No abstract

Background: A RANKL-binding peptide WP9QY (W9) is known to inhibit osteoclastogenesis.Results: W9 showed an anabolic effect on cortical bone in mice. W9 bound RANKL and differentiated osteoblasts with production of autocrine factors like BMP-4.Conclusion: Signaling through RANKL is involved in part in the W9-induced osteoblast differentiation.Significance: The RANKL pathway could be a novel mechanism in osteoblast differentiation.

Background: Receptor activator of nuclear factor-κB ligand is a pivotal osteoclast differentiation factor.Results: Daily injection of parathyroid hormone increased bone mass by stimulating bone formation in the anti-receptor activator of nuclear factor-κB ligand antibody-treated mice.Conclusion: Parathyroid hormone exerted its bone anabolic activity in mice with few osteoclasts.Significance: Parathyroid hormone requires no osteoclasts for stimulating bone formation.

Osteoblasts express two key molecules for osteoclast differentiation, receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG), a soluble decoy receptor for RANKL. RANKL induces osteoclastogenesis, while OPG inhibits it by blocking the binding of RANKL to RANK, a cellular receptor of RANKL. OPG-deficient (OPG–/–) mice exhibit severe alveolar bone loss with enhanced bone resorption. WP9QY (W9) peptide binds to RANKL and blocks RANKL-induced osteoclastogenesis. W9 is also reported to stimulate bone formation in vivo. Here, we show that treatment with W9 restores alveolar bone loss in OPG–/–mice by suppressing osteoclastogenesis and enhancing osteoblastogenesis. Administration of W9 or risedronate, a bisphosphonate, to OPG–/–mice significantly decreased the osteoclast number in the alveolar bone. Interestingly, treatment with W9, but not risedronate, enhanced Wnt/β-catenin signaling and induced alveolar bone formation in OPG–/–mice. Expression of sclerostin, an inhibitor of Wnt/β-catenin signaling, was significantly lower in tibiae of OPG–/–mice than in wild-type mice. Treatment with risedronate recovered sclerostin expression in OPG–/–mice, while W9 treatment further suppressed sclerostin expression. Histomorphometric analysis confirmed that bone formation-related parameters in OPG–/–mice, such as osteoblast number, osteoblast surface and osteoid surface, were increased by W9 administration but not by risedronate administration. These results suggest that treatment of OPG–/–mice with W9 suppressed osteoclastogenesis by inhibiting RANKL signaling and enhanced osteoblastogenesis by attenuating sclerostin expression in the alveolar bone. Taken together, W9 may be a useful drug to prevent alveolar bone loss in periodontitis.

No abstract