FASEB JOURNAL
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2020
·Vol. 34
·期 3
·3583-3593
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IF 4.966
Bu Yang,Shangfu Li,Zheng Chen,Feng Feng,Lei He,Bin Liu,Tianwei He,Xuan Wang,Ruiqiang Chen,Zihao Chen,Peigen Xie,Limin Rong
Background Amyloid β peptide (Aβ) is involved in osteoporosis, but the effects of Aβ on osteoblast and bone formation remain unclear. In this study, we investigated the effect of Aβ on bone formation. Methods An animal model of osteoporosis was established by ovariectomy in C57BL/6 mice. The mice received intraperitoneal injection of Aβ. The effect of Aβ on the osteogenic differentiation of human bone marrow stromal stem cells (hBMSCs) and differentiation of both pre-osteoblasts and pre-osteoclasts in a co-culture system were investigated. Results In the animal study, intraperitoneal injection of Aβ for 8 weeks promoted early and late osteogenic differentiation of hBMSCs. Aβ treatment significantly elevated osterix + (osteoblastic) cells but decreased TRAP + cells (osteoclasts) in the distal femur bone. In vitro study showed that Aβ treatment significantly enhanced matrix mineralization and osteogenic markers (Runx2 and osteocalcin). Aβ treatment activated Wnt/β-catenin signaling in hBMSCs. The effect of Aβ was blocked by DKK1 (a Wnt/β-catenin inhibitor) treatment. In the co-culture system, Aβ treatment significantly increased the ALP activities of MC3T3-E1 cells (pre-osteoblasts) but reduced the TRAP + RAW264.7 cells (pre-osteoclasts). Aβ treatment upregulated TCF1 and OPG proteins in MC3T3-E1 cells. Aβ treatment upregulated IκB-α but downregulated NFATc1protein in RAW264.7 cells. These effects were blocked by XAV-939 (a Wnt signaling antagonist), and then rescued by additional Wnt3a (a Wnt agonist). Conclusion Aβ treatment simultaneously promoted osteogenic differentiation via Wnt/β-catenin signaling, and inhibited osteoclasts differentiation via the OPG/RANKL/RANK system, suggesting Aβ is a positive regulator of osteoblast differentiation and bone formation.
研究领域:
生物学
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医学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2020
·
IF 3.943
Ji Li,Ziquan Sun,Yu Lin,Yan Yan,Haichao Yan,Bao Jing,Zhiyang Han
Periodontitis is a common chronic disease. Osteoclast differentiation contributes to alveolar bone resorption which is a distinct phenomenon during periodontitis. Syndecan 4 (SDC4), a member of the syndecan family, was found to be highly expressed during periodontitis. However, little is known about its role in periodontitis. Herein, we explored the role of SDC4 in osteoclast differentiation. An experimental periodontitis rat model was established by ligating the right first molar. The SDC4 expression in periodontium was detected by western blot and immunofluorescence. Our study demonstrated that SDC4 was highly expressed in the periodontium of periodontitis rats. It was positively transcriptionally regulated by NF-κB. SDC4 silencing abrogated osteoclast differentiation induced by RANKL, while SDC4 overexpression enhanced osteoclast differentiation. Moreover, SDC4 enhanced autophagy induced by RANKL. 3-MA, an autophagy inhibitor, was employed to explore whether SDC4 impacts osteoclast differentiation through activating autophagy. Treatment with 3-MA abolished osteoclast differentiation which was enhanced by SDC4, indicating that SDC4 promotes osteoclast differentiation through activating autophagy. This study reveals that SDC4 may contribute to osteoclast differentiation during periodontitis through activating autophagy. It sheds light on the important role of SDC4 in periodontitis.
