examine the effects of alcohol on bone metabolism. Methods: The effects of alcohol on bone metabolism were demonstrated in vivo by feeding WT and TNF-α KO mice with alcohol. The osteogenesis and adipogenesis of primary bone marrow stromal cells (BMSCs) derived from WT and TNF-α KO mice under alcohol intervention were compared in vitro. Tissue staining, cell staining, micro-CT, and quantitative RT-PCR were used to explore the potential mechanism. Results: Alcohol induced trabecular bone loss, increased BMA, and promoted the mRNA expression of Adipoq, Fabp4, visfatin， Pparg, TNF-α, IL-1β, and IL-6 in BMA in WT mice, but not in TNF-α KO mice. In addition, alcohol promoted BMSC adipogenesis and inhibited BMSC osteogenesis, while TNF-α knockout could restrain this situation. Conclusion: Our study demonstrated that alcohol may reduce bone mass by disrupting the balance of osteogenesis and adipogenesis in bone marrow, and TNF-α plays an important role in this process.

Small cell lung cancer (SCLC) is a rapidly progressing, incurable cancer that frequently spreads to bone. New insights are needed to identify therapeutic targets to prevent or retard SCLC metastatic progression. Human SCLC SBC-5 cells in mouse xenograft models home to skeletal and nonskeletal sites, whereas human SCLC SBC-3 cells only pervade nonskeletal sites. Because microRNAs (miRNA) often act as tumor regulators, we investigated their role in preclinical models of SCLC. miRNA expression profiling revealed selective and reduced expression of miRNA (miR)-335 and miR-29a in SBC-5 cells, compared with SBC-3 cells. In SBC-5 cells, miR-335 expression correlated with bone osteolytic lesions, whereas miR-29a expression did not. Overexpression of miR-335 in SBC-5 cells significantly reduced cell migration, invasion, proliferation, colony formation, and osteoclast induction in vitro. Importantly, in miR-335 overexpressing SBC-5 cell xenografts (n = 10), there were minimal osteolytic lesions in the majority of mice and none in three mice. Expression of RANK ligand (RANKL) and insulin-like growth factor-I receptor (IGF-IR), key mediators of bone metastases, were elevated in SBC-5 as compared with SBC-3 cells. Mechanistically, overexpression of miR-335 in SBC-5 cells reduced RANKL and IGF-IR expression. In conclusion, loss of miR-335 promoted SCLC metastatic skeletal lesions via deregulation of IGF-IR and RANKL pathways and was associated with metastatic osteolytic skeletal lesions.Implications: These preclinical findings establish a need to pursue the role of miR-335 in human SCLC with metastatic skeletal disease. Mol Cancer Res; 12(1); 101–10. ©2013 AACR.

PDF file, 131K, Down-regulation of miRNAs in SBC-5 cells.

Bone marrow (BM) is a heterogeneous niche where bone marrow stromal cells (BMSCs), osteoblasts, osteoclasts, adipocytes, hematopoietic cells, and immune cells coexist. The cellular composition of BM changes with various pathophysiological states. A reduction in osteoblast number and a concomitant increase in adipocyte number in aging and pathological conditions put bone marrow adipose tissue (BMAT) into spotlight. Accumulating evidence strongly supports that an overwhelming production of BMAT is a major contributor to bone loss disorders. Therefore, BMAT-targeted therapy can be an efficient and feasible intervention for osteoporosis. However, compared to blocking bone-destroying molecules produced by BMAT, suppressing BMAT formation is theoretically a more effective and fundamental approach in treating osteoporotic bone diseases. Thus, a deep insight into the molecular basis underlying increased BM adiposity during pathologic bone loss is critical to formulate strategies for therapeutically manipulating BMAT. In this review, we comprehensively summarize the molecular mechanisms involved in adipocyte differentiation of BMSCs as well as the interaction between bone marrow adipocytes and osteoclasts. More importantly, we further discuss the potential clinical implications of therapeutically targeting the upstream of BMAT formation in bone loss diseases.

