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Osteoprotegerin Regulates Bone Formation through a Coupling Mechanism with Bone Resorption

Departments of Pediatric Dentistry (M.N., H.N., H.M.), Biochemistry (N.U.), and Oral Histology (S.M., H.O.), Institute for Oral Science (B.Y.H., Y.K., H.O., H.M., N.T.), Matsumoto Dental University, Nagano 399-0781, Japan; Department of Pharmacology, Aichi Gakuin University School of Dentistry (M.M.), Nagoya 464-8650, Japan; Department of Orthopedic Surgery, Shinshu University School of Medicine (H.H., N.S.), Nagano 399-0781, Japan; and Department of Orthopedic Surgery, Osaka City University School of Medicine (K.T.), Osaka 545-8585, Japan

Address all correspondence and requests for reprints to: Naoyuki Takahashi, Ph.D., Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano 399-0781, Japan. E-mail: takahashinao{at}po.mdu.ac.jp.

Deficiency of osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor-B 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.

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