Osteoclast Proliferation Research Articles

Extracellular Signal-Regulated Kinases Play Essential but Contrasting Roles in Osteoclast Differentiation.

Bone homeostasis is regulated by the balanced actions of osteoblasts that form the bone and osteoclasts (OCs) that resorb the bone. Bone-resorbing OCs are differentiated from hematopoietic monocyte/macrophage lineage cells, whereas osteoblasts are derived from mesenchymal progenitors. OC differentiation is induced by two key cytokines, macrophage colony-stimulating factor (M-CSF), a factor essential for the proliferation and survival of the OCs, and receptor activator of nuclear factor kappa-B ligand (RANKL), a factor for responsible for the differentiation of the OCs. Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinases, play an essential role in regulating the proliferation, differentiation, and function of OCs. ERKs have been known to play a critical role in the differentiation and activation of OCs. In most cases, ERKs positively regulate OC differentiation and function. However, several reports present conflicting conclusions. Interestingly, the inhibition of OC differentiation by ERK1/2 is observed only in OCs differentiated from RAW 264.7 cells. Therefore, in this review, we summarize the current understanding of the conflicting actions of ERK1/2 in OC differentiation.

Angular limb deformity associated with TSPAN18, NRG3 and NOVA2 in Rambouillet rams

Angular limb deformity (ALD) affects many species of livestock and companion animals. The mechanisms of ALD development are not well understood, but previous research suggests the involvement of genetic risk factors. A case-control genome-wide association study (GWAS) was conducted with 40 ALD-affected and 302 unaffected Rambouillet rams and 40,945 single nucleotide polymorphisms (SNPs). Forelimbs of 6 ALD-affected rams were examined and diagnosed with osteochondrosis. Genome-wide or chromosome-wide significant SNPs were positioned exonic, intronic or within the 3′UTR of genes TSPAN18, NRG3 and NOVA2, respectively. These genes have previously described roles related to angiogenesis and osteoblast, osteoclast and chondrocyte proliferation and differentiation, which suggests the possibility for their involvement in the pathogenesis of osteochondrosis. Functional consequences of SNPs were evaluated through transcription factor binding site analysis, which predicted binding sites for transcription factors of known importance to bone growth, including SOX6, SOX9 and RUNX2. The identification of genetic risk factors for ALD may help to improve animal welfare and production in Rambouillet, a breed known to be at risk for ALD development. This study proposes genes TSPAN18, NRG3 and NOVA2 as targets for further research towards understanding the etiology of ALD in Rambouillet sheep.

Therapeutic Effect of Colony Stimulating Factor 1 Receptor Kinase Inhibitor, JTE-952, on Methotrexate-Refractory Pathology in a Rat Model of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and the destruction of bone and cartilage in affected joints. One of the unmet medical needs in the treatment of RA is to effectively prevent the structural destruction of joints, especially bone, which progresses because of resistance to conventional drugs that mainly have anti-inflammatory effects, and directly leads to a decline in the QOL of patients. We previously developed a novel and orally available type II kinase inhibitor of colony-stimulating factor-1 receptor (CSF1R), JTE-952. CSF1R is specifically expressed by monocytic-lineage cells, including bone-resorbing osteoclasts, and is important for promoting the differentiation and proliferation of osteoclasts. In the present study, we investigated the therapeutic effect of JTE-952 on methotrexate (MTX)-refractory joint destruction in a clinically established adjuvant-induced arthritis rat model. JTE-952 did not suppress paw swelling under inflammatory conditions, but it inhibited the destruction of joint structural components including bone and cartilage in the inflamed joints. In addition, decreased range of joint motion and mechanical hyperalgesia after disease onset were suppressed by JTE-952. These results suggest that JTE-952 is expected to prevent the progression of the structural destruction of joints and its associated effects on joint motion and pain by inhibiting CSF1/CSF1R signaling in RA pathology, which is resistant to conventional disease-modifying anti-rheumatic drugs such as MTX.