BACKGROUND Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant genetic disease characterized by severe autoimmune inflammation, caused by mutations in the PSTPIP1 gene. Due to PAPA heterogeneous clinical manifestation, misdiagnosis or delayed diagnoses are difficult to avoid. With the use of whole-exome sequencing, we identified a missense mutation in the PSTPIP1 gene in a Chinese family. To the best of our knowledge, this is the first case of PAPA reported in China. CASE SUMMARY A 9-year-old boy suffered from recurrent aseptic pyogenic arthritis triggered by minor trauma or few obvious predisposing causes for more than 3 years. Pyogenic arthritis occurred every 3-5 mo, affecting his knees, elbows, and ankle joints. Treatments, such as glucocorticoids, antibiotics, even surgeries could alleviate joints pain and swelling to some extent but could not inhibit the recurrence of arthritis. Similar symptoms were present in his younger brother but not in his parents. According to the whole-exome sequencing, a missense mutation in exon 11 of the PSTPIP1 gene (c.748G>C; p.E250Q) was detected in the boy, his younger brother and his father. Taking into account the similar phenotypic features with PAPA syndrome reported previously, we confirmed a diagnosis of PAPA syndrome for the family. CONCLUSION In this case, a missense mutation (c.748G>C; p.E250Q) in PSTPIP1 gene was identified in a Chinese family with PAPA syndrome. Previous studies emphasize the fact that PAPA syndrome is hard to diagnose just through the clinical manifestations owing to its heterogeneous expression. Genetic testing is an effectual auxiliary diagnostic method, especially in the early stages of pyogenic arthritis. Only if we have a deep understanding and rich experience of this rare disease can we make a prompt diagnosis, develop the best clinical treatment plan, and give good fertility guidance.

The interaction between tumor cells and immune system in hepatocellular carcinoma (HCC) remains unclear. Great clinical achievements have progressed in HCC patients treated with immune checkpoint inhibitors (ICIs) for programmed death-1 and its ligands. However, response efficacy for these therapies is limited, thereby requiring alternative ICI candidates for HCC treatment. B7 homolog 3 protein (B7-H3), an immunoregulatory protein, plays a significant role in tumor immunity and disease progression. In this study, we evaluated the correlation between B7-H3 expression and prognosis of HCC patients, and investigated the therapeutic potential of B7-H3 targeting in HCC.B7-H3 expression was analyzed immunohistochemically in HCC patients, and its relationship with tumor-infiltrating lymphocyte infiltration was assessed. The anti-tumor efficacy of anti-B7-H3 antibody therapy was determined using an in vitro co-culture system and a subcutaneous HCC-bearing murine model.We found that B7-H3 overexpressed in tumor cells and positively correlated with poor prognosis in HCC patients. B7-H3 inhibited the infiltration of CD8Altogether, our findings suggest that B7-H3 inhibition in tumor cells restores the immune cytotoxicity of T cells, which in turn promotes apoptosis of target cells. Therefore, B7-H3 serves as a key negative regulator in tumor immunity and the promising clinical utility of B7-H3-based immunotherapies for HCC treatment could be developed.

As the main cells in endochondral osteogenesis, chondrocytes have limited self-repair ability due to weak proliferation activity, low density, and dedifferentiation tendency. Here, a thorough inquiry about the effect and underlying mechanisms of methyltransferase like-3 (Mettl3) on chondrocytes was made. Functionally, it was indicated that Mettl3 promoted the proliferation and hypertrophic differentiation of chondrocytes. Mechanically, Dmp1 (dentin matrix protein 1) was proved to be the downstream direct target of Mettl3 for m

Background: Epidemiologic studies have shown that persons suffering from psychotic disorders are at increased risk of violent behavior. Several factors have been shown to predict violent behavior among persons with psychosis. However, prior research is limited in that these factors have not been explored simultaneously within the same study. Methods: The current study, therefore, aimed to determine which demographic, clinical, cognitive, and developmental characteristics were associated with an increased likelihood of violence among patients diagnosed with a psychotic disorder and which combination of these best predicted a history of violence. Participants (n=53) completed measures of demographics, violence risk, psychotic and personality symptoms, trauma, psychopathy and cognitive functioning. Results: Bivariate relationships were conducted to compare the history of violent behavior between all variables. Additionally, a binary logistic regression was run predicting participants’ history of violence. Several demographic, cognitive, clinical, and developmental factors were associated with increased odds of having a history of violence. The overall correct classification rate for the model was 92.2%, with 87.5% of participants without a history of violence and 91.4% with a history of violence being correctly classified. The model included antisocial personality traits, poor behavioral controls, head injury, not accepting responsibility, lacking goals, prior supervision failures, and HCR-20 total score. Conclusion: The binary logistic regression model showed good accuracy in predicting a history of violence in persons with psychosis. These findings are consistent with prior research and can inform efforts at risk assessment and identification of treatment targets for people with a psychotic disorder who are at highest risk of violence.

