Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I

Membrane-type matrix metalloproteinase I (MT1-MMP)-deficient mice were foun d to have severe defects in skeletal development and angiogenesis, The cran iofacial, axial, and appendicular skeletons were severely affected, leading to a short and domed skull, marked deceleration of postnatal growth, and d eath by 3 wk of age. Shortening of bones is a consequence of decreased chon drocyte proliferation in the proliferative zone of the growth plates. Defec tive vascular invasion of cartilage leads to enlargement of hypertrophic zo nes of growth plates and delayed formation of secondary ossification center s in long bones. In an in vivo corneal angiogenesis assay, null mice did no t have angiogenic response to implanted FGF-2, suggesting that the defect i n angiogenesis is not restricted to cartilage alone. In tissues from null m ice, activation of latent matrix metalloproteinase 2 was deficient, suggest ing that MT1-MMP is essential for its activation in vivo.