The Effect of PDLSCs on Orthodontic Tooth Movement – A Review

Background: Stem cells have been widely used in various fields of the health sector, one of which is dental health. Teeth with malocclusion require orthodontic treatment to achieve good function and aesthetics. Orthodontic tooth movement (OTM) occurs due to a bone remodeling process, namely deposition in areas of tension and resorption in areas of pressure. Differentiated stem cells are thought to influence OTM through several different mechanisms. Purpose: This narrative review seeks to explain how stem cells affect the mobility of orthodontic teeth. Review(s): OTM is aided by inflammatory mediators that are produced as a result of the induction of stem cells in the periodontal ligament. These mediators control osteoclast and osteoblast differentiation and proliferation, as well as bone remodeling. Periodontal ligament stem cells (PDLSCs) are important local immune response modulators in the inflammatory milieu and have an impact on a range of immune cells. Conclusion: PDLSCs, which are included in mesenchymal stem cells (MSCs), play a role in OTM through various mechanisms that can cause acceleration in OTM.

Regulation of cholesterol homeostasis in osteoporosis mechanisms and therapeutics.

Osteoporosis is a metabolic bone disease that affects hundreds of millions of people worldwide and is characterized by excessive loss of bone protein and mineral content. The incidence and mortality of osteoporosis increase with age, creating a significant medical and economic burden globally. The importance of cholesterol levels has been reported in the development of diseases including osteoporosis. It is important to note that key enzymes and molecules involved in cholesterol homeostasis are closely related to bone formation. Excessive cholesterol may cause osteoporosis, cholesterol and its metabolites affect bone homeostasis by regulating the proliferation and stimulation of osteoblasts and osteoclasts. Therefore, antagonism of elevated cholesterol levels may be a potential strategy to prevent osteoporosis. There is sufficient evidence to support the use of bisphosphonates and statin drugs for osteoporosis in the clinic. Therefore, in view of the aggravation of the aging problem, we summarize the intracellular mechanism of cholesterol homeostasis and its relationship with osteoporosis (including cholesterol and cholesterol oxidation products (COPs) in osteoporosis). Furthermore, the current clinical cholesterol-lowering drugs for osteoporosis were also summarized, as are new and promising therapies (cell-based therapies (e.g., stem cells) and biomaterial-delivered target drug therapies for osteoporosis as well).

The Bone Microenvironment Soil in Prostate Cancer Metastasis: An miRNA Approach.

Bone metastatic prostate cancer (PCa) is associated with a high risk of mortality. Changes in the expression pattern of miRNAs seem to be related to early aspects of prostate cancer, as well as its establishment and proliferation, including the necessary steps for metastasis. Here we compiled, for the first time, the important roles of miRNAs in the development, diagnosis, and treatment of bone metastasis, focusing on recent in vivo and in vitro studies. PCa exosomes are proven to promote metastasis-related events, such as osteoblast and osteoclast differentiation and proliferation. Aberrant miRNA expression in PCa may induce abnormal bone remodeling and support tumor development. Furthermore, miRNAs are capable of binding to multiple mRNA targets, a dynamic property that can be harnessed for the development of treatment tools, such as antagomiRs and miRNA mimics, which have emerged as promising candidates in PCa treatment. Finally, miRNAs may serve as noninvasive biomarkers, as they can be detected in tissue and bodily fluids, are highly stable, and show differential expression between nonmetastatic PCa and bone metastatic samples. Taken together, the findings underscore the importance of miRNA expression profiles and miRNA-based tools as rational technologies to increase the quality of life and longevity of patients.

