title: Impaired osteoclast formation in bone marrow cultures of Fgf2 null mice in response to parathyroid hormone.
abstract: Fibroblast growth factor (FGF)-2 and parathyroid hormone (PTH) are potent inducers of osteoclast (OCL) formation, and PTH increases FGF-2 mRNA and protein expression in osteoblasts. To elucidate the role of endogenous FGF-2 in PTH responses, we examined PTH-induced OCL formation in bone marrow cultures from wild type and mice with a disruption of the Fgf2 gene. FGF-2-induced OCL formation was similar in marrow culture from both genotypes. In contrast, PTH-stimulated OCL formation in bone marrow cultures or co-cultures of osteoblast-spleen cells from Fgf2-/mice was significantly impaired. PTH increased RANKL mRNA expression in osteoblasts cultures from both genotypes. After 6 days of treatment, osteoprotegerin protein in cell supernatants was 40-fold higher in vehicle-treated and 30-fold higher in PTH-treated co-cultures of osteoblast and spleen cells from Fgf2-/mice compared with Fgf2+/+ mice. However, a neutralizing antibody to osteoprotegerin did not rescue reduced OCL formation in response to PTH. Injection of PTH caused hypercalcemia in Fgf2+/+ but not Fgf2-/mice. We conclude that PTH stimulates OCL formation and bone resorption in mice in part by endogenous FGF-2 synthesis by osteoblasts. Because RANKL- and interleukin-11-induced OCL formation was also reduced in bone marrow cultures from Fgf2-/mice, we further conclude that endogenous FGF-2 is necessary for maximal OCL formation by multiple bone resorbing factors.
authors.affiliation: Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030-1850, USA.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Okada
authors.forename: Aldemar
authors.initials: A
authors.lastname: Montero
authors.forename: Xuxia
authors.initials: X
authors.lastname: Zhang
authors.forename: Takanori
authors.initials: T
authors.lastname: Sobue
authors.forename: Joseph
authors.initials: J
authors.lastname: Lorenzo
authors.forename: Thomas
authors.initials: T
authors.lastname: Doetschman
authors.forename: J Douglas
authors.initials: JD
authors.lastname: Coffin
authors.forename: Marja M
authors.initials: MM
authors.lastname: Hurley
mesh_terms: D000135:Acid Phosphatase / Q000032:analysis; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology*; D002352:Carrier Proteins / Q000235:genetics / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D004347:Drug Interactions; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000494:pharmacology; D015726:Giant Cells / Q000166:cytology; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D017370:Interleukin-11 / Q000494:pharmacology; D007527:Isoenzymes / Q000032:analysis; D008562:Membrane Glycoproteins / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology* / Q000201:enzymology; D053244:Osteoprotegerin; D010281:Parathyroid Hormone / Q000494:pharmacology*; D053245:RANK Ligand; D012333:RNA, Messenger / Q000032:analysis; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor; D012886:Skull / Q000166:cytology / Q000187:drug effects; D013154:Spleen / Q000166:cytology; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D000906:Antibodies; D002352:Carrier Proteins; D006023:Glycoproteins; D017370:Interleukin-11; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D016222:Fibroblast Growth Factor 2; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase