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Original Article | Open Access

Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling

Ri-Xu Liu1,2,, Rong-He Gu3,, Zhi-Peng Li1,, Zhi-Quan Hao1, Qin-Xiao Hu1, Zhen-Yan Li1, Xiao-Gang Wang4, Wang Tang1, Xiao-He Wang1, Yu-Kai Zeng1, Zhen-Wei Li1, Qiu Dong1, Xiao-Feng Zhu5, Di Chen6, Ke-Wei Zhao7, Rong-Hua Zhang5( ), Zhen-Gang Zha1( ), Huan-Tian Zhang1( )
Department of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University; Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou 510630 Guangdong, China
Department of Orthopedic and Spine Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120 Guangdong, China
School of Basic Medical Sciences of Guangxi Medical University, the Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530022 Guangxi, China
Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, 100191 Beijing, China
Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, College of Pharmacy, Jinan University, Guangzhou 510630 Guangdong, China
Research Center for Computer-aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 518005 Shenzhen, China
Guangzhou Key Laboratory of Chinese Medicine Research on Prevention and Treatment of Osteoporosis, the Third Affiliated Hospital of Guangzhou University of Chinese Medicine, 510375 Guangzhou, China

These authors contributed equally: Ri-Xu Liu, Rong-He Gu, Zhi-Peng Li

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Abstract

Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21−/−) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21−/− and Ctsk-cre; Trim21f/f mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.

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Bone Research
Volume 11,
December 2023
Article number: 56
DOI: 10.1038/s41413-023-00296-3
Cite this article:
Liu R-X, Gu R-H, Li Z-P, et al. Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling. Bone Research, 2023, 11: 56. https://doi.org/10.1038/s41413-023-00296-3

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Received: 15 January 2023
Revised: 26 August 2023
Accepted: 22 September 2023
Published: 26 October 2023
© The Author(s) 2023

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