Statement of problem The internal connection is a widely used implant-abutment connection. However, a meta-analysis comparing the internal tapered and nontapered connection systems is lacking. Purpose The purpose of this systematic review and meta-analysis was to assess whether the internal tapered connection performs better than the internal nontapered connection in terms of implant survival, marginal bone loss, probing depths, and complications. Material and methods The following specific question was formulated based on the Population, Intervention, Control, and Outcome (PICO) model: Do patients receiving internal tapered connection implants show better prognosis than those receiving the internal nontapered connection in terms of implant survival, marginal bone loss, probing depths, and complications? An electronic systematic literature search was conducted in the Cochrane Library databases, MEDLINE (PubMed), and Embase for relevant studies published in English without time restrictions. A manual search was also conducted. In vivo randomized controlled trials (RCTs) and prospective cohort studies were included. Results A total of 592 studies were collected from the electronic and manual searches. After independent screening by 2 reviewers, 5 RCTs and 2 prospective cohort studies were included. No significant difference was observed in implant survival rates (P=.47; RR: 1.01; 95% CI: 0.98, 1.05). Regarding marginal bone loss, the internal tapered connection presented better results than the nontapered connection (P=.003; MD: −0.43 mm; 95% CI: −0.73, −0.14). The internal tapered connection also exhibited lower probing depths than the nontapered one (P=.002; MD: −0.24 mm; 95% CI: −0.39, −0.09). No significant difference was observed in complication rates (P=.47; RR: 1.21; 95% CI: 0.72, 2.04). Conclusions Within the limitations of this systematic review and meta-analysis, the internal tapered connection and nontapered connection were comparable in terms of implant survival rates and complication rates. In contrast to the internal nontapered connection, marginal bone loss and probing depths in the tapered connection were significantly lower.

Endoplasmic reticulum (ER) stress is an evolutionarily conserved cellular stress response related to multiple diseases, including temporomandibular joint (TMJ) cartilage-related diseases. Recent studies have indicated that DDIT3/CHOP (a downstream transcription factor of ER stress) is an important effector in mediating ER stress to inhibit chondrogenesis. However, the underlying mechanism by which DDIT3 regulates chondrogenesis remains unclear. In this study, tunicamycin (an ER stress agonist)-induced ER stress inhibited chondrocyte differentiation and matrix synthesis in vitro and led to an osteoarthritis-like phenotype in mouse TMJ cartilage. Meanwhile, DDIT3 expression in chondrocytes was robustly upregulated. Loss-of-function experiments validated the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Mechanistically, the inhibiting effect was attributed to the direct and indirect regulatory effect of DDIT3 on SIRT1 (sirtuin1, silent mating type information regulation protein type 1, a member of NAD+ dependent class III histone deacetylases). On one hand, DDIT3 directly promoted the transcription of SIRT1. On the other hand, DDIT3 indirectly increased the expression of SIRT1 by promoting AMPKα phosphorylation and activation. Furthermore, activation of AMPKα or SIRT1 with the corresponding agonist AICAR or resveratrol in the DDIT3-knockdown cells partially restored the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Collectively, these novel findings indicate that DDIT3 regulates the inhibitory effect of ER stress on chondrocyte differentiation and matrix synthesis partially via the AMPKα-SIRT1 pathway. A thorough understanding of ER stress in regulating chondrocyte homeostasis and its role in the onset of osteoarthritis may be promising to develop therapeutic targets and prevent condyle cartilage destruction.