CircZNF367 promotes osteoclast differentiation and osteoporosis by interacting with FUS to maintain CRY2 mRNA stability

BackgroundOsteoporosis, characterized by reduced bone mass and deterioration of bone quality, is a significant health concern for postmenopausal women. Considering that the specific role of circRNAs in osteoporosis and osteoclast differentiation remains poorly understood, this study aims to shed light on their involvement in these processes to enhance our understanding and potentially contribute to improved treatment strategies for osteoporosis.MethodsAn osteoporotic model was constructed in vivo in ovariectomized mouse. In vitro, we induced osteoclast formation in bone marrow-derived macrophages (BMDMs) using M-CSF + RANKL. To assess osteoporosis in mice, we conducted HE staining. We used MTT and TRAP staining to measure cell viability and osteoclast formation, respectively, and also evaluated their mRNA and protein expression levels. In addition, RNA pull-down, RIP and luciferase reporter assays were performed to investigate interactions, and ChIP assay was used to examine the impact of circZNF367 knockdown on the binding between FUS and CRY2.ResultsWe observed increased expression of CircZNF367, FUS and CRY2 in osteoporotic mice and M-CSF + RANKL-induced BMDMs. Functionally, knocking down circZNF367 inhibited osteoporosis in vivo. Furthermore, interference with circZNF367 suppressed osteoclast proliferation and the expression of TRAP, NFATc1, and c-FOS. Mechanistically, circZNF367 interacted with FUS to maintain CRY2 mRNA stability. Additionally, knocking down CRY2 rescued M-CSF + RANKL-induced osteoclast differentiation in BMDMs promoted by circZNF367 and FUS.ConclusionThis study reveals that the circZNF367/FUS axis may accelerate osteoclasts differentiation by upregulating CRY2 in osteoporosis and suggests that targeting circZNF367 may have potential therapeutic effects on osteoporosis.

The molecular mechanism of Gorham syndrome: an update.

Gorham syndrome, also known as "vanishing osteopathy" and "invasive hemangiomatosis," is a rare clinical syndrome whose etiology is unknown and can invade the whole-body skeleton. At present, more than 300 cases have been reported at home and abroad, usually manifesting as spontaneous chronic osteolysis with no periosteal reaction at the lysis site and occult onset, often with fractures, scoliosis, chylothorax, etc. When waiting for medical treatment, the condition is serious, and the prognosis is poor. At present, there is no effective treatment. The main pathological manifestations of Gorham syndrome are the non-neoplastic abnormal proliferation of lymphatic vessels or blood vessels and osteolysis caused by osteoclast proliferation or increased activity. At present, there is no unified conclusion regarding Gorham syndrome's pathogenesis. This paper starts with the two most studied osteolysis methods atpresent, osteoclast osteolysis and osteolysis caused by vascular and lymphaticproliferation and summarizes the corresponding most possible molecular mechanisms in recent years to provide more ideas for Gorham syndrome treatment.

Regulatory function and mechanism of autophagy on osteoclast

Osteoclast (OC) is multinucleated, bone-resorbing cells originated from monocyte/macrophage lineage of cells, excessive production and abnormal activation of which could lead to many bone metabolic diseases, such as osteoporosis, osteoarthritis, etc. Autophagy, as a highly conserved catabolic process in eukaryotic cells, which plays an important role in maintaining cell homeostasis, stress damage repair, proliferation and differentiation. Recent studies have found that autophagy was also involved in the regulation of osteoclast generation and bone resorption. On the one hand, autophagy could be induced and activated by various factors in osteocalsts, such as nutrient deficiency, hypoxia, receptor activator of nuclear factor(NF)-κB ligand(RANKL), inflammatory factors, wear particles, microgravity environment, etc, different inducible factors, such as RANKL, inflammatory factors, wear particles, could interact with each other and work together. On the other hand, activated autophagy is involved in regulating various stages of osteoclast differentiation and maturation, autophagy could promote proliferation of osteoclasts, inhibiting apoptosis, and promoting differentiation, migration and bone resorption of osteoclast. The classical autophagy signaling pathway mediated by mammalian target of rapamycin complex 1(mTORC1) is currently a focus of research, and it could be regulated by upstream signalings such as phosphatidylinositol 3 kinase(PI-3K)/protein kinase B (PKB), AMP-activated protein kinase(AMPK). However, the paper found that mTORC1-mediated autophagy may play a bidirectional role in regulating differentiation and function of osteoclasts, and its underlying mechanism needs to be further ciarified. Integrin αvβ3 and Rab protein families are important targets for autophagy to play a role in osteoclast migration and bone resorption, respectively. In view of important role of osteoclast in the occurrence of various bone diseases, it is of great significance to elucidate the role of autophagy on osteoclast and its mechanism for the treatment of various bone diseases. The autophagy pathway could be used as a new therapeutic target for the treatment of clinical bone diseases such as osteoporosis.

