Zhang Yufeng, Li Xiaoguang, Lang Jianlong, Li Wenbo, Huang Dengke, Sun Weizong, Yang Li, Li Wenhui, Wang Yi, Zhang Liang
Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, China.
Department of Pain Management, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
iScience. 2024 Feb 1;27(3):109059. doi: 10.1016/j.isci.2024.109059. eCollection 2024 Mar 15.
Overactivation of osteoclasts due to altered osteoclastogenesis causes multiple bone metabolic diseases. However, how osteoclast differentiation is tightly regulated and involved in multiple pathophysiological states remains mystery. In this study, we noticed that the downregulation of BHLHE41 (basic-helix-loop-helix family member e41) was tightly associated with osteoclast differentiation and osteoporosis. Functionally, the upregulation or downregulation of BHLHE41 suppressed or promoted osteoclast differentiation, respectively, . A mechanism study indicated that the direct binding of BHLHE41 to the promoter region of NFATc1 that led to its downregulation. Notably, the inhibition of NFATc1 abrogated the enhanced osteoclast differentiation in BHLHE41-knockdown bone marrow macrophages (BMMs). Additionally, upregulation of BHLHE41 impeded bone destruction in OVX mice with osteoporosis. Therefore, our research reveals the mechanism by which BHLHE41 regulates osteoclast differentiation and bone resorption via NFATc1, and targeting BHLHE41 is a potential strategy for the treatment of osteoporosis.
破骨细胞生成改变导致破骨细胞过度活化，引发多种骨代谢疾病。然而，破骨细胞分化如何受到严格调控并参与多种病理生理状态仍不清楚。在本研究中，我们注意到BHLHE41（碱性螺旋-环-螺旋家族成员e41）的下调与破骨细胞分化和骨质疏松症密切相关。在功能上，BHLHE41的上调或下调分别抑制或促进破骨细胞分化。机制研究表明，BHLHE41直接结合到NFATc1的启动子区域，导致其下调。值得注意的是，抑制NFATc1可消除BHLHE41基因敲低的骨髓巨噬细胞（BMMs）中增强的破骨细胞分化。此外，BHLHE41的上调可抑制骨质疏松症去卵巢（OVX）小鼠的骨破坏。因此，我们的研究揭示了BHLHE41通过NFATc1调节破骨细胞分化和骨吸收的机制，靶向BHLHE41是治疗骨质疏松症的潜在策略。
