Membrane-type 1 matrix metalloproteinase (MMP-14) modulates tissue homeostasis by a non-proteolytic mechanism

Postnatal development and tissue homeostasis are finely controlled by mechanisms that involve cell differentiation, intracellular signaling and extracellular matrix (ECM) remodeling. The ECM-degrading membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14), a transmembrane proteinase with an extracellular catalytic domain and a short cytoplasmic tail, plays an important role in these processes. MT1-MMP is highly expressed in skeletal stem cells (SSC), in which it controls trafficking and differentiation. Its genetic deficiency in the mouse (Mmp14-/- mouse) causes dwarfism, osteopenia, generalized arthritis and lipodystrophy. These phenotypes have been ascribed to defective collagen turnover. However, we have previously shown in vitro that the MT1-MMP cytoplasmic tail activates the Ras-ERK1/2 and AKT signaling pathways by a proteolysis-independent mechanism that controls cell proliferation, migration and survival. Mutation of the unique tyrosine in the MT1-MMP cytoplasmic tail (Y573D) abrogates MT1-MMP mediated signaling without affecting its proteolytic activity. Here we show that the non-proteolytic, signaling function of MT1-MMP modulates postnatal development and tissue homeostasis by controlling SSC differentiation. We found that mice with the MT1-MMP Y573D mutation (Mmp14Y573D/Y573D) show bone, cartilage and adipose tissue abnormalities similar to those of Mmp14-/- mice. Bone marrow (BM)-derived SSC of Mmp14Y573D/Y573D mice show defects in osteoblast, chondrocyte and adipocyte differentiation consistent with the respective tissue abnormalities. Furthermore, the Mmp14Y573D/Y573D mouse phenotypes are rescued by wild-type BM transplant. These results provide the first in vivo demonstration that MT1-MMP, an ECM-degrading proteinase, modulates bone, cartilage and fat homeostasis through a proteolysis-independent, intracellular signaling mechanism that controls SSC differentiation.