研究领域:
牙医学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 24
·12151
·
IF 4.9
Yuyan Zhang,Xinwei Wei,Ren Sheng,Guijun Yang,Xiaowan Han,Jingrui Wang,Chao Liu,Shunwang Li,Lijuan Lei,Weilian Jiang,Yang Lun,Shuyi Si,Jing Zhang,Yanni Xu
Osteoporosis is a systemic skeletal disease that severely impairs the health of the elderly population. The interaction between the receptor activator of the NF-κB ligand (RANKL) and its receptor RANK is critical for osteoclast differentiation and function. Therefore, targeting the RANKL/RANK interaction represents a promising strategy for osteoporosis. In this study, we employed a newly established yeast two-hybrid system based on RANKL/RANK interaction and identified IMB-R38, a novel benzamide compound that dose-dependently blocked RANKL/RANK interaction by inhibiting the growth of AH109 cells harboring pAD-RANKL/pBD-RANK plasmids in quadruple-dropout medium. IMB-R38 significantly suppressed osteoclast differentiation, disrupted F-actin ring formation, and downregulated the expression of osteoclast-specific genes, including NFATc1 and MMP9 in RANKL-induced RAW264.7 macrophages. IMB-R38 also promoted osteoblast differentiation by upregulating the expression of osteogenic genes. Importantly, in a dexamethasone (DXM)-induced osteoporotic zebrafish model, IMB-R38 significantly increased bone mineralization, with anti-osteoporosis efficacy superior to that of alendronate sodium (Alen). RT-qPCR assays showed that IMB-R38 significantly upregulated the mRNA expression of osteogenesis genes (Bmp2,Runx2a,Runx2b,Sp7,Alp, andOc) while markedly downregulating that of the osteoclastogenesis genes (Mmp9,Mmp13,andMmp2) compared with the DXM group. Mechanistically, an SPR assay confirmed that IMB-R38 directly binds with RANK but not RANKL to disrupt RANKL/RANK interaction. Furthermore, Asp168 of RANK was identified as a key amino acid that mediates both RANKL interaction and IMB-R38 binding. The inhibition of RANKL/RANK by IMB-R38 suppressed JNK phosphorylation and, consequently, osteoclast differentiation and function. Collectively, our findings identify IMB-R38 as a novel RANKL/RANK inhibitor with therapeutic potential for osteoporosis through its regulation of bone metabolism.
研究领域:
药理学
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骨骼生物学
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分子医学
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药物发现
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Chuanyong Zhao,Fanghui Wu,Liben Zhao,Jiangtao Zhong,Chenhao Huang,Zhangchi Jiang,Jingqi Zheng,Shengwu Yang,Chunwu Zhang,Lei Zhang
Osteoporosis is typified by increased bone degradation mediated through osteoclast activity, necessitating innovative interventions. This research explores the therapeutic efficacy of corosolic acid (CA), a triterpenoid recognized for its antioxidative capacity, emphasizing its mechanism through binding to RANKL to inhibit osteoclast development and reinforce redox balance. High-throughput transcriptome sequencing assessed CA's effects on osteoclast gene networks during differentiation. Combined molecular docking and RANKL-induced signaling cascade assessment elucidated CA's molecular regulatory mechanism governing RANKL-activated osteoclastogenesis. CA impeded RANKL-stimulated differentiation of bone marrow-derived macrophages (BMMs) into osteoclasts and disrupted F-actin ring assembly without cytotoxicity. At the molecular level, CA interfered with RANKL-initiated activation of the canonical NF-κB and MAPK pathways, evidenced by suppressed phosphorylation of IκB-α, ERK, JNK, and p38, and concurrent downregulation of osteoclast-specific transcriptional markers. Moreover, CA restricted NFATc1 translocation into the nucleus. In addition to inhibiting osteoclastogenesis, CA modulated oxidative stress by curbing reactive oxygen species (ROS) production and augmenting antioxidant enzyme expression. In vivo, using an ovariectomy-induced bone loss model, CA treatment led to notable improvements in trabecular bone architecture. Collectively, these data highlight CA's potential to mitigate osteoclastic bone resorption through targeted RANKL inhibition, suppressing NF-κB/MAPK signaling and redox regulation, underscoring its therapeutic potential for postmenopausal osteoporosis.
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高影响因子
CURRENT PHARMACEUTICAL BIOTECHNOLOGY
·
2021
·Vol. 22
·期 1
·168-175
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IF 2.837
Sun Lin-Jun,Li Chong,Wen Xiang-hao,Guo Lu,Guo Zi-Fen,Liao Lan-qing,Guo Yu
Background: Icariin (ICA), one of the main effective components isolated from the traditional Chinese herb Epimedium brevicornu Maxim., has been reported to possess extensive pharmacological actions, including enhanced sexual function, immune regulation, anti-inflammation, and antiosteoporosis.
