Matrix metalloproteinase‐12 (MMP12) inhibits myofibroblast differentiation and lung fibrosis

Abstract

Matrix metalloproteinase 12 (MMP12) is implicated in pathogenesis of emphysema; however its role in lung fibrosis is controversial. C/EBPβ represses MMP12 expression in lung fibroblasts, while C/EBPβ deficiency attenuates bleomycin (BLM) induced lung fibrosis and myofibroblast (MF) differentiation accompanied with de‐repression of MMP12 expression. In this study, the hypothesis that MMP12 inhibits MF differentiation and accompanying fibrosis was evaluated. Promoter analysis, gel shift assay and real time PCR analysis confirmed that C/EBPβ was a direct repressor of MMP12 gene expression. C/EBPβ deficiency induced MMP12 expression in fibroblasts, which was accompanied by diminished α‐smooth muscle actin (α‐SMA) expression. Moreover ectopic over‐expression of MMP12 suppressed α‐SMA expression. In contrast, MMP12 deficiency or treatment with an MMP12 inhibitor enhanced α‐SMA expression, thus confirming its suppressor role in MF differentiation. A potential mechanism was suggested by the ability of MMP12 to cleave N‐cadherin, which was inhibited by an MMP12 inhibitor; while over‐expression of N‐cadherin stimulated α‐SMA gene expression. Furthermore MMP12 deficient mice exhibited significantly enhanced BLM‐induced pulmonary fibrosis relative to that in wild type mice as evaluated by analysis of collagen deposition, MF differentiation and histopathology. These findings suggest that fibroblast MMP12 is an endogenous repressor of MF differentiation, perhaps by digestion of N‐cadherin, thus playing an important homeostatic role to maintain fibroblasts in an undifferentiated state and keeping fibrosis in check. This work was supported by National Institute of Health grants (HL052285, HL091775, HL112880 and DK020572).