Membrane-type 1 Matrix Metalloproteinase Modulates Tissue Homeostasis by a Non-proteolytic Mechanism

Mukundan Attur, Cuijie Lu, Xiaodong Zhang, Tianzhen Han, Cassidy Alexandre, Cristina Valacca, Shuai Zheng, Sarina Meikle, Branka Brukner Dabovic, Evelyne Tassone, Qing Yang, Victoria Kolupaeva, Shoshana Yakar, Steven Abramson, Paolo Mignatti

Research output: Contribution to journalArticlepeer-review

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 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 TIMP-2/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.

Original languageEnglish (US)
Article number101789
JournaliScience
Volume23
Issue number12
DOIs
StatePublished - Dec 18 2020

Keywords

  • Cell Biology
  • Pathophysiology

ASJC Scopus subject areas

  • General

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