JOURNAL OF BONE AND MINERAL RESEARCH
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2025
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IF 5.9
Liu Qian,Gan Ying,Hu Xingli,Liu Wei,Liao Xiaoxia,Zhang Jingyun,Li Xiaoxia,Zhou Jie,Wang Baoli
Lysine demethylase 6B (KDM6B) plays a role in regulating osteoblast differentiation and fetal bone ossification. Nevertheless, its involvement in regulating postnatal bone homeostasis and bone mass accrual remains unclear. In this study, we generated mice lacking Kdm6b gene specifically in mesenchyme and osteoprogenitor cells using a conditional strategy. The adult mice of both mutant strains had decreased cancellous bone mass. The absence of Kdm6b in mesenchyme led to decreased numbers of osteoblasts and osteoclasts, increased marrow adipocytes, as well as repressed bone formation and resorption. Additionally, Kdm6b-deficient bone marrow stromal cells (BMSCs) displayed impaired osteogenic differentiation and exerted an inhibitory effect on osteoclastogenesis. RNA-seq combined with gene expression analysis uncovered downregulation of collagen triple helix repeat containing 1 (CTHRC1) and a lower receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) ratio in BMSCs of the mutant mice. Further mechanistic explorations demonstrated that KDM6B epigenetically upregulated CTHRC1 expression by removing the repressive H3K27me3 mark from its promoter, thereby triggering PKCδ/MAPKs signaling to facilitate osteoblast differentiation. CTHRC1 was able to mitigate the dysregulated osteogenic and adipogenic differentiation induced by Kdm6b deficiency. This study provides evidence that KDM6B regulates postnatal bone homeostasis through balancing osteoblast and osteoclast differentiation. Given its predominant promotion of osteoblastic bone formation over osteoclastic bone resorption, KDM6B tends to promote postnatal bone mass accrual.
研究领域:
分子生物学
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骨骼发育
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
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2025
·Vol. 16
·期 1
·1-16
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IF 15.7
Xie Qian,Du Xiangfu,Liang Jianhui,Shen Yanni,Ling Yufan,Huang Zhengji,Ke Zekai,Li Tai,Song Bing,Wu Tailin,Wang Yan,Tao Huiren
Postmenopausal osteoporosis (PMOP) is a condition in women caused by estrogen deficiency, characterized by reduced bone mass and increased fracture risk. Fatty acid-binding protein 4 (FABP4), a lipid-binding protein involved in metabolism and inflammation, has emerged as a key regulator in metabolic disorders and bone resorption; however, its direct role in PMOP remains unclear. Here, we show that serum FABP4 levels in PMOP patients negatively correlate with bone mineral density, a trend also observed in ovariectomized mice. FABP4 promotes osteoclast formation and bone resorption without affecting osteoblast differentiation. The FABP4 inhibitor BMS309403 suppresses osteoclast differentiation by modulating calcium signaling and inhibiting the Ca 2+ -Calcineurin-NFATc1 pathway. Oral BMS309403 increases bone mineral density in ovariectomized mice, though less effectively than alendronate. Notably, bone-targeted delivery of BMS309403 achieves comparable efficacy to alendronate. In this work, we demonstrate that FABP4 is a critical mediator in PMOP and that its inhibition offers a promising therapeutic strategy.
