TY - JOUR
T1 - Membrane-type 1 Matrix Metalloproteinase Modulates Tissue Homeostasis by a Non-proteolytic Mechanism
AU - Attur, Mukundan
AU - Lu, Cuijie
AU - Zhang, Xiaodong
AU - Han, Tianzhen
AU - Alexandre, Cassidy
AU - Valacca, Cristina
AU - Zheng, Shuai
AU - Meikle, Sarina
AU - Dabovic, Branka Brukner
AU - Tassone, Evelyne
AU - Yang, Qing
AU - Kolupaeva, Victoria
AU - Yakar, Shoshana
AU - Abramson, Steven
AU - Mignatti, Paolo
N1 - Funding Information:
This work was supported by the US National Institutes of Health ( NIH) grants R01 CA136715 , R01CA136715-05S1 and R21 AG033735 (to P.M.) and in part by R21 AR069240-01A1 (to S.A.). We gratefully acknowledge the precious collaboration of the Rodent Genetic Engineering, High-Throughput Biology Laboratory, Experimental Pathology Research Laboratory, and Genome Technology Center of NYU School of Medicine, which are partially supported by NIH grant P30CA016087 to the Laura and Isaac Perlmutter Cancer Center and the Shared Instrumentation Grant S10 OD021747 , and the MicroCT Core of NYU College of Dentistry, supported by NIH grant S10 OD010751 to Dr. Nicola C. Partridge.
Publisher Copyright:
© 2020 The Authors
PY - 2020/12/18
Y1 - 2020/12/18
N2 - 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.
AB - 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.
KW - Cell Biology
KW - Pathophysiology
UR - http://www.scopus.com/inward/record.url?scp=85097396750&partnerID=8YFLogxK
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U2 - 10.1016/j.isci.2020.101789
DO - 10.1016/j.isci.2020.101789
M3 - Article
AN - SCOPUS:85097396750
VL - 23
JO - iScience
JF - iScience
SN - 2589-0042
IS - 12
M1 - 101789
ER -