Bone metastasis is the result of complex crosstalk between tumor cells and bone marrow cells. Bone marrow adipocytes (BMAs) are the most abundant cell type in adult bone marrow. Therefore, we explore the effects of BMAs on bone metastasis in lung cancer. RNA-seq was used to compare the mRNA expression level of bone metastatic SBC5 cells and non-bone metastatic SBC3 cells. Rosiglitazone-induced marrow adiposity and intra-femoral injection of SBC5 cells were used to demonstrate the relationship between BMAs and SBC5 cells in vivo. Co-culture system, gene co-expression, gene ontology (GO) enrichment analysis and protein–protein interaction (PPI) network were used to explore the potential mechanism. BMAs specially enhance the invasion of bone metastatic SBC5 instead of non-bone metastatic SBC3 in vitro. SBC5 instead of SBC3 promoted osteoblast and osteoclast differentiation as well as de-differentiation of mature BMAs. Rosiglitazone-induced marrow adiposity significantly enhanced osteolytic lesion induced by SBC5 in vivo. RNA-seq revealed that compared with SBC3, S100A9 and S100A8 genes were the most prominent genes up-regulated in SBC5 cells. High expression of S100A8/9 in SBC5 could be responsible for the crosstalk between lung cancer cells and BMAs. More importantly, interleukin 6 receptor (IL6R), which is adjacent to S100A8/A9 in 1q21.3, was significantly up-regulated by BMAs in vitro. S100A8/A9 (1 μg/ml) could obviously enhance the osteoblastic differentiation and inhibit adipogenic differentiation, whereas TLR4 inhibitor TAK242 (10 μmol/l) significantly attenuated this effect. Our study suggested that bone marrow adipocyte may communicate with lung cancer cells via 1q21.3 (S100A8/A9-IL6R)-TLR4 pathway to promote osteolytic bone destruction. 1q21.3 (S100A8/A9-IL6R) is a potential target for the treatment of lung cancer bone metastasis.

Background:Intercellular crosstalk among osteoblast, osteoclast, osteocyte and chondrocyte is involved in the precise control of bone homeostasis. Disruption of this cellular and molecular signaling would lead to metabolic bone diseases such as osteoporosis. Currently a number of anti-osteoporosis interventions are restricted by side effects, complications and long-term intolerance. This review aims to summarize the bone cellular communication involved in bone remodeling and its usage to develop new drugs for osteoporosis.Methods:We searched PubMed for publications from 1 January 1980 to 1 January 2018 to identify relevant and latest literatures, evaluation and prospect of osteoporosis medication were summarized. Detailed search terms were ‘osteoporosis’, ‘osteocyte’, ‘osteoblast’, ‘osteoclast’, ‘bone remodeling’, ‘chondrocyte’, ‘osteoporosis treatment’, ‘osteoporosis therapy’, ‘bisphosphonates’, ‘denosumab’, ‘Selective Estrogen Receptor Modulator (SERM)’, ‘PTH’, ‘romosozumab’, ‘dkk-1 antagonist’, ‘strontium ranelate’.Results:A total of 170 papers were included in the review. About 80 papers described bone cell interactions involved in bone remodeling. The remaining papers were focused on the novel advanced and new horizons in osteoporosis therapies.Conclusion:There exists a complex signal network among bone cells involved in bone remodeling. The disorder of cell-cell communications may be the underlying mechanism of osteoporosis. Current anti-osteoporosis therapies are effective but accompanied by certain drawbacks simultaneously. Restoring the abnormal signal network and individualized therapy are critical for ideal drug development.

Fibulin-3 is an extracellular matrix glycoprotein that is present in elastic tissue and involved in carcinoma development. Previous studies have indicated that fibulin-3 may affect skeletal development, cartilage, and osteoarthritis (OA). This study aims to investigate the function of fibulin-3 on chondrocytes under tumor necrosis factor alpha (TNF-α) stimulation and in murine OA models, and explore the possible mechanism. It was found that fibulin-3 was increased in the cartilage of OA models and in the chondrogenic cells ATDC5 stimulated by TNF-α. Fibulin-3 promoted the proliferation of ATDC5 cells both in the presence and absence of TNF-α. Moreover, overexpression of fibulin-3 suppressed the chondrogenic and hypertrophic differentiation of ATDC5 cells, while knockdown of fibulin-3 caused the opposite effect. Mechanistically, fibulin-3 partially suppressed the activation of TGF-β/Smad3 signaling by inhibiting the phosphorylation of Smad3. SIS3, a Smad3 inhibitor, decreased the chondrogenesis of articular cartilages in OA models, and partially reversed the chondrogenic differentiation of ATDC5 cells caused by knockdown of fibulin-3 in the presence of TNF-α. Furthermore, co-immunoprecipitation (Co-IP) showed that fibulin-3 could only interact with TGF-β type I receptor (TβRI), although overexpression of fibulin-3 reduced the protein levels of both TβRI and TβRII. In conclusion, this study indicates that fibulin-3 modulates the chondrogenic differentiation of ATDC5 cells in inflammation partially via TGF-β/Smad3 signaling pathway.

