RNA-Seq - membrane-type 1 matrix metalloproteinase

<p>Membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14), a transmembrane proteinase with a short cytoplasmic tail, is a major effector of extracellular matrix (ECM) remodeling. Genetic silencing of MT1-MMP in mouse (<i>Mmp14^-/-</i>) and man causes dwarfism, osteopenia, arthritis and lipodystrophy, abnormalities ascribed to defective collagen turnover. We have previously shown non-proteolytic functions of MT1-MMP mediated by its cytoplasmic tail, where the unique tyrosine (Y573) controls intracellular signaling. The Y573D mutation blocks TIMP2/MT1-MMP-induced Erk and Akt signaling without affecting proteolytic activity. Here we report that a mouse with the MT1-MMP Y573D mutation (<i>Mmp14^Y573D/Y573D</i>) shows abnormalities similar to, but also different from those of <i>Mmp14^-/-</i> mice. Skeletal stem cells (SSC) of <i>Mmp14^Y573D/Y573D</i> mice show defective differentiation consistent with the mouse phenotype, which is rescued by wild-type SSC transplant. These results provide the first <i>in vivo</i> demonstration that MT1-MMP modulates bone, cartilage and fat homeostasis by controlling SSC differentiation through a mechanism independent of proteolysis.</p>