MMP12-dependent myofibroblast formation contributes to nucleus pulposus fibrosis

Abstract

Intervertebral disc degeneration (IDD) is associated with low back pain, a leading cause of disability worldwide. Fibrosis of nucleus pulposus (NP) is a principal component of IDD, featuring an accumulation of myofibroblast-like cells. Previous study indicates that matrix metalloproteinase 12 (MMP12) expression is upregulated in IDD, but its role remains largely unexplored. We here showed that TGF-β1 could promote myofibroblast-like differentiation of human NP cells along with an induction of MMP12 expression. Intriguingly, MMP12 knockdown not only ameliorated the myofibroblastic phenotype but also increased chondrogenic marker expression. Transcriptome analysis revealed that the MMP12-mediated acquisition of myofibroblast phenotype was coupled to processes related to fibroblast activation and osteogenesis and to pathways mediated by MAPK and Wnt signaling. Injury induced mouse IDD showed NP fibrosis with marked increase of collagen deposition and αSMA-expressing cells. In contrast, MMP12-KO mice exhibited largely reduced collagen I and III but increased collagen II and aggrecan deposition, indicating an inhibition of NP fibrosis along with an enhanced cartilaginous matrix remodeling. Consistently, an increase of SOX9⁺ and CNMD⁺ but decrease of αSMA⁺ NP cells was found in the KO. Altogether, our findings suggest a pivotal role of MMP12 in myofibroblast generation, thereby regulating NP fibrosis in IDD.