IntroductionPostmenopausal osteoporosis, caused by ageing and oestrogen deficiency, seriously threatens women’s physical and mental health. Postmenopausal osteopenia is the transition from healthy bone to osteoporosis, and it may be the key period for preventing bone loss. Moxibustion, a physical therapy of Traditional Chinese Medicine, has potential benefits for osteoporosis treatment and prevention, but it has not been adequately studied. This study aims to explore the clinical effects and safety of moxibustion in delaying bone loss in postmenopausal women.Methods and analysisIn this parallel-design, randomised, patient-blind and assessor-blind, controlled clinical study, 150 women with osteopenia at low fracture risk will be randomly assigned to a moxibustion treatment (MT) group or a placebo-moxibustion control (PMC) group in a 1:1 ratio. In addition to the fundamental measures (vitamin D3 and calcium) as recommended by the guidelines, participants of the two groups will receive MT or PMC treatment for 42 sessions over 12 months. The primary outcome will be the bone mineral density (BMD) of the lumbar spine at the end of the 12-month treatment, and secondary outcomes will be the BMD of the femoral neck and total hip, T-scores, bone turnover markers, serum calcium levels, serum magnesium levels, serum phosphorus levels, serum parathyroid hormone levels and 25-hydroxyvitamin D levels, intensity of bone pain, quality of life, incidence of osteoporosis and fractures, usage of emergency drugs or surgery, participant self-evaluation of therapeutic effects and the rate of adverse events. All statistical analyses will be performed based on the intention-to-treat and per-protocol principle.Ethics and disseminationEthics approval has been obtained from the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University (permission number: 2021-1243). The results are expected to be published in peer-reviewed journals.Trial registration numberChiCTR2100053953.

Osteoporosis is the most common metabolic skeletal disease. It is characterized by the deterioration of the skeletal microarchitecture and bone loss, leading to ostealgia, and even bone fractures. Accumulating evidence has indicated that there is an inextricable relationship between the gut microbiota (GM) and bone homeostasis involving host-microbiota crosstalk. Any perturbation of the GM can play an initiating and reinforcing role in disrupting the bone remodeling balance during the development of osteoporosis. Although the GM is known to influence bone metabolism, the mechanisms associated with these effects remain unclear. Herein, we review the current knowledge of how the GM affects bone metabolism in health and disease, summarize the correlation between pathogen-associated molecular patterns of GM structural components and bone metabolism, and discuss the potential mechanisms underlying how GM metabolites regulate bone turnover. Deciphering the complicated relationship between the GM and bone health will provide new insights into the prevention and treatment of osteoporosis.

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To review the pathological effects of cellular senescence in the occurrence and development of osteoarthritis (OA) and potential therapeutic targets.The role of chondrocyte senescence, synovial cell senescence, mesenchymal stem cells senescence in OA, and the biological mechanism and progress of chondrocyte senescence were summarized by consulting relevant domestic and abroad literature.The existing evidence has basically made clear that chondrocyte senescence, mesenchymal stem cells senescence, and cartilage repair abnormalities, and the occurrence and development of OA have a certain causal relationship, and the role of the senescence of synovial cells, especially synovial macrophages in OA is still unclear. Transcription factors and epigenetics are the main mechanisms that regulate the upstream pathways of cellular senescence. Signal communication between cells can promote the appearance of senescent phenotypes in healthy cells. Targeted elimination of senescent cells and promotion of mesenchymal stem cells rejuvenation can effectively delay the progress of OA.Cellular senescence is an important biological phenomenon and potential therapeutic target in the occurrence and development of OA. In-depth study of its biological mechanism is helpful to the early prevention and treatment of OA.综述细胞衰老在骨关节炎（osteoarthritis，OA）发生、发展中的病理作用及潜在治疗靶点。.查阅国内外相关文献，对软骨细胞衰老、滑膜细胞衰老、MSCs 衰老在 OA 中的作用及软骨细胞衰老发生的生物学机制和进展进行总结。.现有证据已基本明确软骨细胞衰老、MSCs 衰老与软骨修复异常及 OA 的发生、发展存在一定因果关系，而滑膜细胞衰老，特别是滑膜巨噬细胞衰老在 OA 中的作用尚不明确。转录因子、表观遗传是调控衰老上游通路的主要机制，细胞间的信号交流可促进健康细胞出现衰老表型。定向清除衰老细胞和促进 MSCs 年轻化可有效延缓 OA 的进展。.细胞衰老是 OA 发生、发展中的重要生物学现象及潜在治疗靶点，深入研究其生物学机制有助于 OA 的早期防治。.