Methods: Our study was designed to investigate the effect of ICA on cell proliferation and differentiation and the molecular mechanism of OPG/RANKL mediated by the Estrogen Receptor (ER) in hFOB1.19 human osteoblast cells. Results: The experimental results show that ICA can stimulate
cell proliferation and increase the activity of Alkaline Phosphatase (ALP), Osteocalcin (BGP) and I Collagen (Col I) and a number of calcified nodules. Furthermore, the mRNA and protein expression of OPG and RANKL and the OPG/ RANKL mRNA and protein expression ratios were upregulated by ICA.
The above-mentioned results indicated that the optimal concentration of ICA for stimulating osteogenesis was 50ng/mL. Subsequent mechanistic studies comparing 50ng/mL ICA with an estrogen receptor antagonist demonstrated that the effect of the upregulated expression is connected with the estrogen
receptor. In conclusion, ICA can regulate bone formation by promoting cell proliferation and differentiation and upregulating the OPG/RANKL expression ratio by the ER in hFOB1.19 human osteoblast cells.
研究领域:
药理学
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细胞生物学
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分子生物学
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内分泌学
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骨科
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DOI
PubMed
高影响因子
FOOD RESEARCH INTERNATIONAL
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2026
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IF 8.8
Chunqing Ai,Lu Wang,Xingchen Ye,Xiaomeng Ren,Shuang Song,Xuelu Li
Fucoidan (GKP) alleviates OVX-induced bone loss by suppressing osteoclastogenesis. • GKP improves systemic metabolism and identifies betaine as a key metabolite effector. • Betaine attenuates osteoclastogenesis by regulating the OPG/RANK/RANKL signaling. Postmenopausal osteoporosis (PMOP), characterized by excessive bone resorption and impaired bone remodeling, remains a significant global health challenge. This study investigated the protective effects of fucoidan from giant kelp (GKP) against PMOP and its underlying mechanisms in ovariectomized mice. GKP supplementation attenuated bone loss by preserving trabecular microarchitecture, normalizing systemic mineral homeostasis, and suppressing osteoclastogenesis, as evidenced by the downregulation of osteoclast-related genes. 16S rRNA gene sequencing revealed that GKP reshaped the gut microbiota by decreasing the Bacteroidota/Firmicutes ratio and enriching beneficial taxa, which promoted short-chain fatty acid production. Targeted metabolomics revealed that GKP induced profound systemic metabolic reprogramming, particularly amino acid metabolism, and identified betaine as a key systemic metabolite effector upregulated following GKP treatment. In vitro assays demonstrated that betaine suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and mitigated inflammation. In vivo validation demonstrated that betaine intervention recapitulated the osteoprotective phenotype observed in GKP-treated mice, which was associated with regulation of the osteoprotegerin/RANKL/RANK signaling axis. These results indicate that GKP exerts anti-osteoporotic effects in association with changes in gut microbiota and systemic metabolism, while betaine-mediated regulation of the OPG/RANKL/RANK signaling may contribute to its osteoprotective activity. Download: Download high-res image (177KB) Download: Download full-size image
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高影响因子
BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH
·
2019
·
IF 1.85
Mo Hui,Zhang Ning,Li Huifu,Li Fan,Pu Rong
Cuscuta chinensis Lam. (Convolvulaceae) is an important herbal medicine widely used to improve sexual function, treat osteoporosis, and prevent aging, and has been reported to exhibit anti-osteoporotic effects in vitro. However, the activity of Cuscuta chinensis Lam. on glucocorticoid-induced osteoporosis still remains unclear. The present study aimed to assess the protective effect and the underlying mechanism of action of Cuscuta chinensis extract (CCE) against glucocorticoid-induced osteoporosis in vivo. Sprague-Dawley rats were randomly divided into four groups as follows: control group, osteoporosis group, and 2 CCE-treated osteoporosis groups (100 mg·kg-1·day-1). Blood samples and femur bones were collected for immunohistochemistry, biochemical, mRNA expression, and western blot analysis. HPLC analysis revealed that chlorogenic acid, quercetin, and hyperin were the major constituents of CCE. The results indicated that CCE increased bone length, bone weight, and bone mineral density and suppressed dexamethasone (DEX)-induced reduction in body weight. In addition, TRAP staining indicated that CCE reduced osteoclasts in DEX-induced osteoporosis rats. Mechanistically, CCE treatment alleviated the increase of bone resorption markers and the decline of osteogenic markers, which might be partially mediated by regulation of RANKL/OPG and RunX2 pathways. These results suggest that CCE showed promising effects in the protection against glucocorticoid-induced osteoporosis through protecting osteoblasts and suppressing osteoclastogenesis.
