Bone morphogenetic protein (BMP)-9, a systemic homeostasis factor with diverse functions in the liver and beyond

Bone Morphogenetic Protein-9 (BMP-9), a circulating cytokine belonging to the TGF-β superfamily, is increasingly recognized as a critical regulator of tissue homeostasis with diverse roles in both health and disease. This review recapitulates current knowledge regarding BMP-9, shifting focus beyond its traditional association with bone formation to highlight its significant influence on physiology and pathology in the liver but also in other tissues and organs. We discuss how BMP-9 exerts intricate control over various cell types, affecting key processes such as angiogenesis, macrophage polarization, and regeneration. Intriguingly, while in the liver, BMP-9 contributes to the maintenance of sinusoidal endothelial cell quiescence and Kupffer cell identity, dysregulation of its signaling can as well promote fibrosis. The complexity of BMP-9 function is further compounded by its cross-talks with other signaling molecules like TGF-β, as well as non-Smad pathways. In this review, we summarize current knowledge about the functions of BMP-9 in humans and discuss its therapeutic potential.