MMP12-dependent myofibroblast formation contributes to nucleus pulposus fibrosis

Area of Science:

• Biochemistry
• Cell Biology
• Orthopedics

Background:

• Intervertebral disc degeneration (IDD) is a major cause of low back pain, characterized by nucleus pulposus (NP) fibrosis and myofibroblast accumulation.
• Matrix metalloproteinase 12 (MMP12) expression is elevated in IDD, but its specific role in NP fibrosis is not well understood.

Purpose of the Study:

• To investigate the role of MMP12 in TGF-β1-induced myofibroblast differentiation and NP fibrosis in IDD.
• To explore the therapeutic potential of targeting MMP12 in IDD.

Main Methods:

• Human NP cells were treated with TGF-β1 to induce myofibroblast differentiation, with and without MMP12 knockdown.
• Transcriptome analysis was performed to identify signaling pathways affected by MMP12.
• MMP12 knockout (KO) mice were used to model IDD, and NP fibrosis and matrix composition were assessed.

Main Results:

• TGF-β1 induced MMP12 expression and myofibroblast differentiation in human NP cells.
• MMP12 knockdown reversed the myofibroblastic phenotype and enhanced chondrogenic marker expression.
• MMP12-KO mice showed reduced NP fibrosis, decreased collagen I/III, increased collagen II/aggrecan, and altered cell populations (more SOX9+/CNMD+, fewer αSMA+).
• MMP12-mediated myofibroblast phenotype acquisition involved fibroblast activation, osteogenesis, MAPK, and Wnt signaling pathways.

Conclusions:

• MMP12 plays a critical role in promoting myofibroblast generation and nucleus pulposus fibrosis in IDD.
• Targeting MMP12 could be a promising strategy to inhibit NP fibrosis and restore cartilaginous matrix in IDD.