ZMAT1 promotes osteoclast formation and bone loss through TRIM46 mediated YAP1 degradation.
Osteoclasts and osteoblasts play a critical role in bone remodeling, and their dysregulation leads to pathological bone loss. However, precise regulation of their differentiation remains not fully elucidated. This study investigates the role of transcriptional regulator Zinc Finger Matrin-Type 1 (Zmat1) in both osteoclastogenesis and osteoblastogenesis. Zmat1 deficiency resulted in decreased osteoclast activity, and reduced bone resorption. Mechanististically, ZMAT1 was significantly upregulated during osteoclast differentiation and acted as a transcriptional repressor of the E3 ubiquitin ligase TRIM46, which then regulates YAP1 degradation via K48-linked ubiquitination. Furthermore, Zmat1 deficiency also enhanced osteoblast activity and bone formation. These findings highlight a novel ZMAT1/TRIM46/YAP1 axis, providing new insights into the transcriptional regulation of both osteoclast and osteoblast differentiation, and present potential therapeutic targets for osteoporosis. Overall design: Extract bone marrow-derived mononuclear macrophages from wild-type C57BL/6 mice and stimulate with M-CSF for 3 days. Set up control groups: Control_1, Control_2, Control_3. The experimental groups are set up as follows: stimulate with LPS for 3 days: LPS_3d_1, LPS_3d_2, LPS_3d_3; stimulate with LPS for 4 hours: LPS_4h_1, LPS_4h_2, LPS_4h_3; stimulate with RANKL for 3 days: RANKL_3d_1, RANKL_3d_2, RANKL_3d_3; stimulate with RANKL for 4 hours: RANKL_4h_1, RANKL_4h_2, RANKL_4h_3.