研究领域:
骨骼生物学
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代谢疾病
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药理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2025
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IF 8.3
Xueling Hu,Chunxia Liu,Ziling Tang,Mingyu Pan,Ailing Fang,Ling Li,Xiangbo Meng,Xiyang Tang,Yanzhi Liu,Xinluan Wang,Hao Gao,Jian Zou,Zuocheng Qiu
Background Cathepsin K (CTSK) is a key enzyme in bone resorption, making it a promising target for osteoporosis treatment. Active-site inhibitors of CTSK are effective but have undesirable side effects, while ectosteric inhibitors may provide a safer alternative. Purpose This study investigates whether Sophoraflavanone G (SG), derived from Rhizoma Drynariae , can act as an ectosteric CTSK inhibitor to attenuate osteoporotic bone loss and explores its underlying mechanisms. Study Design SG's effects were evaluated in an ovariectomized (OVX) osteoporotic mice model, with in vitro experiments assessing SG's interaction and binding affinity with CTSK. Methods Micro-CT, histology, and mechanical testing were used to evaluate bone density and strength. CTSK activity and expression were assessed by immunohistochemistry and western blotting. Cell thermal shift assays, isothermal titration calorimetry, CTSK site-specific degradation assays, molecular docking and dynamic simulation were performed to study SG's binding affinity and inhibitory effects. Biosafety, including body weight, uterine histomorphometry, and toxicity of the heart and lung, was also assessed. Results SG improved bone mineral density, microarchitecture, and strength, primarily by inhibiting bone resorption. It inhibited CTSK's enzymatic activity with a strong binding affinity (KD: 8.49 μM) and effectively inhibited osteoclast function. CTSK site-specific assays showed SG inhibited CTSK-mediated degradation of type I collagen. Unlike odanacatib, SG did not affect gelatin or TGF-β1 degradation in fibroblasts. Biosafety assessments revealed no adverse effects. Conclusion SG acts as an ectosteric CTSK inhibitor, offering a safer alternative for postmenopausal osteoporosis treatment by selectively inhibiting bone resorption without the side effects associated with active-site inhibitors.
研究领域:
药理学
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骨生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Orthopaedic Translation
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2025
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IF 7.8
Hongbo Ai,Ce Dou,Yutong Wu,Dongyang Zhang,Ziyang Zhang,Chao Zhang,Yuhang Xi,Ying Qu,Jiulin Tan,Pengbin Yin,Jianzhong Xu,Shuquan Guo,Fei Luo
Objective To investigate the role of osteoclast-derived apoptotic bodies (OC-ABs) in osteoarthritis (OA), specifically their impact on subchondral bone remodeling and disease progression, and to explore potential therapeutic strategies targeting OC-AB-induced pathways. Methods We utilized a mouse model of anterior cruciate ligament transection (ACLT) to simulate post-traumatic osteoarthritis (PTOA). Levels of OC-ABs were assessed in subchondral bone and correlated with OA severity. Additionally, apoptotic body-deficient MRL/lpr mice were analyzed to evaluate the direct contribution of OC-ABs to OA progression and subchondral bone remodeling. The involvement of OC-ABs in osteogenesis was further examined using mesenchymal stem cells (MSCs), with a focus on the RANKL reverse signaling pathway. The therapeutic potential of rapamycin to counteract OC-AB effects was tested. Results Increased OC-AB accumulation in subchondral bone was positively correlated with OA severity in ACLT-induced mice. Apoptotic body-deficient MRL/lpr mice demonstrated slower OA progression and maintained more stable subchondral bone architecture, indicating a pathogenic role of OC-ABs in OA. OC-ABs significantly stimulated osteogenesis in MSCs via the RANKL reverse signaling pathway. Treatment with rapamycin effectively reversed OC-AB-induced subchondral bone formation, mitigated OA progression, and inhibited the RANKL reverse signaling pathway. Conclusion OC-ABs play a critical role in exacerbating OA by promoting subchondral bone remodeling via the RANKL reverse signaling pathway. Rapamycin presents as a promising therapeutic agent capable of mitigating OC-AB-driven pathology, highlighting new avenues for targeted OA treatment.
研究领域:
骨生物学
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病理学
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风湿病学
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DOI
PubMed
高影响因子
iScience
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2021
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IF 5.458
Jun Ma,Jiajia Lu,Zhibin Zhou,Nan Lu,Jia He,Lei Zhu,Tianwen Ye
Summary The precise effect of estrogen (E2) on osteoclast function is still poorly understood. The aim of this study was to investigate the potential role of transient receptor potential vanilloid 6 (TRPV6) in E2-mediated osteoclast function and to characterize the relevant underlying mechanisms. Here, we found that Trpv6 is drastically decreased in ovariectomy operation animals and the administration of E2 results in an increased expression of Trpv6 in osteoclasts. In contrast, Trpv6 depletion significantly blocked the inhibitory effects of E2 on bone resorption activity, and silencing Trpv6 alleviated E2-induced osteoclast apoptosis. In addition, we found that E2 regulates the transcription of Trpv6 through ERα, by interacting with C/EBPβ and NF-κB. Chip assay analysis indicated that C/EBPβ regulates Trpv6 transcription by binding to Trpv6 promoter fragments −1,866 nt to −1,761 nt and −2,685 nt to −2,580 nt, whereas NF-κB binds to the −953 nt to −851 nt region. We conclude that TRPV6 has a significant effect on E2-mediated osteoclast function.
