REGγ is essential to maintain bone homeostasis by degrading TRAF6, preventing osteoporosis

• 成果类型: Article
• 署名作者: Du, Yingying; Chen, Hui; Zhou, Lei; Guo, Qunfeng; Gong, Shuangming; Feng, Siyuan; Guan, Qiujing; Shi, Peilin; Lv, Tongxin; Guo, Yilan; Yang, Cheng; Sun, Peng; Li, Kun; Xu, Shuogui; Li, Lei
• 署名单位: East China Normal University; Fudan University; East China Normal University; East China Normal University; Shanghai Jiao Tong University; Naval Medical University; East China Normal University; East China Normal University; Naval Medical University; East China Normal University; East China Normal University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12289
• DOI: 10.1073/pnas.2405265121
• 发表日期: 2024-11-19
• 关键词: osteoclast; rankl; women

摘要

Primary osteoporosis, manifesting as decreased bone mass and increased bone fragility, is a silent disease that is often ignored until a bone breaks. Accordingly, it is urgent to develop reliable biomarkers and novel therapeutic strategies for osteoporosis treatment. Here, we identified REG gamma as a potential biomarker of osteoporotic populations through proteomics analysis. Next, we demonstrated that REG gamma deficiency increased osteoclast activity and triggered bone mass loss in REG gamma knockout (KO) and bone marrow- derive macrophage (BMM)- conditional REG gamma KO mice. However, the osteoclast activity decreased in BMM- conditional REG gamma overexpression mice. Mechanistically, we defined that REG gamma-20S proteasome directly degraded TRAF6 to inhibit bone absorption in a ubiquitin- independent pathway. More importantly, BMM- conditional Traf6KO with REG gamma KO mice could rescue the osteoporosis phenotypes. Based on NIP30 (a REG gamma inhibitor) dephosphorylation by CKII inhibition activated the ubiquitin- independent degradation of TRAF6, we selected TTP22, an inhibitor of CKII, and defined that TTP22 could alleviate osteoporosis in vitro and in vivo. Overall, our study reveals a unique function of NIP30/REG gamma/TRAF6 axis in osteoporosis and provides a potential therapeutic drug TTP22 for osteoporosis.