期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 18, 页码 14760-14771出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.340232
关键词
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资金
- Korea Science and Engineering Foundation [R01-2006-000-11046-0]
- Korean Government Ministry of Science and Technology
- National Research Foundation of Korea [2010-0026741, 2009-0084887]
- Ministry of Education, Science and Technology
- National Research Foundation of Korea [R01-2006-000-11046-0, 핵06A3103, 2010-0026741, 2009-0084887] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The regulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) during endochondral bone formation is not fully understood. Here, we investigated the cross-talk between HIF-1 alpha and Runt-related transcription factor 2 (Runx2) in the growth plate. Runx2 caused the accumulation of HIF-1 alpha protein in ATDC5 chondrocytes and HEK293 cells under normoxic conditions. Runx2 also increased the nuclear translocation of HIF-1 alpha when coexpressed in HEK293 cells and interacted with HIF-1 alpha at the oxygen-dependent degradation domain (ODDD). In addition, Runx2 competed with von Hippel-Lindau tumor suppressor protein by directly binding to ODDD-HIF-1 alpha and significantly inhibited the ubiquitination of HIF-1 alpha, even though Runx2 did not change the hydroxylation status of HIF-1 alpha. Furthermore, overexpression of Runx2 resulted in the significant enhancement of vascular endothelial growth factor (VEGF) promoter reporter activity and protein secretion. Runx2 significantly increased angiogenic activity in human umbilical vein endothelial cells in vitro. In wild-type mice, HIF-1 alpha and Runx2 were colocalized in hypertrophic chondrocytes in which the cluster of differentiation 31 (CD31) protein was expressed at embryonic day 15.5 (E15.5). In contrast, the expression of HIF-1 alpha was markedly reduced in areas of CD31 expression in Runx2(-/-) mice. These results suggest that Runx2 stabilizes HIF-1 alpha by binding to ODDD to block the interaction between von Hippel-Lindau protein and HIF-1 alpha. In conclusion, Runx2, HIF-1 alpha, and VEGF may regulate vascular angiogenesis spatially and temporally in the hypertrophic zone of the growth plate during endochondral bone formation.
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