Abstract 1324: EphA2 Expression in Breast Cancer Mediates Osteoclast Expansion and Promotes Osteolytic Bone Metastasis

Abstract Breast cancer is the most diagnosed cancer in the U.S., with a 5-year survival rate of less than 30% for patients with distant metastases. Bone metastases are present in over 70% of metastatic breast cancer patients, and current treatments treat the symptoms of osteolytic bone metastasis (OBM), but do not improve survival rates. OBM is characterized by an increase in osteoclast proliferation and bone-resorbing activity. Moreover, receptor tyrosine kinase, Ephrin-type-A 2 receptor (EphA2), is highly expressed in bone metastases, and previous evidence suggests its involvement in OBM and anti-tumor immunity. EphA2 participates in both forward and reverse signaling during receptor/ligand engagement and mediates various biological processes such as tissue organization and homeostasis and inflammation, as well as oncogenic processes like epithelial-mesenchymal transition. However, the mechanism by which EphA2 mediates the expansion of osteoclasts is not well understood. Analysis of transcriptomic data of patients with bone metastases in The Metastatic Breast Cancer Project (Provisional, December 2021) resulted in over 3500 genes that significantly correlated with EphA2 expression (Spearman's Correlation ≥ 0.35). Using a publicly available Gene Ontology reference list for myeloid differentiation, we identified 155 genes that have a significant positive correlation with EphA2 expression. To assess the effect of EphA2 expression on genes associated with osteoclasts, we compared the same samples to reference lists for osteoclast differentiation and proliferation. We identified 17 genes of interest that significantly correlate with EphA2 expression, further underscoring the possible involvement of EphA2 in OBM. We then compared the patients without bone metastases to the same osteoclast reference lists and found no significant correlations. We hypothesize that increased expression of EphA2 in breast cancer cells at the site of bone metastasis promotes osteoclast expansion, leading to OBM. We aim to investigate EphA2 reverse signaling in myeloid progenitor cells, osteoclasts, and bone metastasis-associated macrophages. We will utilize breast cancer mouse models to elucidate the effects of EphA2 inhibition on immune cell populations, bone metastasis, and tumor progression. We aim to reduce OBM and tumor burden by reducing the expansion of osteoclasts and shifting the immune cells to an anti-tumorigenic phenotype, which will offer new treatment strategies for osteolytic breast cancer. Citation Format: Dominique Parker, Verra Ngwa, Logan Northcutt, Natalie Bennett, Erik Beadle, Jade Miller, JIn Chen, Julie Rhoades. EphA2 Expression in Breast Cancer Mediates Osteoclast Expansion and Promotes Osteolytic Bone Metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1324.

