Bone Abstracts

Hypoxia and the hypoxia-inducible factor 1alpha (Hif1alpha) are known to play critical physiological functions in endochondral bone development. However, their role in abnormal cartilage formation (chondrodysplasia) is unknown. Our goal was to test the possibility that altered oxygen homeostasis, which would result in abnormal Hif1alpha expression and activity, could lead to chondrodysplasia. This was done using matrix metalloproteinase (MMP) 9 and 13 deficient mice, which present a chondrodysplasic phenotype characterized by a modest dwarfism, and a mild bowing on the long bones. This mouse phenotype recapitulates that observed in humans lacking MMP9/13 function. The postnatal growth plates of MMP-deficient mice are characterized by a dramatic accumulation of hypertrophic chondrocytes, and delayed ossification. Interestingly, we observed that a significant increase in hypoxia and Hif1alpha protein levels in fetal growth plates precedes the postnatal growth plate defects of MMP-deficient mice. We used a conditional knockout approach (Col2-CreERt2) to remove Hif1alpha specifically from chondrocytes of newborn MMP-deficient animals. Importantly, removing Hif1alpha from newborn cartilage abolished the growth plate defects in these mice. This result demonstrates that Hif1alpha is responsible for the chondrodysplasic phenotype of MMP-deficient mice. All animal protocols were approved by an animal ethics committee. Mechanistically, our data indicate that increased Hif1alpha activity in MMP-deficient mice slows down hypertrophic maturation of chondrocytes, and increases cell survival of hypertrophic chondrocytes. Together, these cellular effects likely explain the accumulation of hypertrophic chondrocytes and delayed ossification observed in MMP-deficient mice. Hence, our results establish for the first time that extracellular matrix homeostasis maintains oxygen homeostasis to ensure proper skeletal development. Our work also demonstrates the importance of oxygen homeostasis in postnatal skeletal growth, and suggests that Hif1alpha constitutes a pertinent therapeutic target to prevent chondrodysplasia in MMP-deficient patients.