研究领域:
药理学
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骨骼生物学
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中药学
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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
FASEB JOURNAL
·
2025
·Vol. 39
·期 3
·e70379
·
IF 4.2
Jiancheng Yang,Qinghua Tang,Siyu Li,Lei Yang,Ming Yang,Qingmei Li,Yan Feng,Mingming Pan,Yuhong Zeng
The accumulation of intracellular reactive oxygen species (ROS) is widely recognized to stimulate the development of osteoclasts, a crucial factor in the onset of osteoporosis. The ROS scavenging capability of Prussian blue nanoparticles (PBNPs) is exceptional, and they possess excellent biocompatibility. However, the effects of PBNPs on osteoporosis remain unknown. Present study aimed to investigate whether PBNPs could inhibit osteoclast differentiation and prevent ovariectomy (OVX)-induced bone loss by suppressing ROS. In vitro experiments demonstrated that PBNPs attenuated osteoclastogenesis and downregulated the expression of osteoclast-related genes. Mechanistically, PBNPs reduce cellular ROS by blocking RANKL-induced ROS generation and increasing the expression of ROS scavenging enzymes, which in turn block the NF-κB, ERK, JNK, and p38 pathways, thereby reducing NFATc1 signaling. According to in vivo experimental results, OVX caused a significant rise in ROS in the bone marrow, an increase in osteoclastic number on the bone surface, and substantial bone loss; however, PBNPs significantly reduced ROS and successfully protected OVX-induced bone damages. In conclusion, this study showed for the first time that PBNPs prevented OVX-induced bone loss and attenuate osteoclastogenesis, indicating that PBNPs may be a viable alternative therapy for the management of osteoclast-associated bone disorders. Graphical Once RANKL binds to RANK on the cell membrane of BMMs, the NF-κB and MAPK pathways become activated, resulting in the amplification of NFATc1, which upregulates the expression of osteoclast-specific genes such as CTSK , Integrin αV , Atp6v0d2 , and MMP9 . These signaling events are mediated by the RANKL-induced ROS signaling. PBNPs decreased levels of ROS and mitigated these signaling pathways by decreasing ROS production and enhancing the expression of antioxidant enzymes. Consequently, PBNPs prevented osteoclastogenesis.
研究领域:
骨生物学
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纳米医学
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药理学
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PubMed
高影响因子
JOURNAL OF DRUG TARGETING
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2019
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IF 3.277
Jun Ma,Di Du,Jia Liu,Lei Guo,Yongchuan Li,Aimin Chen,TianWen Ye
Hydrogen sulphide (H2S), a gasotransmitter, plays an important role in the regulation of bone homeostasis. However, the precise effect of H2S on osteoclasts was still elusive. The goal of this study was to determine the potential role of H2S in regulation of osteoclasts and the underlying mechanisms by which H2S affected osteoclastogenesis. The present study applied western blot, quantitative real-time PCR, tartrate-resistant acid phosphatase staining, pit formation assay, immunofluorescence confocal microscopy, transmission electron microscopy and annexin V-fluorescein isothiocyanate/propidium iodide double-staining assay. The results showed that the expressions of cystathionine b-synthase (CBS) and cystathionine c-lyase (CSE) were obviously increased in osteoclast differentiation induced by the receptor activator of nuclear factor kappa-β ligand (RANKL). In addition, H2S promoted RANKL-induced osteoclastogenesis and inhibited apoptosis of mature osteoclasts. Mechanistically, H2S inhibited autophagy in Raw 264.7 cells. Autophagy activator (rapamycin) alleviated the induction of osteoclast differentiation by H2S. Further studies showed that H2S inhibited autophagy by activating the PI3K/AKT/mTOR signalling pathway. Taken together, our results implicated that exogenous H2S could promote osteoclastogenesis by activating the PI3K/AKT/mTOR pathway to downregulate autophagy.
