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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-?B 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/?-catenin signaling and induced alveolar bone formation in OPG-/-mice. Expression of sclerostin, an inhibitor of Wnt/?-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.

SUBMITTER: Ozaki Y

PROVIDER: S-EPMC5609750 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Ozaki Yuki Y Koide Masanori M Furuya Yuriko Y Ninomiya Tadashi T Yasuda Hisataka H Nakamura Midori M Kobayashi Yasuhiro Y Takahashi Naoyuki N Yoshinari Nobuo N Udagawa Nobuyuki N

PloS one 20170922 9

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 s ...[more]

PMID: 28937990

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Project description:Postmenopausal osteoporosis (PMO) has been recognized as an inflammatory condition. CD4+ T cells serve a key role in the interaction between bone metabolism and the immune system. Bu‑Shen‑Ning‑Xin decoction (BSNXD), a traditional Chinese medicine, has been ultilized as a remedy for PMO. In the present study, the aim was to investigate the immune modulatory effects of BSNXD on CD4+ T cells, receptor activation of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) imbalance, skeletal parameters and osteoclastogenesis. Ovariectomized (OVX) mice were treated with a series of concentrations of BSNXD and then autopsied. The bone phenotype was analyzed by micro computed tomography. CD4+ T cells were isolated and their percentage was measured using flow cytometry (FCM). RANKL and OPG expression by the CD4+ T cells at the transcriptional and translational levels were quantified by reverse transcription-quantitative polymerase chain reaction, ELISA and FCM. CD4+ T cells were cultured with blood serum derived from BSNXD‑treated OVX mice (BSNXD‑derived serum) and the apoptosis rate was quantified by FCM. CD4+ T cells were co-cultured with bone marrow‑derived macrophages and exposed to BSNXD‑derived serum to whether CD4+ T cells are involved in BSNXD‑modulated osteoclastogenesis and the results were quantified via tartrate‑resistant acid phosphatase staining. The results revealed that BSNXD ameliorated OVX‑induced bone loss, prevented the expansion of CD4+ T cells and restored the RANKL/OPG imbalance in the CD4+ T cells of OVX mice. In vitro, BSNXD‑derived serum promoted the apoptosis of CD4+ T cells. The co‑culture system demonstrated that CD4+ T cells from OVX mice increase osteoclastogenesis, while this effect was suppressed by BSNXD administration. The findings of the study collectively suggest that BSNXD exerts an immunoprotective effect on the bone phenotype of OVX mice by ameliorating RANKL/OPG imbalance in CD4+ T cells and attenuating osteoclastogenesis.

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Dataset Information

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

Publications

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

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