Stimulation of Bone Formation in Cortical Bone of Mice Treated with a Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-binding Peptide That Possesses Osteoclastogenesis Inhibitory Activity

Furuya, Yuriko; Inagaki, Atsushi; Khan, Masud; Mori, Kaoru; Penninger, Josef; Nakamura, Midori; Udagawa, Nobuyuki; Aoki, Kazuhiro; Ohya, Keiichi; Uchida, Katsuo; Yasuda, Hisataka

doi:10.1074/jbc.m112.426080

Cited by 72 publications

(61 citation statements)

References 38 publications

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“…This was not because the BMP‐2 used in this study was unable to regenerate bone – as 1 μg of the same BMP‐2 was shown to cover the entire calvarial defect in the same murine model 12. We demonstrated that the RANKL‐binding peptide OP3‐4 stimulated the BMP‐2‐induced bone formation to the same extent as another RANKL‐binding peptide, W9, which is already known to be a stimulator of bone formation 12, 13, 14 (Figs 2 and 3). However, the RANKL‐binding peptides seem to induce osteogenic effects only in the presence of BMP‐2 in vivo since no apparent bone formation appeared after administering the RANKL‐binding peptides in this study (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 60%

“…We have previously reported that the stimulated effects of W9 on the ALP activity, one of the osteoblast differentiation markers, decreased when using cells where RANKL was either knocked down or deleted, thereby indicating the existence of RANKL‐reverse signals 13. Given that OP3‐4 binds to RANKL to a similar extent as that to W9 17, 18, these data suggest that both W9 and OP3‐4 stimulate osteoblast differentiation through membrane‐bound RANKL in osteoblasts.…”

Section: Discussionmentioning

confidence: 71%

“…Considering the relevance of RANKL and BMP‐2 in this study, some crosstalk might exist between the BMP‐2 signals and the RANKL‐mediated signals since we have previously shown that the RANKL‐binding peptide‐induced increase of ALP activity was partially blocked by adding the neutralizing antibody of BMP‐2/4 in the 5 days culture of an osteoblast cell line 13. In addition, there is some activation of phosphorylation of Smad 1/5/8 at 30 and 60 minutes after the W9 stimulation 13.…”

Section: Discussionmentioning

confidence: 92%

“…There are several candidates for increasing local bone formation: parathyroid hormone (PTH) 5, 6, anti‐sclerostin antibody 7, transforming growth factor (TGF)‐β1 8, fibroblast growth factor (FGF)‐2 9, FGF‐4 10, and various peptide drugs 11, 12, 13, 14, 15. Among these agents, small peptide drugs, which have a molecular weight of approximately 1,000–1,500, have many advantages because of their properties, which include their low production cost, non‐immunogenic properties, and facile modulation characteristics that allow for structural changes to be made to fit a drug target 11.…”

Section: Introductionmentioning

confidence: 99%

“…WP9QY peptide (W9) was designed to mimic the critical site of binding between TNF type 1 receptor and TNF‐α 16 and was recently found to be a stimulator of BMP‐2‐induced ectopic bone formation as well as osteoblast differentiation 13, 14. OP3‐4, another peptide, which was recently demonstrated to be a systemic stimulator of bone formation in an inflammatory bone destruction model 15, was originally designed to mimic osteoprotegerin, a natural antagonist of receptor activator of NF‐κB ligand (RANKL) 17.…”

Section: Introductionmentioning

confidence: 99%

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Peptide drugs accelerate BMP‐2‐induced calvarial bone regeneration and stimulate osteoblast differentiation through mTORC1 signaling

et al. 2016

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Both W9 and OP3‐4 were known to bind the receptor activator of NF‐κB ligand (RANKL), inhibiting osteoclastogenesis. Recently, both peptides were shown to stimulate osteoblast differentiation; however, the mechanism underlying the activity of these peptides remains to be clarified. A primary osteoblast culture showed that rapamycin, an mTORC1 inhibitor, which was recently demonstrated to be an important serine/threonine kinase for bone formation, inhibited the peptide‐induced alkaline phosphatase activity. Furthermore, both peptides promoted the phosphorylation of Akt and S6K1, an upstream molecule of mTORC1 and the effector molecule of mTORC1, respectively. In the in vivo calvarial defect model, W9 and OP3‐4 accelerated BMP‐2‐induced bone formation to a similar extent, which was confirmed by histomorphometric analyses using fluorescence images of undecalcified sections. Our data suggest that these RANKL‐binding peptides could stimulate the mTORC1 activity, which might play a role in the acceleration of BMP‐2‐induced bone regeneration by the RANKL‐binding peptides.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Peptide drugs accelerate BMP‐2‐induced calvarial bone regeneration and stimulate osteoblast differentiation through mTORC1 signaling

et al. 2016

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NF-κB RelB Negatively Regulates Osteoblast Differentiation and Bone Formation