研究领域:
骨骼生物学
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细胞信号传导
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分子生物学
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PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2020
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IF 3.347
Haoyi Zheng,Haitao Feng,Wenzhong Zhang,Yantao Han,Wenwen Zhao
With the growth of the aging population, osteoporosis is becoming a global health problem. Ursolic acid (UA) is an active ingredient existed in a variety of foods and nature plants and owns plenty of pharmacological effects especially in treating metabolic disease . Our predication from network pharmacology hinted that UA has potential for ameliorating osteoporosis. Firstly through in vivo experiment, we confirmed that UA administration obviously protected against ovariectomy (OVX)-induced osteoporosis in rats by improving microarchitectural deterioration of trabecular bone ( P < 0.001), decreasing numbers of TRAP positive osteoclast in vertebra ( P < 0.001), as well as decreasing serum osteoclast-specific cytokines release ( P < 0.001). Besides, UA ameliorated kidney damage secondary to OVX-induced osteoporosis by ameliorating glomerular atrophy, decreasing BUN and creatinine levels in OVX rats. In vitro , UA noticeably decreased osteoclastic-special marker proteins c-Fos and NFATc1 expressions ( P < 0.001) in response to RANKL stimulation in macrophagy. Importantly, autophagy pathway was activated in the process of osteoclast differentiation and blocked by UA pretreatment . Furthermore, autophagy inhibitors suppressed osteoclast differentiation ( P < 0.001). Collectively, UA may ameliorate osteoporosis by suppressing osteoclast differentiation mediated by autophagy. Our research provides scientific support for UA treating osteoporosis and offers an optimal dose for daily intake of UA safely to prevent bone diseases.
研究领域:
药理学
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老年医学
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骨骼生物学
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DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2025
·
IF 5.1
Xuehui Deng,Bingfeng Lin,Wenlong Xiao,Fang Wang,Pingcui Xu,Nani Wang
Background Specnuezhenide (SPN) is an iridoid glycoside isolated from Fructus Ligustri Lucidi, an herb prescribed for the treatment of senile osteoporosis. However, the direct role of SPN on bone metabolism remains unclear. In this study, the effects of SPN on d-galactose (d-gal)-induced mice, bone marrow mesenchymal stem cells (BMSCs), and nuclear factor-κB ligand-induced osteoclasts were examined.Methods Micro-computed tomography was used to observe the bone microstructure. Osteogenesis was examined using Western blotting and alkaline phosphatase staining. Osteoclastogenesis was examined using Western blotting and F-actin ring staining. Senescence-associated β-galactosidase was used to detect cell senescence. In addition, the expression of Takeda G protein-coupled receptor 5 (TGR5)/farnesoid X receptor (FXR) signaling pathway-related genes and proteins was determined through quantitative real-time polymerase chain reaction and immunofluorescence.Results Oral administration of SPN improved the bone microstructure in d-gal-induced mice and increased bone mineral density, bone volume, trabecular thickness, and trabecular number. SPN also upregulated the expression of the osteogenesis markers osteocalcin, bone morphogenetic protein 2, and runt-related transcription factor 2 and downregulated the expression of the osteoclasis markers tartrate-resistant acid phosphatase, nuclear factor-κB, and nuclear factor of activated T-cells in the d-gal-induced bone. Furthermore, SPN increased alkaline phosphatase staining, inhibited F-actin ring formation, and reduced the activity of senescence-associated β-galactosidase in vitro. Mechanistically, SPN activated the TGR5/FXR pathway in d-gal-induced BMSCs and osteoclasts. The protective effects of SPN were abolished after addition of the TGR5 inhibitor SBI-115 or FXR inhibitor DY268. Moreover, SPN could elevate the protein and mRNA levels of TGR5, FXR, and the downstream small heterodimer partner in d-gal-induced bone.Conclusion SPN alleviated senile osteoporosis and cell senescence by activating the TGR5/FXR pathway.
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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PubMed
高影响因子
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