Osteoprotegerin regulates bone formation through a coupling mechanism with bone resorption.
Deficiency of osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor-kappaB ligand (RANKL), in mice induces osteoporosis caused by enhanced bone resorption, but also accelerates bone formation. We examined whether bone formation is coupled with bone resorption in OPG-deficient (OPG-/-) mice using risedronate, an inhibitor of bone resorption. Histomorphometric analysis showed that bone formation-related parameters (e.g. mineral apposition rate and osteoblast surface/bone surface) in OPG-/- mice sharply decreased with suppression of bone resorption by daily injection of risedronate for 30 d. OPG-/- mice exhibited high serum alkaline phosphatase activity and osteocalcin concentration, both of which were decreased to the levels in wild-type mice by the risedronate injection. Serum levels of RANKL were markedly elevated in OPG-/- mice, but were unaffected by risedronate. The ectopic bone formation induced by bone morphogenetic protein-2 implantation into OPG-/- mice was not accelerated even with a high turnover rate of bone, but attenuation of mineral density from the ectopic bone was more pronounced than that in wild-type mice. These results suggest that bone formation is coupled with bone resorption at local sites in OPG-/- mice, and that serum RANKL levels do not reflect this coupling.
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D001862:Bone Resorption / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000097:blood; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002352:Carrier Proteins / Q000097:blood; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis / Q000502:physiology*; D053244:Osteoprotegerin; D010758:Phosphorus / Q000097:blood; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D000068296:Risedronic Acid; D016212:Transforming Growth Factor beta
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; 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; D016212:Transforming Growth Factor beta; D015675:Osteocalcin; D010758:Phosphorus; D000068296:Risedronic Acid; D012968:Etidronic Acid; D002118:Calcium