研究领域:
骨骼生物学
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内分泌学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHIMIE
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2018
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IF 3.188
Ji Li,Yanping Li,Shuang Pan,Lin Zhang,Lina He,Yumei Niu
Paeonol is a natural phenolic compound in Moutan Cortex with multiple biological functions, such as anti-inflammatory and anti-oxidant activity. Recent evidence has proven that persistent inflammation, oxidative stress , along with nuclear factor E2-related factor 2 (Nrf2) signaling dysfunction in periodontium are the possible causes of alveolar bone resorption , and ultimately lead to periodontitis. The present study was designed to explore the protective effects of paeonol on ligation-induced periodontitis in rats, and investigate the possible mechanism. We found that treatment with paeonol (40, 80 mg/kg, intraperitoneal injection) for 7 days remarkably decreased the expression of receptor activator of nuclear factor kappa-B ligand increased the expression of osteoprotegrin and inhibited the formation of osteoclasts . This function of paeonol might be correlated with its ability to reduce inflammatory factors (IL-1β, IL-6 and TNF-α) and alleviate oxidative stress (SOD, MDA, GSH and ROS) in gingival tissues. Besides, paeonol increased Nrf2 activity. Silence of Nrf2 using specific siRNA diminished the inhibitory effect of paeonol on NF-κB p65 activation and downstream expression, suggesting that Nrf2 was essential for protective effect of paeonol. These results showed that paeonol protected against periodontitis-aggravated osteoclastogenesis and alveolar bone lesion via regulating Nrf2/NF-κB/NFATc1 signaling pathway .
研究领域:
药理学
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牙医学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Cellular and Infection Microbiology
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2022
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IF 6.073
Zhou Shuhui,Ji Yaoting,Yao Hantao,Guo Haiying,Zhang Zichen,Wang Zijun,Du Minquan
Periodontitis is a worldwide oral disease induced by the interaction of subgingival bacteria and host response and is characterized by local inflammation, bone resorption, and tooth loss. Ginsenoside Rd (Rd) is a biologically active component derived from Panax ginseng and has been demonstrated to exert antibacterial and anti-inflammatory activities. This study aims to investigate the inhibitory efficiency of Rd towards Porphyromonas gingivalis (P. gingivalis), periodontal inflammatory response, and osteoclastogenesis in vitro and to further validate the results in a mouse periodontitis model, thus, evaluate the potential effects of Rd on the control and prevention of periodontitis. According to the results, Rd exerted excellent antibacterial activities against planktonic P. gingivalis, along with attenuating P. gingivalis virulence and inhibiting its biofilms. Meanwhile, the inflammatory cytokine production and osteoclastogenesis were remarkably inhibited by Rd both in vitro and in vivo. Furthermore, Rd efficiently ameliorated the subgingival P. gingivalis abundance and suppressed the alveolar bone resorption in vivo as well. In conclusion, Rd has the potential to be developed as a promising medication in the control and prevention of periodontitis.
研究领域:
口腔科学
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药理学
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微生物学
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DOI
PubMed
高影响因子
Advanced Science
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2025
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IF 14.1
Zhengrong Chen,Wenxin Yang,Yong Tang,Qianqian Dong,Kui Huang,Jiulin Tan,Jie Zhang,Juan Cai,Qixiu Yu,Qijie Dai,Jianzhong Xu,Shuquan Guo,Ce Dou,Fei Luo
Osteoporotic bone defects are challenging to repair due to imbalances in bone resorption and formation, coupled with insufficient vascularization. To address these issues, it develops a trifunctional hydrogel (SF-ZIF@NA) designed to selectively inhibit osteoclast activity and enhance vascularized bone regeneration. By enzymatically removing sialic acid, SF-ZIF@NA prevents precursor osteoclasts (pOCs) from fusing into bone-resorbing mature osteoclasts (mOCs), thereby preserving pOCs and their anabolic functions. Additionally, the hydrogel releases Zinc ion (Zn 2 ⁺) in response to acidic conditions, promoting osteogenesis and angiogenesis. In vitro results confirmed that SF-ZIF@NA impedes osteoclast fusion, enhances platelet-derived growth factor-BB (PDGF-BB secretion from pOCs, and activates the FAK (focal adhesion kinase) signaling pathway to stimulate vascularized bone formation. In osteoporotic bone defect models, SF-ZIF@NA accelerated bone repair with increased bone density and vascularization. These findings demonstrate that SF-ZIF@NA offers a targeted and multifunctional strategy for osteoporotic bone regeneration by concurrently modulating osteoclast activity and promoting angiogenesis.
