ZMAT1 Promotes Osteoclastogenesis Through TRIM46 Mediated YAP1 Degradation and Inhibits Osteoblastogenesis

Osteoclasts and osteoblasts play critical roles in bone remodeling, and their dysregulation leads to pathological bone loss. However, the precise mechanisms underlying the regulation of differentiation remain unclear. This study investigated the role of the transcriptional regulator Zinc Finger Matrin-Type 1 (Zmat1) in both osteoclastogenesis and osteoblastogenesis. Zmat1 deficiency resulted in decreased osteoclast activity, and bone resorption. Mechanistically, ZMAT1 was significantly upregulated during osteoclast differentiation and acted as a transcriptional repressor of the E3 ubiquitin ligase TRIM46, which regulates YAP1 degradation via K48-linked ubiquitination. Furthermore, Zmat1 deficiency 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.