Attur Mukundan, Lu Cuijie, Zhang Xiaodong, Han Tianzhen, Alexandre Cassidy, Valacca Cristina, Zheng Shuai, Meikle Sarina, Dabovic Branka Brukner, Tassone Evelyne, Yang Qing, Kolupaeva Victoria, Yakar Shoshana, Abramson Steven, Mignatti Paolo
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.
iScience. 2020 Nov 10;23(12):101789. doi: 10.1016/j.isci.2020.101789. eCollection 2020 Dec 18.
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 ( ) 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 ( ) shows abnormalities similar to but also different from those of mice. Skeletal stem cells (SSC) of mice show defective differentiation consistent with the mouse phenotype, which is rescued by wild-type SSC transplant. These results provide the first demonstration that MT1-MMP modulates bone, cartilage, and fat homeostasis by controlling SSC differentiation through a mechanism independent of proteolysis.
膜型1基质金属蛋白酶（MT1-MMP，MMP-14）是一种具有短胞质尾的跨膜蛋白酶，是细胞外基质重塑的主要效应因子。MT1-MMP在小鼠和人类中的基因沉默会导致侏儒症、骨质减少、关节炎和脂肪营养不良，这些异常归因于胶原蛋白周转缺陷。我们之前已经证明了MT1-MMP由其胞质尾介导的非蛋白水解功能，其中独特的酪氨酸（Y573）控制细胞内信号传导。Y573D突变阻断了TIMP-2/MT1-MMP诱导的Erk1/2和Akt信号传导，而不影响蛋白水解活性。在这里，我们报告说，具有MT1-MMP Y573D突变的小鼠表现出与MT1-MMP基因敲除小鼠相似但也不同的异常。MT1-MMP基因敲除小鼠的骨骼干细胞（SSC）表现出与小鼠表型一致的分化缺陷，野生型SSC移植可挽救这种缺陷。这些结果首次证明MT1-MMP通过一种独立于蛋白水解的机制控制SSC分化来调节骨骼、软骨和脂肪的稳态。
