RNA-Seq - membrane-type 1 matrix metalloproteinase

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, 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 (Mmp14Y573D/Y573D)
shows abnormalities similar to, but also different from 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 modulates bone, cartilage and fat homeostasis
by controlling SSC differentiation through a mechanism independent of
proteolysis.