Glucocorticoids are widely used to treat varieties of allergic and autoimmune diseases, however, long-term application results in glucocorticoid-induced osteoporosis (GIOP). Inflammatory cytokines: tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) play important regulatory roles in bone metabolism, but their roles in GIOP remain largely unknown. Osteocytes can modulate the formation and function of both osteoblasts and osteoclasts, directly via gap junctions, or indirectly by transferring molecule signaling. Apoptotic osteocytes release RANKL, HMGB1 and pro-inflammatory cytokines to stimulate osteoclastogenesis. Moreover, osteocytes can secrete FGF23 to regulate bone metabolism. Exposure to high levels of GCs can drive osteocyte apoptosis and influence gap junctions, leading to bone loss. GCs treatment is regarded to produce more FGF23 to inhibit bone mineralization. GCs also disrupt the vascular to decrease osteocyte feasibility and mineral appositional rate, resulting in a decline in bone strength. Apoptotic bodies from osteocytes induced by GCs treatment can enhance production of TNF-α and IL-6. On the other hand, TNF-α and IL-6 show synergistic effects by altering osteocytes signaling towards osteoclasts and osteoblasts. In addition, TNF-α can induce osteocyte apoptosis and attribute to a worsened bone quality in GCs. IL-6 and osteocytes may interact with each other. Therefore, we hypothesize that GCs regulate osteocyteogenesis through TNF-α and IL-6, which are highly expressed around osteocyte undergoing apoptosis. In the present review, we summarized the roles of osteocytes in regulating osteoblasts and osteoclasts. Furthermore, the mechanism of GCs altered relationship between osteocytes and osteoblasts/osteoclasts. In addition, we discussed the roles of TNF-α and IL-6 in GIOP by modulating osteocytes. Lastly, we discussed the possibility of using pro-inflammatory signaling pathway as therapeutic targets to develop drugs for GIOP.

The complex crosstalk between the immune and the skeletal systems plays an indispensable role in the maintenance of skeletal homeostasis. Various cytokines are involved, including interleukin (IL)-17A. A variety of immune and inflammatory cells produces IL-17A, especially Th17 cells, a subtype of CD4+ T cells. IL-17A orchestrates diverse inflammatory and immune processes. IL-17A induces direct and indirect effects on osteoclasts. The dual role of IL-17A on osteoclasts partly depends on its concentrations and interactions with other factors. Interestingly, IL-17A exerts a dual role in osteoblasts in vitro. IL-17A is a bone-destroying cytokine in numerous immune-mediated bone diseases including postmenopausal osteoporosis (PMOP), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondylarthritis (axSpA). This review will summarize and discuss the pathophysiological roles of IL-17A on the skeletal system and its potential strategies for application in immune-mediated bone diseases.

