HIF-2α Critically Regulates Metabolism And Homeostasis In Long Bones
Kavitha Ranganathan, MD, Michael Sorkin, MD, Christophe Merceron, PhD, Angela Yao, PhD, Laura Mangiavini, MD, Amato Giaccia, PhD, Shailesh Agarwal, MD, Benjamin Levi, MD, Ernestina Schipani, MD, PhD.
University of Michigan, Ann Arbor, MI, USA.
Hypoxia inducible factor-1 alpha (HIF-1α) plays a critical role in angiogenesis and regulation of osteoblast metabolism. Similarly, HIF-2α is expressed in cells of the osteoblast lineage, however, its exact role in bone formation and homeostasis remains to be determined.
We generated a novel gain-of-function mouse model in which PRX-1Cre transgenic mice were crossed to HIF-2α dPAf/f. In vivo analysis was conducted at 6 and 12 weeks of age, respectively, by nano CT, routine histology, and histomorphometry. Moreover, bone marrow stromal cells overexpressing HIF-2α were subjected to microarray analysis.
HIF-2a overexpressing mice demonstrated distinct morphologic changes in long bone size and shape. While trabecular density was increased in mutant mice on nano CT, this was highly disorganized with thinner trabeculae as compared to controls. Furthermore, increased number of cartilage remnants was observed in mutant mice suggesting elevated resorption due to altered osteoclast function. This may be contributed by up regulation of lysyl oxidase and down regulation of metalloproteinase 13 in mutant cells as seen on microarray analysis.
We demonstrate that overexpression of HIF-2α affects the overall size, shape, and composition of long bones. Moreover, HIF-2α critically modulates bone metabolism and may alter the quality of matrix deposited by osteoblasts. These findings help define the role of HIF-2α in osteogenesis and may enable strategies in treatment of patients with disorders of bone development.
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