研究领域:
生物材料学
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骨组织工程
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再生医学
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产品关联
DOI
PubMed
高影响因子
METABOLISM-CLINICAL AND EXPERIMENTAL
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2025
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IF 11.9
Chunmei Xiu,Lei Zhang,Chenxi Zhang,Yuannan Zhang,Xi Luo,Ziyi Zhang,Hangkai Zhao,Kaizhong Ji,Zhiyuan Chen,Guangxu He,Jianquan Chen
Aberrant increases in osteoclast formation and/or activity are the underlying cause of bone loss in a variety of osteolytic diseases. Fatty acid synthase (Fasn)-mediated de novo lipogenesis ( DNL ) is one of the major lipid metabolic pathways and has been shown to play critical roles in diverse physiological and pathological processes. However, little is known about its role in osteoclastogenesis. Here, we investigate the direct role of DNL in osteoclastogenesis and its therapeutic potential in osteolytic diseases. We found that Fasn expression and DNL levels are upregulated during receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Inhibition of Fasn by shRNA knockdown or its pharmacological inhibitors (ASC40 and trans-C75) impairs osteoclast differentiation in vitro . Mechanistically, pharmacological inhibition of Fasn suppresses RANKL-induced c-Fos/NFATc1 expression and thus osteoclastogenesis partly by disrupting STAT3 palmitoylation, while promoting ROS scavenging to impair mitogen-activated protein kinase (MAPK) signaling. Finally, the therapeutic potential of ASC40 for the treatment of osteolytic bone loss is tested in two mouse models of osteolytic diseases, i.e. ovariectomy (OVX)-induced osteoporosis and titanium nanoparticle-induced calvarial osteolysis. The results show that ASC40 significantly attenuates bone loss and osteoclastogenesis in both models. In conclusion, our results demonstrate that Fasn-mediated DNL is a novel positive regulator of osteoclastogenesis and may serve as a promising therapeutic target for the treatment of osteoclast-driven osteolytic bone diseases.
研究领域:
骨生物学
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代谢医学
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药理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Microbiology
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2025
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IF 4.5
Yuqi Wang,Jun Ma,Haoyu Wang,Jingzheng Yi,Yuxin Bai,Min Hu,Jiaqing Yan
Introduction: Periodontitis and inflammatory bowel disease are chronic inflammatory diseases with shared epidemiological, biological, and therapeutic associations. Given the similarities in their pathogenic factors, this study hypothesized that mesalazine, a key treatment agent for inflammatory bowel disease, could also be effective in managing periodontitis.Methods: The antimicrobial effect of mesalazine on Porphyromonas gingivalis was investigated in vitro, including observations of morphological changes on the surface of P. gingivalis. Additionally, the impact of mesalazine on both the formation and established plaque biofilms was examined. The antimicrobial mechanism was elucidated by assessing the expression of P. gingivalis virulence genes and by determining the disruptive effect on P. gingivalis cell membranes. An in vivo rat model of periodontitis was constructed to evaluate mesalazine’s efficacy and its influence on the periodontal bacterial flora in the context of periodontitis.Results and discussion: Our results demonstrated that mesalazine concentrations ranging from 0.5 to 2 mg/mL significantly inhibited P. gingivalis proliferation over 72 h. Flow cytometry revealed a marked reduction in the number of viable cells following mesalazine treatment. At the nanometer scale, mesalazine induced crumpling and rupture of the P. gingivalis surface, compromising cell membrane integrity. Mesalazine not only suppressed the formation of plaque biofilms by P. gingivalis and polymicrobial communities but also disrupted pre-existing biofilms. The data also suggested that mesalazine could disrupt the integrity of the P. gingivalis cell membrane and inhibit the expression of virulence factors. An animal model of periodontitis in rats was successfully constructed in vivo. Mesalazine treatment inhibited alveolar bone resorption, alleviated inflammation of periodontal tissues, and improved the composition of the periodontal flora to a healthier state. This study establishes that mesalazine can treat periodontitis through modulation of the periodontal flora and its anti-inflammatory properties, thus broadening its classical therapeutic applications.
