Schipani Lab

Hypoxia and Mitochondria in Endochondral Bone Development


We are studying the interplay between the mitochondria and HIF1- dependent reprogramming of metabolism in skeletal development

We discovered that HIF1, a transcription factor and a key mediator of the cellular adaptation to hypoxia, is a crucial survival and differentiation factor for growth plate chondrocytes with mechanisms that involve, at least in part, the suppression of mitochondrial respiration. We are currently investigating how the interplay between mitochondria and HIF1-dependent reprogramming of metabolism controls skeletal development (R01 AR074079, Dr. Schipani PI).

Suppressing Mitochondrial Respiration Is Critical for Hypoxia Tolerance in the Fetal Growth Plate
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Highlights

  • Mitochondrial respiration is dispensable for survival of fetal chondrocytes
  • Loss of Hif1a enhances mitochondrial respiration in fetal chondrocytes
  • Mitochondrial respiration augments intracellular hypoxia of fetal chondrocytes
  • Enhancing mitochondrial respiration is detrimental to survival of fetal chondrocytes

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Hif-1α regulates differentiation of limb bud mesenchyme and joint development
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Recent evidence suggests that low oxygen tension (hypoxia) may control fetal development and differentiation. A crucial mediator of the adaptive response of cells to hypoxia is the transcription factor Hif-1α. In this study, we provide evidence that mesenchymal condensations that give origin to endochondral bones are hypoxic during fetal development, and we demonstrate that Hif-1α is expressed and transcriptionally active in limb bud mesenchyme and in mesenchymal condensations. To investigate the role of Hif-1α in mesenchymal condensations and in early chondrogenesis, we conditionally inactivated Hif-1α in limb bud mesenchyme using a Prx1 promoter-driven Cre transgenic mouse. Conditional knockout of Hif-1α in limb bud mesenchyme does not impair mesenchyme condensation, but alters the formation of the cartilaginous primordia. Late hypertrophic differentiation is also affected as a result of the delay in early chondrogenesis. In addition, mutant mice show a striking impairment of joint development. Our study demonstrates a crucial, and previously unrecognized, role of Hif-1α in early chondrogenesis and joint formation.

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Hypoxia in cartilage: HIF-1α is essential for chondrocyte growth arrest and survival
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Breakdown or absence of vascular oxygen delivery is a hallmark of many common human diseases, including cancer, myocardial infarction, and stroke. The chief mediator of hypoxic response in mammalian tissues is the transcription factor hypoxia-inducible factor 1 (HIF-1), and its oxygen-sensitive component HIF-1α. A key question surrounding HIF-1α and the hypoxic response is the role of this transcription factor in cells removed from a functional vascular bed; in this regard there is evidence indicating that it can act as either a survival factor or induce growth arrest and apoptosis. To study more closely how HIF-1α functions in hypoxia in vivo, we used tissue-specific targeting to delete HIF-1α in an avascular tissue: the cartilaginous growth plate of developing bone. We show here the first evidence that the developmental growth plate in mammals is hypoxic, and that this hypoxia occurs in its interior rather than at its periphery. As a result of this developmental hypoxia, cells that lack HIF-1α in the interior of the growth plate die. This is coupled to decreased expression of the CDK inhibitor p57, and increased levels of BrdU incorporation in HIF-1α null growth plates, indicating defects in HIF-1α-regulated growth arrest occurs in these animals. Furthermore, we find that VEGF expression in the growth plate is regulated through both HIF-1α-dependent and -independent mechanisms. In particular, we provide evidence that VEGFexpression is up-regulated in a HIF-1α-independent manner in chondrocytes surrounding areas of cell death, and this in turn induces ectopic angiogenesis. Altogether, our findings have important implications for the role of hypoxic response and HIF-1α in development, and in cell survival in tissues challenged by interruption of vascular flow; they also illustrate the complexities of HIF-1α response in vivo, and they provide new insights into mechanisms of growth plate development.

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