Mmp14 is essential for circadian clock rhythmicity in fibroblasts

Membrane type I-matrix metalloproteinase (MT1-MMP/Mmp14) is an unusual MMP because it is essential for survival in mice with multiple organ systems being affected for reasons that are unclear. Here, we show that the protein (MT1-MMP) and gene (Mmp14) are under strict circadian clock control and conditional knockout in fibroblasts leads to ~16% of the proteome losing or inverting circadian rhythmicity. The result is loss of the actin cytoskeleton and cell-matrix adhesions and major imbalance of the matrisome. Lack of collagen-I monomer turnover results in excess fibril formation in the absence of Mmp14. In the absence of Mmp14, paired-like homeodomain transcription factor 2 (Pitx2) is upregulated and remains in the nucleus where it drives Plod2 expression. The overall result is accumulation of collagen fibrils and elevated pyridinoline crosslinking that renders collagen fibrils insoluble. In conclusion, Mmp14 is a master regulator of circadian rhythms affecting the actin cytoskeleton and cell microenvironment.