Basic fibroblast growth factor stimulates osteoclast recruitment, development, and bone pit resorption in association with angiogenesis in vivo on the chick chorioallantoic membrane and activates isolated avian osteoclast resorption in vitro.
Increased local osteoclast (OC)-mediated bone resorption coincides with angiogenesis in normal bone development and fracture repair, as well as in pathological disorders such as tumor-associated osteolysis and inflammatory-related rheumatoid arthritis or periodontal disease. Angiogenic stimulation causes recruitment, activation, adhesion, transmigration, and differentiation of hematopoietic cells which may therefore enable greater numbers of pre-OC to emigrate from the circulation and develop into bone-resorptive OCs. A chick chorioallantoic membrane (CAM) model, involving coimplantation of a stimulus in an agarose plug directly adjacent to a bone chip was used to investigate if a potent angiogenic stimulator, basic fibroblast growth factor (bFGF), could promote OC recruitment, differentiation, and resorption in vivo. Angiogenesis elicited by bFGF on the CAM was accompanied by increased OC formation and bone pit resorption (both overall and on a per OC basis) on the bone implants in vivo. In complementary in vitro assays, bFGF did not directly stimulate avian OC development from bone marrow mononuclear cell precursors, consistent with their low mRNA expression of the four avian signaling FGF receptors (FGFR)-1, FGFR-2, FGFR-3, and FGFR-like embryonic kinase (FREK). In contrast, bFGF activated isolated avian OC bone pit resorption via mechanisms inhibited by a selective cyclo-oxygenase (COX)-2 prostaglandin inhibitor (NS-398) or p42/p44 MAPK activation inhibitor (PD98059), consistent with a relatively high expression of FGFR-1 by differentiated avian OCs. Thus, bFGF may sensitively regulate local bone resorption and remodeling through direct and indirect mechanisms that promote angiogenesis and OC recruitment, formation, differentiation, and activated bone pit resorption. The potential for bFGF to coinduce angiogenesis and OC bone remodeling may find clinical applications in reconstructive surgery, fracture repair, or the treatment of avascular necrosis. Alternatively, inhibiting such bFGF-dependent processes may aid in the treatment of inflammatory-related or metastatic bone loss.
D000482:Allantois / Q000187:drug effects*; D000818:Animals; D001862:Bone Resorption / Q000139:chemically induced*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002642:Chick Embryo; D002823:Chorion / Q000187:drug effects*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004343:Drug Implants; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009578:Nitrobenzenes / Q000494:pharmacology; D010010:Osteoclasts / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004343:Drug Implants; D005419:Flavonoids; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D013449:Sulfonamides; D016222:Fibroblast Growth Factor 2; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C086864:FGFR4 protein, Coturnix coturnix; D020794:Receptor Protein-Tyrosine Kinases; D051499:Receptor, Fibroblast Growth Factor, Type 4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one