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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2024
·
IF 18.5
Wenqian Zhang,Shengming Zhang,Minghao He,Weixian Hu,Wenhao Han,Kangkang Zha,Qian Feng,Guohui Liu,Yanli Zhao,Bobin Mi
Postmenopausal bone loss due to estrogen deficiency necessitates effective therapeutic strategies. Our study explores targeting macrophage Aurora A kinase to mitigate bone loss. Aurora A kinase phosphorylation is observed being increased in bone marrow-derived macrophages (BMDMs) from ovariectomy (OVX) mice, along with a reduction in programmed death-ligand 1 (PD-L1) expression. Detailed analysis reveals that PD-L1 plays an immunomodulatory role by lowering the ratio of T helper 17 cells and regulatory T cells. The metabolic shift toward glycolysis through transcriptome sequencing, induced by Aurora A kinase inhibition, is essential for PD-L1 expression in BMDMs. The interaction between Aurora A kinase and cytochrome C oxidase subunit 5B is found to enhance PD-L1 expression. To apply these findings therapeutically, a multifunctional system is developed using a Nickel-metal organic framework combined with bisphosphonate and MLN8237 (BP@Ni-MOF/MLN8237). This system targets bone tissues through bisphosphonate and effectively delivers MLN8237 to macrophages, promoting PD-L1 expression for a favorable immune environment. Moreover, this system exhibits an obvious angiogenic effect. The present study highlights the crucial roles of macrophage Aurora A kinase and PD-L1 in maintaining bone homeostasis as well as the angiogenesis effect by Ni-MOF engineered system, presenting a promising therapeutic approach to prevent postmenopausal bone loss.
研究领域:
医学
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免疫学
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骨科学
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
CELLULAR SIGNALLING
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2021
·
IF 4.315
Jinpeng Zhuang,Hua Ning,Maoqing Wang,Wei Zhao,Yongbin Jing,Xiaoqi Liu,Jianing Zu,Pengyu Kong,Xiaoyan Wang,Changhao Sun,Jinglong Yan
During osteoporosis, fat mass and obesity-associated protein (FTO) promotes the shift of bone marrow mesenchymal stem cells to adipocytes and represses osteoblast activity. However, the role and mechanisms of FTO on osteoclast formation and bone resorption remain unknown. In this study, we investigated the effect of FTO on RAW264.7 cells and bone marrow monocytes (BMMs)-derived osteoclasts in vitro and observed the influence of FTO on ovariectomized (OVX) mice model to mimic postmenopausal osteoporosis in vivo. Results found that FTO was up-regulated in BMMs from OVX mice. Double immunofluorescence assay showed co-localization of FTO with tartrate-resistant acid phosphatase (TRAP) in femurs of OVX mice. FTO overexpression enhanced TRAP-positive osteoclasts and F-actin ring formation in RAW264.7 cells upon RANKL stimulation. The expression of osteoclast differentiation-related genes, including nuclear factor of activated T cells c1 (NFATc1) and c-FOS, was upregulated in BMMs and RAW264.7 cells after FTO overexpression. FTO overexpression induced the phosphorylation and nuclear translocation of factor-kappa B (NF-κB) p65 in BMMs and RAW264.7 cells exposed to RANKL. ChIP and dual-luciferase assays revealed that FTO overexpression contributed to RANKL-induced binding of NF-κB to NFATc1 promoter. Rescue experiments suggested that FTO overexpression-mediated osteoclast differentiation was suppressed after intervention with a NF-κB inhibitor pyrrolidine dithiocarbamate . Further in vivo evidence revealed that FTO knockdown increased bone trabecula and bone mineral density, inhibited bone resorption and osteoclastogenesis in osteoporotic mice. Collectively, our research demonstrates that downregulated FTO inhibits bone resorption and osteoclastogenesis through NF-κB inactivation, which provides a novel reference for osteoporosis treatment.
研究领域:
骨骼生物学
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分子生物学
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细胞生物学
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内分泌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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