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
Affiliations
Mukundan Attur
Department of Medicine, Division of Rheumatology, NYU School of Medicine, 301 East 17th Street, Suite 1612A, NY 10003, USA
Cuijie Lu
Department of Medicine, Division of Rheumatology, NYU School of Medicine, 301 East 17th Street, Suite 1612A, NY 10003, USA
Xiaodong Zhang
Department of Cardiothoracic Surgery, NYU School of Medicine, 550 First Avenue, NY 10016, USA
Tianzhen Han
Department of Medicine, Division of Rheumatology, NYU School of Medicine, 301 East 17th Street, Suite 1612A, NY 10003, USA
Cassidy Alexandre
Department of Cardiothoracic Surgery, NYU School of Medicine, 550 First Avenue, NY 10016, USA
Cristina Valacca
Department of Cardiothoracic Surgery, NYU School of Medicine, 550 First Avenue, NY 10016, USA
Shuai Zheng
Department of Cardiothoracic Surgery, NYU School of Medicine, 550 First Avenue, NY 10016, USA
Sarina Meikle
Department of Cardiothoracic Surgery, NYU School of Medicine, 550 First Avenue, NY 10016, USA
Branka Brukner Dabovic
Department of Cell Biology, NYU School of Medicine, 550 First Avenue, NY 10016, USA
Evelyne Tassone
Department of Cardiothoracic Surgery, NYU School of Medicine, 550 First Avenue, NY 10016, USA
Qing Yang
Department of Medicine, Division of Rheumatology, NYU School of Medicine, 301 East 17th Street, Suite 1612A, NY 10003, USA
Victoria Kolupaeva
Department of Microbiology, NYU School of Medicine, 550 First Avenue, NY 10016, USA
Shoshana Yakar
Department of Basic Science & Craniofacial Biology, NYU College of Dentistry, 345 E. 24th Street, NY 10010, USA
Steven Abramson
Department of Medicine, Division of Rheumatology, NYU School of Medicine, 301 East 17th Street, Suite 1612A, NY 10003, USA
Paolo Mignatti
Department of Medicine, Division of Rheumatology, NYU School of Medicine, 301 East 17th Street, Suite 1612A, NY 10003, USA; Department of Cardiothoracic Surgery, NYU School of Medicine, 550 First Avenue, NY 10016, USA; Department of Cell Biology, NYU School of Medicine, 550 First Avenue, NY 10016, USA; Corresponding author
Summary: 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.