Yao

et al. 2013

Journal of Bone and Mineral Research

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RelA-mediated NF-κB canonical signaling promotes mesenchymal progenitor cell (MPC) proliferation, but inhibits differentiation of mature osteoblasts (OBs) and thus negatively regulates bone formation. Previous studies suggest that NF-κB RelB may also negatively regulate bone formation through non-canonical signaling, but they involved a complex knockout mouse model and the molecular mechanisms involved were not investigated. Here, we report that RelB−/− mice develop age-related increased trabecular bone mass associated with increased bone formation. RelB−/− bone marrow stromal cells expanded faster in vitro and have enhanced OB differentiation associated with increased expression of the osteoblastogenic transcription factor, Runx2. In addition, RelB directly targeted the Runx2 promoter to inhibit its activation. Importantly, RelB−/− bone-derived MPCs formed bone more rapidly than wild-type cells after they were injected into a murine tibial bone defect model. Our findings indicate that RelB negatively regulates bone mass as mice age and limits bone formation in healing bone defects, suggesting that inhibition of RelB could reduce age-related bone loss and enhance bone repair.

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Enhanced Immunoprotective Effects by Anti-IL-17 Antibody Translates to Improved Skeletal Parameters Under Estrogen Deficiency Compared With Anti-RANKL and Anti-TNF-α Antibodies

Tyagi

Mansoori

Srivastava

et al. 2014

Journal of Bone and Mineral Research

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Activated T cell has a key role in the interaction between bone and immune system. T cells produce proinflammatory cytokines, including receptor activator of NF-kB ligand (RANKL), tumor necrosis factor a (TNF-a), and interleukin 17 (IL-17), all of which augment osteoclastogenesis. RANKL and TNF-a are targeted by inhibitors such as denosumab, a human monoclonal RANKL antibody, and infliximab, which neutralizes TNF-a. IL-17 is also an important mediator of bone loss, and an antibody against IL-17 is undergoing phase II clinical trial for rheumatoid arthritis. Although there are a few studies showing suppression of Th17 cell differentiation and induction of regulatory T cells (Tregs) by infliximab, the effect of denosumab remains poorly understood. In this study, we investigated the effects of anti-TNF-a, anti-RANKL, or anti-IL-17 antibody administration to estrogen-deficient mice on CD4 þ T-cell proliferation, CD28 loss, Th17/Treg balance and B lymphopoesis, and finally, the translation of these immunomodulatory effects on skeletal parameters. Adult Balb/c mice were treated with anti-RANKL/-TNF-a/-IL-17 subcutaneously, twice a week, postovariectomy (Ovx) for 4 weeks. Animals were then autopsied; bone marrow cells were collected for FACS and RNA analysis and serum collected for ELISA. Bones were dissected for static and dynamic histomorphometry studies. We observed that although anti-RANKL and anti-TNF-a therapies had no effect on Ovx-induced CD4 þ T-cell proliferation and B lymphopoesis, anti-IL-17 effectively suppressed both events with concomitant reversal of CD28 loss. Anti-IL-17 antibody reduced proinflammatory cytokine production and induced Tregs. All three antibodies restored trabecular microarchitecture with comparable efficacy; however, cortical bone parameters, bone biomechanical properties, and histomorphometry were best preserved by anti-IL-17 antibody, likely attributable to its inhibitory effect on osteoblast apoptosis and increased number of bone lining cells and Wnt10b expression. Based on the superior immunoprotective effects of anti-IL-17, which appears to translate to a better skeletal preservation, we propose beginning clinical trials using a humanized antibody against IL-17 for treatment of postmenopausal osteoporosis.

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Stimulation of Bone Formation in Cortical Bone of Mice Treated with a Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-binding Peptide That Possesses Osteoclastogenesis Inhibitory Activity

Cited by 72 publications

References 38 publications

Peptide drugs accelerate BMP‐2‐induced calvarial bone regeneration and stimulate osteoblast differentiation through mTORC1 signaling

Peptide drugs accelerate BMP‐2‐induced calvarial bone regeneration and stimulate osteoblast differentiation through mTORC1 signaling

NF-κB RelB Negatively Regulates Osteoblast Differentiation and Bone Formation

Enhanced Immunoprotective Effects by Anti-IL-17 Antibody Translates to Improved Skeletal Parameters Under Estrogen Deficiency Compared With Anti-RANKL and Anti-TNF-α Antibodies

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