Furthermore, activating mutations of mitogen-activated protein kinase kinase 1 (MAP2K1) in non-canonical TGF-β signaling also caused sporadic melorheostosis.161 At the molecular level, TGF-β positively regulates the expression of Runx2, Osterix, Dlx5, and Msx2 to initiate the osteogenic program.153 TGF-β1 induces the expression of integrin Vα5 to promote osteoblast adhesion.162 TGF-β1-SMAD signaling also regulates the expression of connective tissue growth factor (CTGF), a matrix protein that positively regulates osteoblast differentiation and function.163. Here, CCN2 is linked to melorheostosis.