The Interstitial Collagenases MMP13 and MMP14 Are Dispensable for the Early Onset of Skin Morphogenesis but Modulate Endochondral Ossification.

Connective tissue remodeling is vital for organ development and tissue stability. Matrix metalloproteinases (MMPs), especially MMP14 and MMP13, are important collagenases that break down interstitial collagen in bone and skin. In mice, the loss of MMP14 results in perinatal death and severe skeletal defects, whereas Mmp13 deficiency causes transient bone defects that later resolve. Despite abundant dermal collagen, single knockouts usually do not display defects in skin formation, likely due to compensatory mechanisms. To examine their combined roles, mice lacking both enzymes were generated. These double knockout mice were viable at birth but rapidly developed severe symptoms resembling Mmp14 deficiency, including growth retardation, wasting, and death within 3 weeks. Surprisingly, skin structure remained largely normal, aside from early subcutaneous fat loss also observed in the Mmp14-deficient mice, indicating that neither enzyme is essential for early dermal remodeling. In contrast, skeletal defects worsened, showing shortened long bones, delayed primary ossification, impaired collagen type I breakdown, and reduced vascular invasion. These findings indicate that MMP13 partly compensates for MMP14 during bone development, while both enzymes are unnecessary for postnatal dermal collagen remodeling. Because MMP mutations are linked to human skeletal dysplasia, fibrosis, and wound-healing issues, these results underscore the distinct roles of MMP14 and MMP13 in collagen turnover and highlight their potential importance in human bone and connective tissue disorders.