title: Parathyroid hormone regulation of hypoxia-inducible factor signaling in osteoblastic cells.
abstract: Osteoblasts perceive and respond to changes in their pericellular environment, including biophysical signals and oxygen availability, to elicit an anabolic or catabolic response. Parathyroid hormone (PTH) affects each arm of skeletal remodeling, with net anabolic or catabolic effects dependent upon duration of exposure. Similarly, the capacity of osteoblastic cells to perceive pericellular oxygen has a profound effect on skeletal mass and architecture, as mice expressing stable hypoxia-inducible factor (HIF)-1α and -2α demonstrate age-dependent increases in bone volume per tissue volume and osteoblast number. Further, HIF levels and signaling can be influenced in an oxygen-independent manner. Because the cellular mechanisms involved in PTH regulation of the skeleton remain vague, we sought whether PTH could influence HIF-1α expression and HIF-α-driven luciferase activity independently of altered oxygen availability. Using UMR106.01 mature osteoblasts, we observed that 100nM hPTH(1-34) decreased HIF-1α and HIF-responsive luciferase activity in a process involving heat shock protein 90 (Hsp90) and cyclic AMP but not intracellular calcium. Altering activity of the small GTPase RhoA and its effector kinase ROCK altered HIF-α-driven luciferase activity in the absence and presence of PTH. Taken together, these data introduce PTH as a regulator of oxygen-independent HIF-1α levels through a mechanism involving cyclic AMP, Hsp90, and the cytoskeleton.
authors.affiliation: Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, CA, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Wong
authors.affiliation: Biology and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA, USA; School of Natural Sciences, University of California, Merced, CA, USA.
authors.forename: Gabriela G
authors.initials: GG
authors.lastname: Loots
authors.affiliation: Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, CA, USA.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Yellowley
authors.affiliation: Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, CA, USA.
authors.forename: Andréa C
authors.initials: AC
authors.lastname: Dosé
authors.affiliation: Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, CA, USA. Electronic address: dgenetos@ucdavis.edu.
authors.forename: Damian C
authors.initials: DC
authors.lastname: Genetos
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D015153:Blotting, Western; D002460:Cell Line; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D016297:Mutagenesis, Site-Directed; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D010281:Parathyroid Hormone / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010281:Parathyroid Hormone; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: Cytoskeleton; HIF; Hsp90; Hypoxia; Osteoblast; PTH; Rho