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 (BMP2) is a growth factor that maintains bone homeostasis through the BMP receptor type Ia (BMPRIa) and type II (BMPRII). BMP2 promotes osteogenesis by inducing the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts; however, it can also trigger BMSC differentiation into adipocytes. BMP2's osteo-inductive ability has made it a potential treatment for osteoporosis, yet its dual role in BMSC differentiation complicates its efficacy. High BMP2 levels cause BMPRIa cleavage, but the downstream effects and the mechanisms governing BMP2-induced osteogenesis or adipogenesis 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 BMP2 concentrations, to explore BMP2-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 BMP2-induced adipogenesis and Caspase-1 inhibition could improve BMP2 therapeutic efficacy for osteoporosis by promoting osteogenesis over adipogenesis.