| First Author | Attur M | Year | 2020 |
| Journal | iScience | Volume | 23 |
| Issue | 12 | Pages | 101789 |
| PubMed ID | 33294797 | Mgi Jnum | J:305628 |
| Mgi Id | MGI:6705926 | Doi | 10.1016/j.isci.2020.101789 |
| Citation | Attur M, et al. (2020) Membrane-type 1 Matrix Metalloproteinase Modulates Tissue Homeostasis by a Non-proteolytic Mechanism. iScience 23(12):101789 |
| abstractText | 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 (Mmp14 (Y573D/Y573D) ) shows abnormalities similar to but also different from those of Mmp14 (-/-) mice. Skeletal stem cells (SSC) of Mmp14 (Y573D/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. |
