Unexpected Promotion of Bone Regeneration by Inhibition of BMPR1A-Mediated BMP Signalling

Bone morphogenetic protein (BMP) signalling plays a pivotal role in bone regeneration by regulating osteoprogenitor cell (OPC) function, and BMPs have been widely used in clinical treatment. However, their limited specificity for OPCs often lead to side effects, highlighting that the regulatory mechanisms of BMP signalling remain to be further elucidated. BMPR1A, a key type I BMP receptor, has emerged as a critical regulator of bone development, yet its precise role in bone regeneration and downstream mechanisms remains unclear. Using OPC-specific conditional knockout (cKO) and constitutively activated (CA) BMPR1A mouse, we found conditional knockout of BMPR1A in OPCs during the first 2 weeks of healing significantly accelerated bone regeneration. At the cellular level, BMPR1A knockout promoted the proliferation of OPCs, thereby accelerating bone regeneration in cKO mice. Mechanistically, BMPR1A knockout reduced ID1 expression, releasing its inhibition of TCF3, which in turn induced GNG4 expression and ultimately activated the PI3K-AKT pathway. Finally, a double-knockdown cell line further demonstrated the role of the BMPR1A-ID1-TCF3-GNG4 signalling axis. This study reveals the function and mechanism of BMPR1A in bone regeneration and provides new insights for more precise BMP-targeted strategies.