Ma Qingliang, Wang Shiyu, Xue Hong, Ni Linhui, Yuan Putao, Shen Yang, Zheng Bingjie, Wang Qingqing, Zhang Jiateng, Wang Haoming, Xie Hongwei, Jiang Chao, Qin An, Fan Shunwu, Xie Ziang, Jie Zhiwei
Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Mechanism Research and Precision Repair of Orthopaedic Trauma and Aging Diseases of Zhejiang Province, Hangzhou, China.
Nat Commun. 2025 Aug 6;16(1):7228. doi: 10.1038/s41467-025-61938-0.
Highly conserved homeobox genes are closely related to bone formation during embryogenesis, while their role in adult bone resorption remains unclear. In this study, we found that the homeobox gene MSX2 actively participates bone metabolism. Myeloid-specific Msx2 deficiency safeguards bone mass under physiological and pathological conditions. Loss of Msx2 acts as a "brake" in the fusion fate of osteoclasts, resulting in a larger population of pre-osteoclasts. Pre-osteoclasts secrete platelet-derived growth factor-BB (PDGF-BB), which promotes angiogenesis-mediated bone formation. Mechanistically, MSX2 directly binds to the vital osteoclastogenic transcription factor PU.1 and protects it from FBXW7-mediated ubiquitination degradation. Msx2 and Fbxw7 double knockout mitigated the protective effect of MSX2 deficiency on bone mass. Finally, we identified a natural compound, morusinol, that specifically destroys the combination of MSX2 and PU.1, promoting PU.1 degradation and attenuating ovariectomy-induced bone loss. Overall, our results demonstrate that targeting Msx2 is a promising anabolic therapy for osteoporosis.
高度保守的同源框基因在胚胎发育过程中与骨形成密切相关，而它们在成年骨吸收中的作用仍不清楚。在本研究中，我们发现同源框基因MSX2积极参与骨代谢。髓系特异性Msx2缺乏在生理和病理条件下可保护骨量。Msx2的缺失在破骨细胞的融合命运中起“刹车”作用，导致前破骨细胞数量增加。前破骨细胞分泌血小板衍生生长因子-BB（PDGF-BB），其促进血管生成介导的骨形成。机制上，MSX2直接与重要的破骨细胞生成转录因子PU.1结合，并保护其免受FBXW7介导的泛素化降解。Msx2和Fbxw7双敲除减轻了MSX2缺乏对骨量的保护作用。最后，我们鉴定出一种天然化合物桑辛醇，它特异性破坏MSX2和PU.1的结合，促进PU.1降解并减轻卵巢切除诱导的骨丢失。总体而言，我们的结果表明靶向Msx2是一种有前景的骨质疏松症合成代谢疗法。