N6-methyladenosine (m6A) methylation is one of the most common internal modifications in eukaryotic messenger RNA occurring on N6 nitrogen of adenosine. However, the roles of m6A in temporomandibular joint osteoarthritis (TMJ OA) are still elusive. Here, we investigate the function and mechanism of methyltransferase-like 3 (Mettl3) in chondrocytes in inflammation. We found that the expression of Mettl3 decreased both in vivo TMJ OA mice and in vitro inflammatory stimulation. Functionally, loss and gain studies illustrated that Mettl3 inhibited the apoptosis and autophagy of chondrocytes induced by TNF-α stimulation in vitro. Mettl3 inhibitor, S-adenosylhomocysteine (SAH) promoted the apoptosis and autophagy of chondrocytes with inflammation in vitro and aggravated the degeneration of chondrocytes and subchondral bone in monosodium iodoacetate (MIA) induced TMJ OA mice in vivo. Mechanistically, the bioinformatics analysis, m6A-RNA immunoprecipitation (MeRIP) and RNA immunoprecipitation (RIP) were used to identify that Bcl2 mRNA was the downstream target of Mettl3 for m6A modification. Furthermore, the results revealed that Yth m6A RNA binding protein 1 (Ythdf1) mediated the stability of Bcl2 mRNA catalyzed by Mettl3. Co-immunoprecipitation (Co-IP) showed that Bcl2 protein interacted with Beclin1 protein in chondrocytes induced by TNF-α stimulation. In conclusion, our findings identify that Mettl3 inhibits the apoptosis and autophagy of chondrocytes in inflammation through m6A/Ythdf1/Bcl2 signal axis which provides promising therapeutic strategy for TMJ OA.

Postmenopausal osteoporosis (PMOP) is a prevalent skeletal disorder associated with menopause-related estrogen withdrawal. PMOP is characterized by low bone mass, deterioration of the skeletal microarchitecture, and subsequent increased susceptibility to fragility fractures, thus contributing to disability and mortality. Accumulating evidence indicates that abnormal expansion of marrow adipose tissue (MAT) plays a crucial role in the onset and progression of PMOP, in part because both bone marrow adipocytes and osteoblasts share a common ancestor lineage. The cohabitation of MAT adipocytes, mesenchymal stromal cells, hematopoietic cells, osteoblasts and osteoclasts in the bone marrow creates a microenvironment that permits adipocytes to act directly on other cell types in the marrow. Furthermore, MAT, which is recognized as an endocrine organ, regulates bone remodeling through the secretion of adipokines and cytokines. Although an enhanced MAT volume is linked to low bone mass and fractures in PMOP, the detailed interactions between MAT and bone metabolism remain largely unknown. In this review, we examine the possible mechanisms of MAT expansion under estrogen withdrawal and further summarize emerging findings regarding the pathological roles of MAT in bone remodeling. We also discuss the current therapies targeting MAT in osteoporosis. A comprehensive understanding of the relationship between MAT expansion and bone metabolism in estrogen deficiency conditions will provide new insights into potential therapeutic targets for PMOP.

Bisphosphonates are wildly used in breast cancer patients with bone metastasis and generally administrated every 4 weeks to lessen the risk of subsequent skeletal-related events. Bisphosphonates administration every 12 weeks is also recommended in some guidelines. Recent clinical trials suggested that bisphosphonate treatment with reduced frequency (every 12 weeks) to be non-inferior to standard therapy. The object of this analysis was to contrast the efficacy and safety of these two treatment strategies. We systematically retrieved databases such as MEDLINE, PubMed, Embase, and Cochrane library from 1947 to present for clinical trials comparing the efficacy between standard (every 4 weeks) and de-escalation (every 12 weeks) treatment of bisphosphates. We identified 4 articles with available data from 4 randomized clinical trials (n = 1721). Administration of bisphosphate every 12 weeks was non-inferior to administration every 4 weeks. There existed no significant difference in on-study skeletal-related events, renal dysfunction, and osteonecrosis of jaw. In the exploratory study, patients who received intravenous bisphosphates before enrollment experienced less on-study skeletal-related events and significant difference was observed between groups. This analysis suggested that de-escalation treatment with bisphosphates may be superior to standard treatment in terms of efficacy, safety, and economic costs. But it would be better that all the patients receive bisphosphates every 4 weeks for several months before de-escalation.