Role of denosumab in bone erosions in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammation and synovitis which evolve into joint destruction and deformity. Bone abnormalities are represented by marginal bone erosions and iuxta-articular and generalized osteoporosis. Overactivation of osteoclasts along with dysregulation of osteoblasts are the key events. Bone resorption is mediated by the receptor activator of nuclear factor (NF)-κB (RANK) ligand (RANK-L), responsible for the differentiation, proliferation, and activation of osteoclasts. RANK-L binds its receptor RANK, localized on the surface of preosteoclasts and mature osteoclasts promoting osteoclastogenesis. High levels of RANK-L were demonstrated in active RA patients. Denosumab, a fully human monoclonal antibody, binds RANK-L and suppresses the RANK-RANK-L signaling pathway leading to the inhibition of osteoclastogenesis. A retrospective analysis of published studies such as clinical trials evidenced the efficacy of denosumab in preventing bone erosion progression in RA patients. Key messages Key questions to answer in future include the following: Could denosumab be associated with other biologic therapies in RA patients? Could denosumab block the progression of bone damage in RA? Could denosumab be used for the prevention of bone erosion in RA?

Transcriptional Ontogeny Platform of Sex Determination/Sex Differentiation Genes in Almaco Jack Larvae

AbstractThe fish sex determination/sex differentiation (SD) system is still intriguing in many species, such as Seriola fish. Marine amberjacks have a conserved ZW/ZZ SD system. We aimed to identify how early SD genes were expressed in larval Almaco Jack Seriola rivoliana by RNA sequencing and to determine whether there was an early developmental differential expression up to the onset of exogenous feeding. Transcriptome analysis identified sox5 and sox7 (female) and sox3 and sox8 (male) genes; all of the known female SD genes, including hsd17b1 (master sex gene in Seriola), foxl2, and cyp19a, plus genes involved in female sexual development and maintenance, estrogen signaling, and osteoclast proliferation; and all of the known male SD genes, including dmrt1, nr5a1, gsdf, amhy, and amhr2. The expression of most SD genes occurred on each day during larval development. However, most of them showed low abundance levels and null differential expression except for the downregulation of the sox and foxl2 genes, which might have served an unknown function or were maternally derived rather than autonomously downregulated. We suggest that the concomitant expression of female and male SD genes in early larval stages is a biological transcriptional ontogeny sex platform that ensures posterior sex‐specific expression and sex differentiation. A single missense single‐nucleotide polymorphism (SNP) near the catalytic center of hsd17b1 has been suggested to differentiate phenotypic sex in Seriola by an endocrine regulation on estradiol synthesis. In that case, the ontogeny sex platform would be directed by the SNP but still critical to differentiate gonads.

D-Mannose prevents bone loss under weightlessness

BackgroundAstronauts undergo significant microgravity-induced bone loss during space missions, which has become one of the three major medical problems hindering human's long-term space flight. A risk-free and antiresorptive drug is urgently needed to prevent bone loss during space missions. D-mannose is a natural C-2 epimer of D-glucose and is abundant in cranberries. This study aimed to investigate the protective effects and potential mechanisms of D-mannose against bone loss under weightlessness.MethodsThe hind legs of tail-suspended (TS) rats were used to mimic weightlessness on Earth. Rats were administered D-mannose intragastrically. The osteoclastogenic and osteogenic capacity of D-mannose in vitro and in vivo was analyzed by micro-computed tomography, biomechanical assessment, bone histology, serum markers of bone metabolism, cell proliferation assay, quantitative polymerase chain reaction, and western blotting. RNA-seq transcriptomic analysis was performed to detect the underlying mechanisms of D-mannose in bone protection.ResultsThe TS rats showed lower bone mineral density (BMD) and poorer bone morphological indices. D-mannose could improve BMD in TS rats. D-mannose inhibited osteoclast proliferation and fusion in vitro, without apparent effects on osteoblasts. RNA-seq transcriptomic analysis showed that D-mannose administration significantly inhibited the cell fusion molecule dendritic cell-specific transmembrane protein (DC-STAMP) and two indispensable transcription factors for osteoclast fusion (c-Fos and nuclear factor of activated T cells 1 [NFATc1]). Finally, TS rats tended to experience dysuria-related urinary tract infections (UTIs), which were suppressed by treatment with D-mannose.ConclusionD-mannose protected against bone loss and UTIs in rats under weightlessness. The bone protective effects of D-mannose were mediated by inhibiting osteoclast cell fusion. Our findings provide a potential strategy to protect against bone loss and UTIs during space missions.

