Membrane-Type 1 Matrix Metalloproteinase (MMP-14) Modulates Tissue Homeostasis by a Non-Proteolytic Mechanism

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 (Mmp14-/-) and man causes dwarfism, osteopenia, generalized arthritis and lipodystrophy. These abnormalities have been 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. Mutation of Y573 (Y573D) blocks signaling without affecting proteolytic activity. Here we report that a mouse with the MT1-MMP Y573D mutation (Mmp14Y573D/Y573D) shows abnormalities similar to those of Mmp14-/- mice. Skeletal stem cells (SSC) of Mmp14Y573D/Y573D mice show defective differentiation consistent with the mouse phenotype, which is rescued by wild-type SSC transplant. These results provide the first in vivo demonstration that MT1-MMP, an ECM-degrading proteinase, modulates bone, cartilage and fat homeostasis by controlling SSC differentiation through a mechanism independent of proteolysis.