Background : Chronic consumption of alcohol has an adverse effect on the skeletal system, which may lead to osteoporosis, delayed fracture healing and osteonecrosis of the femoral head. Currently, the treatment is limited, therefore, there is an urgent need to determine the underline mechanism and develop a new treatment. It is well-known that normal bone remodeling relies on the balance between osteoclast-mediated bone resorption and - mediated bone formation. Various factors can destroy the balance, including the dysfunction of the immune system. In this review, we summarized the relevant research in the alcoholic osteopenia with a focus on the abnormal osteoimmunology signals. We provided a new theoretical basis for the prevention and treatment of the alcoholic bone. Methods: We searched PubMed for publications from 1 January 1980 to 1 February 2020 to identify relevant and recent literature, summarizing evaluation and the prospect of alcoholic osteopenia. Detailed search terms were ‘alcohol’, ‘alcoholic osteoporosis’, ‘alcoholic osteopenia’ ‘immune’, ‘osteoimmunology’, ‘bone remodeling’, ‘osteoporosis treatment’ and ‘osteoporosis therapy’. Results: A total of 135 papers are included in the review. About 60 papers described the mechanisms of alcohol involved in bone remodeling. Some papers were focused on the pathogenesis of alcohol on bone through osteoimmune mechanisms. Conclusion: There is a complex network of signals between alcohol and bone remodeling and intercellular communication of osteoimmune may be a potential mechanism for alcoholic bone. Studying the osteoimmune mechanism is critical for drug development specific to the alcoholic bone disorder.

XLαs, the extra-large isoform of alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gsα), is paternally expressed. The significance of XLαs in humans remains largely unknown. Here, we report a patient who presented with increased bone mass, hypophosphatemia, and elevated parathyroid hormone (PTH) levels. His serum calcium was in the lower limit of the normal range. Whole exome sequencing of this subject found a novel non-sense variant c.424G>T (p. G142*) in the first exon of XLαs, which was inherited from his father and transmitted to his daughter. This variant was predicted to exclusively influence the expression of XLαs, while possibly having no significant effects on other gene products of this locus. Ellsworth-Howard test revealed normal renal response to PTH in proband. Human SaOS2 cells transfected with mutant XLαs failed to generate cyclic adenosine monophosphate under PTH stimulation, indicating skeletal resistance to this hormone. This subject showed higher circulating sclerostin, dickkopf1, and osteoprotegerin (OPG) levels, while lower receptor activator of nuclear factor kappa-B ligand/OPG ratio, leading to reduced bone resorption. Our findings indicate that XLαs plays a critical role in bone metabolism and GNAS locus should be considered as a candidate gene for high bone mass.

We examined the effects of tumor necrosis factor-α (TNFα) and interleukin-6 (IL6) gene knockout in preserving the bone loss induced by ovariectomy (OVX) and the mechanisms involved in bone metabolism. Twenty female wild-type (WT), TNFα-knockout (TNFα−/−) or IL6-knockout (IL6−/−) mice aged 12 weeks were sham-operated (SHAM) or subjected to OVX and killed after 4 weeks. Bone mass and skeletal microarchitecture were determined using micro-CT. Bone marrow stromal cells (BMSCs) from all three groups (WT, TNFα−/− and IL6−/−) were induced to differentiate into osteoblasts or osteoclasts and treated with 17-β-estradiol. Bone metabolism was assessed by histological analysis, serum analyses and qRT-PCR. OVX successfully induced a high turnover in all mice, but a repair effect was observed in TNFα−/− and IL6−/− mice. The ratio of femoral trabecular bone volume to tissue volume, trabecular number and trabecular thickness were significantly decreased in WT mice subjected to OVX, but increased in TNFα−/− mice (1.62, 1.34, 0.27-fold respectively; P −/− mice (1.34, 0.80, 0.22-fold respectively; P −/− mice when compared to the IL6−/− mice. Both, TNFα−/− and IL6−/− BMSCs exhibited decreased numbers of TRAP-positive cells and an increase in ALP-positive cells, with or without E2 treatment (P TNFα or IL6 significantly upregulated mRNA expressions of osteoblast-related genes (Runx2 and Col1a1) and downregulated osteoclast-related mRNA for TRAP, MMP9 and CTSK in vivo and in vitro, TNFα knockout appeared to have roles beyond IL6 knockout in upregulating Col1a1 mRNA expression and downregulating mRNA expressions of WNT-related genes (DKK1 and Sost) and TNF-related activation-induced genes (TRAF6). TNFα seemed to be more potentially invasive in inhibiting bone formation and enhancing TRAF6-mediated osteoclastogenesis than IL6, implying that the regulatory mechanisms of TNFα and IL6 in bone metabolism may be different.