Treatment of OPG-deficient mice with WP9QY, a RANKL-binding peptide, recovers alveolar bone loss by suppressing osteoclastogenesis and enhancing osteoblastogenesis

Abstract

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.

The relationship between T‐helper cell polarization and the RANKL/OPG ratio in gingival tissues from chronic periodontitis patients

“…However, this progression could be blocked by the high level of OPG, a localized decoy receptor for RANKL (Liu, Lerner, & Teng, ). Collectively, no significant difference in OPG expression was found between the two groups, which is not consistent with some previous reports (Oliveira et al, ; Ozaki et al, ), but both higher RANKL levels and higher RANKL/OPG ratios in gingival tissues in the CP group suggested that progressive bone resorption occurs in severe periodontitis. The presence of Porphyromonas gingivalis can increase the RANKL/OPG ratio at periodontitis sites (Belibasakis, Meier, Guggenheim, & Bostanci, ; Sakellari, Menti, & Konstantinidis, ), and a high RANKL/OPG ratio can facilitate inorganic matrix dissolution by cathepsin‐K and metalloprotease (Bostanci et al, ; Mogi & Otogoto, ).…”

Macrophage immunomodulation in chronic osteolytic diseases—the case of periodontitis

“…In PD, excessive bone resorption occurs either due to up‐regulation of RANKL or down‐regulation of OPG, leading to an overall increase in the RANKL/OPG ratio . Using murine models of PD and genetic manipulation of the RANKL/OPG system, multiple studies found that this axis is a core element of PD, and that an increase in RANKL mRNA expression and protein production leads to high RANKL/OPG ratio and uncoupling of bone formation‐resorption cycle through enhanced osteoclastogenesis and osteoclast survival . Inflammatory mediators released by DC and iMac stimulate differentiation of Th17 lymphocytes, the major immune producers of RANKL, leading to increased RANKL/OPG ratio .…”

“…36,37 Using murine models of PD and genetic manipulation of the RANKL/OPG system, multiple studies found that this axis is a core element of PD, and that an increase in RANKL mRNA expression and protein production leads to high RANKL/OPG ratio and uncoupling of bone formation-resorption cycle through enhanced osteoclastogenesis and osteoclast survival. [38][39][40] Inflammatory mediators released by DC and iMac stimulate differentiation of Th17 lymphocytes, the major immune producers of RANKL, leading to increased RANKL/OPG ratio. 29 Thus, the optimal approaches to treat PD seem to be modulation of immune responses to putative periodontal pathogens for efficient nonself clearance and inflammation resolution to control proosteolytic environments and recouple physiologic bone formation and resorption.…”

Local injection of RANKL facilitates tooth movement and alveolar bone remodelling

“…RANKL molecules bind to the RANK receptors on the surface of osteoclast lineage cells and promote osteoclast formation, function and survival. In contrast, osteoprotegerin (OPG) has been shown to counterbalance severe bone loss, playing a role as a decoy receptor that competes with RANK for RANKL binding (Ozaki et al, ). Various experimental approaches using RANKL to facilitate bone resorption and turnover have been attempted.…”

“…receptor that competes with RANK for RANKL binding (Ozaki et al, 2017). Various experimental approaches using RANKL to facilitate bone resorption and turnover have been attempted.…”