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

Attur, M. G.; Lu, C.; Zhang, X.; Alexandre, C.; Valacca, C.; Zheng, S.; Meikle, S.; Brukner Dabovic, B.; Tassone, E.; Yang, Q.; Kolupaeva, V.; Yakar, S.; Abramson, S. B.; Mignatti, P.

doi:10.1101/631739

bioRxiv · 10.1101/631739

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

Attur, M. G.·Lu, C.·Zhang, X.·Alexandre, C.·Valacca, C.·Zheng, S.·Meikle, S.·Brukner Dabovic, B.·Tassone, E.·Yang, Q.·Kolupaeva, V.·Yakar, S.·Abramson, S. B.·Mignatti, P.

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Abstract

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 Erk1/2 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.

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Attur, M. G., Lu, C., Zhang, X., Alexandre, C., Valacca, C., Zheng, S., Meikle, S., Brukner Dabovic, B., Tassone, E., Yang, Q., Kolupaeva, V., Yakar, S., Abramson, S. B., Mignatti, P.. 2019-05-08. Membrane-type 1 matrix metalloproteinase (MMP-14) modulates tissue homeostasis by a non-proteolytic mechanism. https://doi.org/10.1101/631739

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