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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acid Phosphatase / analysis
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Animals
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Antibodies / pharmacology
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Bone Marrow Cells / cytology*
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Carrier Proteins / genetics
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Carrier Proteins / pharmacology
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Cell Differentiation / drug effects
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Cells, Cultured
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Coculture Techniques
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Drug Interactions
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Fibroblast Growth Factor 2 / genetics*
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Fibroblast Growth Factor 2 / pharmacology
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Giant Cells / cytology
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Glycoproteins / antagonists & inhibitors
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Glycoproteins / genetics
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Glycoproteins / immunology
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Interleukin-11 / pharmacology
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Isoenzymes / analysis
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / pharmacology
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Mice
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Mice, Transgenic
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Osteoclasts / cytology*
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Osteoclasts / enzymology
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Osteoprotegerin
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Parathyroid Hormone / pharmacology*
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RANK Ligand
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RNA, Messenger / analysis
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / immunology
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Receptors, Tumor Necrosis Factor
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Skull / cytology
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Skull / drug effects
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Spleen / cytology
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Tartrate-Resistant Acid Phosphatase
Substances
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Antibodies
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Carrier Proteins
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Glycoproteins
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Interleukin-11
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Isoenzymes
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Membrane Glycoproteins
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Osteoprotegerin
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Parathyroid Hormone
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RANK Ligand
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RNA, Messenger
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear
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Receptors, Tumor Necrosis Factor
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Tnfrsf11a protein, mouse
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Tnfrsf11b protein, mouse
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Tnfsf11 protein, mouse
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Fibroblast Growth Factor 2
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Acid Phosphatase
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Tartrate-Resistant Acid Phosphatase