Osteolytic Bone Lesions As an Initial Presenting Manifestation of Acute Lymphoblastic Leukemia in Adults

Introduction Hematological malignancies can lead to bone lesions, most commonly the osteolytic lesions found in multiple myeloma (MM). Cases of osteolytic lesions have been rarely reported in acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma, Waldenström macroglobulinemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and myeloproliferative neoplasms (MPN). This review sheds light on the association between ALL and osteolytic bone lesions. Methods A literature search was performed for English language articles using PubMed, Scopus, and Google Scholar, for any date up to May 2022. The following keywords were used "ALL," "acute lymphoblastic leukemia," osteolytic bone lesions," and "osteolysis." Search results were initially reviewed by title and abstract, and articles were selected for more in-depth analysis if deemed relevant. Pertinent articles were examined in-depth for this report. Results To our knowledge, we found 15 cases of patients with ALL who developed osteolytic lesions. They were reported in 14 articles published between April 1998 and May 2022. Most patients were males (12 out of 15). The median age was 29 years (ranging from 22 to 78 years), with most patients being young (in the third and fourth decades). B-ALL was the most common type of ALL associated with osteolytic lesions (14 cases). All patients presented with bone pain, and hypercalcemia was found in 80% of the reported cases. Osteolytic lesions were detected by plain radiography(x-ray) in approximately half of the patients. The osteolytic lesions were confirmed in the remaining patients by CT, MRI, or PET scans. The most affected bones were the vertebrae, skull, and pelvis. The clinical outcomes among these patients were variable; two of the reported cases died after the diagnosis of osteolytic lesions. Discussion Bone metastases are classified as osteolytic, osteoblastic, or mixed based on the primary interference mechanism with bone remodeling. The destruction of normal bone characterizes osteolytic bone metastasis, occurring in multiple myeloma (MM), renal cell carcinoma, melanoma, non-small cell lung cancer, non-Hodgkin lymphoma, thyroid cancer, or Langerhans-cell histiocytosis. Osteolytic metastasis in adults with ALL is an extremely rare condition. The exact pathophysiology of osteolysis in ALL patients is unknown.PTHrP secretion by lymphoblasts has been shown to be the primary cause of osteolysis in ALL patients. Additionally, serum from ALL patients with osteolysis can induce in vitro proliferation of osteoclasts, indicating the mechanism of lymphoblasts induces osteoclasts activation in vivo. Based on our review, there was no association between osteolytic bone lesions and the Philadelphia chromosome detected in only one patient. Osteolytic bone lesions in ALL patients mainly present with bone pain. Pathological fracture of the vertebral body leading to spinal cord compression is a complication of osteolytic lesions in patients with MM. However, there is no case of spinal cord compression in ALL patients attributed to osteolytic lesions of the vertebra. Given that our review is based on case reports, we could not conclude if the presence of osteolytic bone lesions is a prognostic factor for adverse outcomes or indicates an "aggressive" form of leukemia in adult patients with ALL. Conclusion Osteolytic bone lesions in adult patients with ALL is an infrequent finding and mainly occurs in young adults. Plain radiography is often sufficient in diagnosing osteolytic bone lesions; however, other imaging modalities are sometimes required. Based on our review, the osteolytic lesions do not indicate a poor prognosis in adult patients with ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The regulatory activities of MALAT1 in the development of bone and cartilage diseases.

