Zfp462 Is a Key Mediator of Osteoblast Differentiation and Might Contribute to Age‐Related Bone Loss

Senile osteoporosis is characterized by a progressive decline in bone formation. Our study identifies Zfp462/ZNF462 as a novel regulator of osteoblast differentiation, providing new mechanistic insights into the aging-related change in bone formation. Here, we demonstrate that ZNF462, MOZ, and RUNX2 physically interact with each other and promote osteoblastic bone formation by increasing RUNX2 activity and histone H3 acetylation. Importantly, we reveal that aging decreases ZNF462 expression in bone cells, a process linked to reduced occupancy of the histone variant H2A.Z at the ZNF462 locus, leading to lower transcriptional activator histone H3K4 trimethylation. The osteoblast-specific Zfp462 deficiency in mice results in decreased bone mass and strength, primarily due to impaired osteoblast function. By uncovering a previously unknown ZNF462-MOZ-RUNX2 axis, this work provides a molecular basis for understanding the development of senile osteoporosis. Thus, targeting ZNF462 or MOZ could offer a new strategy to restore bone formation in aging populations.