Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis

Qingliang Ma, Shiyu Wang, Hong Xue, Linhui Ni, Putao Yuan, Yang Shen, Bingjie Zheng, Qingqing Wang, Jiateng Zhang, Haoming Wang, Hongwei Xie, Chao Jiang, An Qin, Shunwu Fan (), Ziang Xie () and Zhiwei Jie ()
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Qingliang Ma: Zhejiang University School of Medicine
Shiyu Wang: Zhejiang University School of Medicine
Hong Xue: Zhejiang University School of Medicine
Linhui Ni: Zhejiang University
Putao Yuan: Zhejiang University School of Medicine
Yang Shen: Zhejiang University School of Medicine
Bingjie Zheng: Zhejiang University School of Medicine
Qingqing Wang: Zhejiang University School of Medicine
Jiateng Zhang: Zhejiang University School of Medicine
Haoming Wang: Zhejiang University School of Medicine
Hongwei Xie: Zhejiang University School of Medicine
Chao Jiang: Zhejiang University School of Medicine
An Qin: Shanghai Jiaotong University School of Medicine
Shunwu Fan: Zhejiang University School of Medicine
Ziang Xie: Zhejiang University School of Medicine
Zhiwei Jie: Zhejiang University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61938-0

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