ZMAT1 promotes osteoclast formation and bone loss through TRIM46 mediated YAP1 degradation. [CUT&Tag]

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. There are no relevant reports on the role of Zmat1 as a transcription factor in osteoclast differentiation. To clarify the role of Zmat1 as a transcription factor in osteoclastogenesis, we constructed a Zmat1-overexpressing RAW264.7 cell line and set up a control group. Under RANKL stimulation, cells were collected, incubated with antibodies, and DNA was extracted. The DNA was then sequenced using Second Generation high-throughput sequencing technology. The results indicated that Zmat1 plays a regulatory role in gene transcription one sample were set up for each group.