Caspase-1 Mediated Cleavage of BMP Type I Receptor Drives BMP2-Induced Differentiation of Bone Marrow Mesenchymal Stem Cells into Adipocytes

Bone Morphogenetic Protein-2 (BMP-2) is a growth factor that maintains bone homeostasis through BMP receptor type-I (BMPRIa) and type II (BMPRII). BMP-2 promotes osteogenesis by inducing bone marrow mesenchymal stem cell (BMSC) differentiation into osteoblasts, but it can also trigger BMSC differentiation into adipocytes. BMP-2's osteo-inductive ability has made it a potential treatment for osteoporosis, yet its dual role in BMSC differentiation complicates its efficacy. The mechanisms governing BMP-2-induced adipogenesis remain unclear. High BMP-2 levels cause BMPRIa cleavage, but the downstream effects and determinants of osteogenesis or adipogenesis activation are unresolved. Here, we identify Caspase-1 as a key mediator of BMPRIa cleavage and its downstream effects on adipogenesis. We used primary BMSCs from C57BL/6 mice, stimulated with varying BMP-2 concentrations, to explore BMP-2-induced BMPRIa cleavage and its impact on PPARγ – a key regulator of adipogenesis. Western blotting and immunostaining using antibodies against BMPRIa and PPARγ uncovered BMPRIa cleavage and revealed the nuclear translocation of the cleaved segment, colocalizing with PPARγ. Caspase-1 inhibition significantly reduced BMPRIa cleavage and PPARγ expression, highlighting its pivotal role in adipogenic differentiation. Understanding the molecular mechanisms of BMP-2-induced adipogenesis and Caspase-1 inhibition could improve BMP-2 therapeutic efficacy for osteoporosis by promoting osteogenesis over adipogenesis.