Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling
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 osteob...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-10-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-023-00296-3 |
| _version_ | 1797647339339382784 |
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| author | Ri-Xu Liu Rong-He Gu Zhi-Peng Li Zhi-Quan Hao Qin-Xiao Hu Zhen-Yan Li Xiao-Gang Wang Wang Tang Xiao-He Wang Yu-Kai Zeng Zhen-Wei Li Qiu Dong Xiao-Feng Zhu Di Chen Ke-Wei Zhao Rong-Hua Zhang Zhen-Gang Zha Huan-Tian Zhang |
| author_facet | Ri-Xu Liu Rong-He Gu Zhi-Peng Li Zhi-Quan Hao Qin-Xiao Hu Zhen-Yan Li Xiao-Gang Wang Wang Tang Xiao-He Wang Yu-Kai Zeng Zhen-Wei Li Qiu Dong Xiao-Feng Zhu Di Chen Ke-Wei Zhao Rong-Hua Zhang Zhen-Gang Zha Huan-Tian Zhang |
| author_sort | Ri-Xu Liu |
| collection | DOAJ |
| description | 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; Trim21 f/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. |
| first_indexed | 2024-03-11T15:15:54Z |
| format | Article |
| id | doaj.art-7e558dc5024546f48cd9b2d8571239a5 |
| institution | Directory Open Access Journal |
| issn | 2095-6231 |
| language | English |
| last_indexed | 2024-03-11T15:15:54Z |
| publishDate | 2023-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj.art-7e558dc5024546f48cd9b2d8571239a52023-10-29T12:17:35ZengNature Publishing GroupBone Research2095-62312023-10-0111111510.1038/s41413-023-00296-3Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signalingRi-Xu Liu0Rong-He Gu1Zhi-Peng Li2Zhi-Quan Hao3Qin-Xiao Hu4Zhen-Yan Li5Xiao-Gang Wang6Wang Tang7Xiao-He Wang8Yu-Kai Zeng9Zhen-Wei Li10Qiu Dong11Xiao-Feng Zhu12Di Chen13Ke-Wei Zhao14Rong-Hua Zhang15Zhen-Gang Zha16Huan-Tian Zhang17Department of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University; Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan UniversitySchool of Basic Medical Sciences of Guangxi Medical University, the Fifth Affiliated Hospital of Guangxi Medical UniversityDepartment of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University; Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan UniversityDepartment of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University; Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan UniversityDepartment of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University; Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan UniversityDepartment of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University; Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan UniversityKey Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang UniversityDepartment of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University; Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan UniversityDepartment of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University; Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan UniversityDepartment of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University; Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan UniversityDepartment of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University; Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan UniversityDepartment of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University; Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan UniversityGuangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, College of Pharmacy, Jinan UniversityResearch Center for Computer-aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesGuangzhou Key Laboratory of Chinese Medicine Research on Prevention and Treatment of Osteoporosis, the Third Affiliated Hospital of Guangzhou University of Chinese MedicineGuangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, College of Pharmacy, Jinan UniversityDepartment of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University; Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan UniversityDepartment of Bone and Joint Surgery, the First Affiliated Hospital of Jinan University; Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan UniversityAbstract 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; Trim21 f/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.https://doi.org/10.1038/s41413-023-00296-3 |
| spellingShingle | Ri-Xu Liu Rong-He Gu Zhi-Peng Li Zhi-Quan Hao Qin-Xiao Hu Zhen-Yan Li Xiao-Gang Wang Wang Tang Xiao-He Wang Yu-Kai Zeng Zhen-Wei Li Qiu Dong Xiao-Feng Zhu Di Chen Ke-Wei Zhao Rong-Hua Zhang Zhen-Gang Zha Huan-Tian Zhang Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling Bone Research |
| title | Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling |
| title_full | Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling |
| title_fullStr | Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling |
| title_full_unstemmed | Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling |
| title_short | Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling |
| title_sort | trim21 depletion alleviates bone loss in osteoporosis via activation of yap1 β catenin signaling |
| url | https://doi.org/10.1038/s41413-023-00296-3 |
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