Long non-coding RNAs (lncRNAs) have been comprehensively implicated in various cellular functions by mediating transcriptional or post-transcriptional activities. MALAT1 is involved in the differentiation, proliferation, and apoptosis of multiple cell lines, including BMSCs, osteoblasts, osteoclasts, and chondrocytes. Interestingly, MALAT1 may interact with RNAs or proteins, regulating cellular processes. Recently, MALAT1 has been reported to be associated with the development of bone and cartilage diseases by orchestrating the signaling network. The involvement of MALAT1 in the pathological development of bone and cartilage diseases makes it available to be a potential biomarker for clinical diagnosis or prognosis. Although the potential mechanisms of MALAT1 in mediating the cellular processes of bone and cartilage diseases are still needed for further elucidation, MALAT1 shows great promise for drug development.

Boiogito, a Japanese Traditional Herbal Medicine, Inhibits the Osteoclast Differentiation and Proliferation in the Subchondral Bone of an In Vivo Knee Osteoarthritis Rat Model

Boiogito (BO), a Japanese traditional herbal medicine, has been reported to prevent knee osteoarthritis (KOA) development in in vivo studies. In the early stage of KOA, osteoclasts proliferate in the subchondral bone. This study aimed to investigate the preventive effect of BO on osteoclast proliferation, which remains unclear, in a KOA-induced rat model. KOA was induced in 12-week-old male Wistar rats using surgical destabilization of the medial meniscus (DMM). BO was mixed with powdered chow, applying 1%, 3%, and 5% of the total feed, and administered to KOA-induced rats. The rats were divided into 6 groups: control, sham, DMM, DMM + BO 1%, DMM + BO 3%, and DMM + BO 5%. Rotarod tests were performed each week to assess the locomotor function, and the right knees were harvested 28 days after surgery for histological analysis. Oral administration of BO significantly inhibited the decrease in the latency to fall off in the rotarod test, which was aggravated in the DMM group. Furthermore, KOA development was significantly prevented in the BO-administrated groups as assessed by the Osteoarthritis Research Society International score. The number of multinucleated activated osteoclasts in the subchondral bone was decreased in the BO-treated groups, which was increased in the DMM group. Therefore, oral administration of BO may reduce articular cartilage degeneration, osteoclast differentiation and proliferation in the KOA patients.

Association between SEMA3A signaling pathway genes and BMD/OP risk: An epidemiological and experimental study.

This study aimed to explore the associations of genetic variants in the semaphorin 3A (SEMA3A) signaling pathway genes, including SEMA3A, NRP1, PLXNA1, PLXNA2 and PLXNA3 with osteoporosis (OP) risk and bone mineral density (BMD) in a Chinese Han older adult population. A two-stage design was adopted. Total of 47.8kb regions in the 5 genes were sequenced using targeted next-generation sequencing (NGS) technology in the discovery stage, and the discovered OP-related single nucleotide polymorphisms (SNPs) were further genotyped using improved multiple linkage detection reaction technique in the validation stage. Methods of ALP/TRAP staining, real-time fluorescent quantitative PCR, and cell proliferation and apoptosis assays were performed with MC3T3-E1 and RAW 264.7 cell lines to clarify biological effects of observed functional variants in cell lines responsible for bone mass remodeling. Total of 400 postmenopausal women (211 OP cases) were involved in the discovery stage, where 6 common and 4 rare genetic variants were found to be associated with OP risk. In the validation stage among another 859 participants (417 women, 270 OP cases), the PLXNA2 rs2274446 T allele was associated with reduced OP risk and increased femoral neck (FN) BMD compared to the C allele. Moreover, significant associations of NRP1 rs2070296 with FN BMD/OP risk and of NRP1 rs180868035 with lumbar spine and FN BMDs were also observed in the combination dataset analysis. Compared to the osteoblasts/osteoclasts transfected with the wild-type NRP1 rs180868035, those transfected with the mutant-type had reduced mRNA expression of osteoblastic genes (i.e., ALP, RUNX2, SP7 and OCN), while elevated mRNA expression of osteoclastic genes (i.e., TRAP, NFATc1 and CTSK). Furthermore, mutant NRP1 rs180868035 transfection inhibited osteoblast proliferation and osteoclast apoptosis, while promoted osteoclast proliferation and osteoblast apoptosis in corresponding cell lines. Genetic variants located in NRP1 and PLXNA2 genes were associated with OP risk and BMD. The NRP1 rs180868035 affects bone metabolism by influencing osteoblasts and osteoclasts differentiation, proliferation and apoptosis.

