Cryptic Ligand on Collagen Matrix Unveiled by Mmp13 Accelerates Bone Tissue Regeneration Via Mmp13/Integrin Α3/Runx2 Feedback Loop

Extracellular matrix (ECM) remodeling is necessary for the development and self-healing of tissue, and the process is tissue specific. Matrix metalloproteinases (MMPs) play a role in ECM remodeling by unwinding and cleaving ECM. We hypothesized that ECM remodeling by MMPs is involved in the differentiation of stem cells into specific lineages during self-healing. We investigated which MMPs are involved in the osteogenic differentiation of human mesenchymal stem cells (hMSCs) grown on a type I collagen (Col I) matrix. The expression of MMP13 specifically increased during osteogenic differentiation of hMSCs grown on a Col I matrix. Moreover, the knockdown and overexpression of MMP13 reduced and increased osteogenic differentiation, respectively. Remodeling of the Col I matrix by MMP13 promoted osteogenic differentiation of hMSCs and in vivo bone formation by upregulating the expression of RUNX2, integrin α3, and focal adhesion kinase. Furthermore, the transcription factor RUNX2 bound to the MMP13 promoter. These results suggest that growth on a remodeled Col I matrix by MMP13 stimulates osteogenic differentiation of hMSCs and self-healing of bone tissue via an MMP13/integrin α3/RUNX2 positive feedback loop.