Stratified control of IGF-I expression by hypoxia and stress hormones in osteoblasts.
Bone cells respond to the integrated effects of local and systemic regulation. Here we show that hypoxia and the stress hormones PGE2 and glucocorticoid interact in complex ways in osteoblasts, converging on insulin like growth factor I (IGF-I) expression. Whereas hypoxia alone rapidly increased transcription factor HIF activity, it suppressed DNA synthesis, had no significant effects on protein synthesis or alkaline phosphatase activity, and drove discrete changes in a panel of osteoblast mRNAs. Notably, hypoxia increased expression of the acute phase response transcription factor C/EBPδ which can induce IGF-I in response to PGE2, but conversely prevented the stimulatory effect of PGE2 on IGF-I mRNA. However, unlike its effect on C/EBPδ, hypoxia suppressed expression of the obligate osteoblast transcription factor Runx2, which can activate an upstream response element in the IGF-I gene promoter. Hypoxic inhibition of IGF-I and Runx2 were enforced by glucocorticoid, and continued with prolonged exposure. Our studies thus reveal that IGF-I expression is stratified by two critical transcriptional elements in osteoblasts, which are resolved by the individual and combined effects of hypoxic stress and stress hormones. In so doing, hypoxia suppresses Runx2, limits the enhancing influence of PGE2, and interacts with glucocorticoid to reduce IGF-I expression by osteoblasts.
Yale University School of Medicine, Department of Surgery, New Haven, CT 06520-8041, USA; Yale University School of Medicine, Department of Pathology, New Haven, CT 06520-8023, USA. Electronic address: thomas.mccarthy@yale.edu.
Thomas L
TL
McCarthy
Yale University School of Medicine, Department of Therapeutic Radiology, New Haven, CT 06520-8040, USA.
Zhong
Z
Yun
Yale University School of Medicine, Department of Pathology, New Haven, CT 06520-8023, USA.
Joseph A
JA
Madri
Yale University School of Medicine, Department of Surgery, New Haven, CT 06520-8041, USA; Yale University School of Medicine, Department of Pathology, New Haven, CT 06520-8023, USA. Electronic address: michael.centrella@yale.edu.
Michael
M
Centrella
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000096:biosynthesis / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics*; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication; D015232:Dinoprostone / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D006854:Hydrocortisone / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D050436:Regulatory Elements, Transcriptional / Q000235:genetics
C497254:Cebpd protein, rat; D050659:Core Binding Factor Alpha 1 Subunit; D012333:RNA, Messenger; C493717:Runx2 protein, rat; D051743:CCAAT-Enhancer-Binding Protein-delta; D007334:Insulin-Like Growth Factor I; D004247:DNA; D000469:Alkaline Phosphatase; D015232:Dinoprostone; D010100:Oxygen; D006854:Hydrocortisone
C/EBP; Glucocorticoid; HIF; PGE2; Runx2