Composite monetite/amorphous calcium phosphate bone cement promotes bone regeneration

Monetite (MC) is a type of calcium phosphate cement (CPC). It has various morphologies, continuous degradation and absorption properties; however, its high porosity will affect its mechanical properties. There is minimal research on MC is immature. Amorphous calcium phosphate (ACP) is widely used and exhibits good biocompatibility; however, it is unstable. In this study, MC was combined with ACP at different weight ratios to form new types of bone cements. The mechanical properties, biocompatibility, and inductive ability for osteogenesis and osteoclasts of different MC/ACP composite bone cements were evaluated. The biocompatibility and effects on osteogenic and osteoclast differentiation of MC/ACP composite bone cements were investigated in vitro using mouse bone marrow mesenchymal stem cells (mBMMSCs) and mouse monocyte/macrophage cell line RAW 264.7. RAW 264.7 cells can differentiate into osteoclasts by osteoclast differentiation. The results indicated that the overall performance of the MC/ACP composite bone cement was better than that of the MC or ACP alone. Compared to the other groups, the biocompatibility of MC75 (75 wt% MC and 25 wt% ACP) was optimal; it was able to induce mBMMSCs osteogenesis to a greater extent. MC75 was the least favorable for the proliferation, migration, and differentiation of osteoclasts. The mechanical properties, setting time and injectability of MC75 meet clinical application requirements. This study demonstrated that MC75 is a promising bone cement for repairing bone defects.

Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration

Sexually dimorphic tissues are formed by cells that are regulated by sex hormones. While a number of systemic hormones and transcription factors are known to regulate proliferation and differentiation of osteoblasts and osteoclasts, the mechanisms that determine sexually dimorphic differences in bone regeneration are unclear. To explore how sex hormones regulate bone regeneration, we compared bone fracture repair between adult male and female mice. We found that skeletal stem cell (SSC) mediated regeneration in female mice is dependent on estrogen signaling but SSCs from male mice do not exhibit similar estrogen responsiveness. Mechanistically, we found that estrogen acts directly on the SSC lineage in mice and humans by up-regulating multiple skeletogenic pathways and is necessary for the stem cell’s ability to self- renew and differentiate. Our results also suggest a clinically applicable strategy to accelerate bone healing using localized estrogen hormone therapy.

Osteopontin, a bridge links osteoarthritis and osteoporosis.

Osteoarthritis (OA) is the most prevalent joint disease characterized by degradation of articular cartilage, inflammation, and changes in periarticular and subchondral bone of joints. Osteoporosis (OP) is another systemic skeletal disease characterized by low bone mass and bone mineral density (BMD) accompanied by microarchitectural deterioration in bone tissue and increased bone fragility and fracture risk. Both OA and OP are mainly affected on the elderly people. Recent studies have shown that osteopontin (OPN) plays a vital role in bone metabolism and homeostasis. OPN involves these biological activities through participating in the proliferation, migration, differentiation, and adhesion of several bone-related cells, including chondrocytes, synoviocytes, osteoclasts, osteoblasts, and marrow mesenchymal stem cells (MSCs). OPN has been demonstrated to be closely related to the occurrence and development of many bone-related diseases, such as OA and OP. This review summarizes the role of OPN in regulating inflammation activity and bone metabolism in OA and OP. Furthermore, some drugs that targeted OPN to treat OA and OP are also summarized in the review. However, the complex mechanism of OPN in regulating OA and OP is not fully elucidated, which drives us to explore the depth effect of OPN on these two bone diseases.