Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival.

By E. Schipani, H. E. Ryan, Susanna Didrickson, Tatsuya Kobayashi, M. Knight, Richard J. Johnson. Genes & Development, 2001

829 citations recorded by the source corpus.

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-1alpha. A key question surrounding HIF-1alpha 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-1alpha functions in hypoxia in vivo, we used tissue-specific targeting to delete HIF-1alpha 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-1alpha 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-1alpha null growth plates, indicating defects in HIF-1alpha-regulated growth arrest occurs in these animals. Furthermore, we find that VEGF expression in the growth plate is regulated through both HIF-1alpha-dependent and -independent mechanisms. In particular, we provide evidence that VEGF expression is up-regulated in a HIF-1alpha-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-1alpha in development, and in cell survival in tissues challenged by interruption of vascular flow; they also illustrate the complexities of HIF-1alpha response in vivo, and they provide new insights into mechanisms of growth plate development.

Subfields: Cancer Research, Genetics

View Paper: https://www.semanticscholar.org/paper/eb6b1b9fc73e87e6da7b2c5973dbb76e4b824651

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In Cancer Research

1. G. Semenza
2. M. C. Simon
3. B. Keith
4. Richard J. Johnson
5. V. Haase
6. E. Wagner
7. Zena Werb
8. C. V. Dang

In Genetics

1. G. Semenza
2. M. C. Simon
3. Richard J. Johnson
4. V. Haase
5. B. Keith
6. M. Goldring
7. E. Wagner
8. Zena Werb

Citations in the corpus

• Reaching a genetic and molecular understanding of skeletal development. (2002, background): “…abnormality in PTHrP-deficientHowever, this survival function of HIF1 is partly due to its regulation of Vegf, a gene required for vascular mice is dwarfism caused by premature differentiation of nonhypertrophic chondrocytes into hypertrophicinvasion of the growth plate (Schipani et al., 2001).”
• Cloning of hif-1α and hif-2α and mRNA expression pattern during development in zebrafish (2007, background): “In eukaryotic organisms, oxygen homeostasis is critical for normal development and physiology and therefore, hypoxia has been proposed as a key regulator of various morphogenetic processes such as angiogenesis (Pugh and RatcliVe, 2003), lung, brain and cartilage development (Compernolle et al., 2002”
• Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development (2003, background): “The transcription factor hypoxia inducible factor 1α(HIF1α) is expressed by hypertrophic chondrocytes and is required, but not sufficient, for VEGF expression (Schipani et al., 2001).”
• The role of oxygen availability in embryonic development and stem cell function (2008, background): “Targeted deletion of Hif1α in murine growth plate chondrocytes results in cell death owing to defects in HIF-1α-regulated growth arres”
• The control of chondrogenesis (2006, background): “Thehypoxia-inducible factor (HIF) 1a is required for chondrocyte survival during hypertrophic differentiation, partly due to its regulation of VEGF expression [Schipani et al., 2001; Provot andSchipani, 2005].”
• Hypoxia-Inducible Factors in Physiology and Medicine (2012, background): “Conditional knockout of HIF-1a in specific types of cells has demonstrated important roles in chondrogenesis (the production of cartilage) (Schipani et al., 2001), adipogenesis (Yun et al.”
• Altered endochondral bone development in matrix metalloproteinase 13-deficient mice (2004, methodology): “Col2-Cre and Col1-Cre transgenic mice where the Cre recombinase is expressed under the rat Col2α1 or the Col1α1 promoter, respectively, were generated as described elsewhere (Dacquin et al., 2002; Schipani et al., 2001).”
• The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. (2007, background): “In their model, chondrocytes lacking Hif1a in the center of both the proliferative and the upper hypertrophic zones underwent programmed cell death, which caused disorganization of chondrocyte palisades and led to the misshaped growth plates (9).”