研究领域:
牙科
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微生物学
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药理学
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感染病学
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DOI
PubMed
高影响因子
Biomaterials Science
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2025
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IF 5.7
Ying Qi,Jing Zheng,Qian Zhang,Yage Sun,Jiaxing Shao,Hongying Wang,Rong Yang,Ziyang Xu,Chunyan Cui,Wenguang Liu
Chronic periodontitis is a long-standing thorny issue for oral health, characterized primarily by the excessive production and accumulation of reactive oxygen species, pathogenic bacterial infection, and the continuous loss of alveolar bone. In the present study, a poly(lipoic acid) (PolyLA) coenzyme-based tissue adhesive (PolyLA/Arg/Ga) was developed for the treatment of periodontitis. It functions by combining the nonantibiotic antimicrobial ion gallium ion (Ga3+ ) to resist pathogenic bacteria and promote osteogenesis; while the basic arginine not only stabilizes PolyLA at room temperature by forming salt bridge hydrogen bonds with its carboxyl groups but also serves as a cofactor, effectively regulating the release behavior of LA-based active molecules and Ga3+ by partially deprotonating the carboxyl groups on PolyLA. This, in turn, imparts significant antioxidant and antimicrobial properties to the adhesive. Thanks to the rich adhesive carboxyl groups on the surface of the adhesive and the structural stability of the hydrophobic PolyLA skeleton in a wet environment, The PolyLA/Arg/Ga exhibits long-lasting wet-resistant adhesion properties to biological tissues. Moreover, in vitro cell experiments and in vivo subcutaneous implantation studies demonstrate that the PolyLA/Arg/Ga adhesive has better cytocompatibility and histocompatibility. The PolyLA/Arg/Ga is explored as a tissue adhesive to treat a periodontitis model in rats.The results demonstrate that the PolyLA/Arg/Ga adhesive more effectively inhibited alveolar bone resorption and promoted periodontal tissue regeneration within 4 weeks compared to commercial patch. Thus, the simply designed yet multifunctional PolyLA/Arg/Ga bioadhesive offers an innovative approach for periodontitis management.
研究领域:
生物材料
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生物医学工程
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牙科医学
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组织工程
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传染病学
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产品关联
DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
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2021
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IF 7.328
Yujie Zhang,Chuanfeng An,Yang Zhang,Haoyue Zhang,Abdullah Faqeer Mohammad,Qiao Li,Weijian Liu,Fei Shao,Jiayi Sui,Changle Ren,Kai Sun,Fang Cheng,Jia Liu,Huanan Wang
Cell microenvironment is a collection of dynamic biochemical and biophysical cues which functions as the key factor in determining cell behavior. Encapsulating single cell into micrometer-scale hydrogels which mimics the cell microenvironment can be used for single cell analysis, cell therapies, and tissue engineering. Here, we developed a microfluidics-based platform to engineer the niche environment at single cell level using alginate microgels crosslinked by different metal ions to regulate stem cell behavior for bone regeneration. Specifically, we revealed that Ca 2+ in the engineered microenvironment promoted osteogenic differentiation of encapsulated stem cells and substantially accelerated the matrix mineralization compared to Sr 2+ in vitro . However, the superior osteoinductive capacity of Ca 2+ compared with Sr 2+ led to comparable bone healing in a rat bone defect model. This attributed to Sr 2+ in microgels to inhibit the osteoclast activity and bone resorption after implantation. In summary, the present study demonstrates metal ions as a critical factor in the environmental cues to affect cell behavior and influence the efficacy of stem cell-based therapy in tissue regeneration, and provides new insights to engineer an expecting microenvironment for regenerative medicine.
研究领域:
组织工程
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干细胞生物学
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再生医学
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生物医学工程
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DOI
PubMed
高影响因子
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