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

Abstract

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.

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

“…In the present study, we demonstrated that treatment of OPG –/– mice with W9 restored their alveolar bone loss through two independent mechanisms: One is suppression of osteoclastogenesis by inhibiting RANK signaling in osteoclast precursors, and the other is enhancement of osteoblastogenesis by suppressing sclerostin expression in osteocytes. In addition to W9, OP3-4, a cyclic peptide, to mimic OPG, was reported to bind to RANKL, thereby inhibiting osteoclastogenesis [ 33 ]. OP3-4 could accelerate bone formation by affecting RANKL signaling in osteoblasts in a similar manner to W9 [ 33 ].…”

“…In addition to W9, OP3-4, a cyclic peptide, to mimic OPG, was reported to bind to RANKL, thereby inhibiting osteoclastogenesis [ 33 ]. OP3-4 could accelerate bone formation by affecting RANKL signaling in osteoblasts in a similar manner to W9 [ 33 ]. These results suggest that RANKL-binding peptides may have unique characteristics in the regulation of bone resorption and formation.…”

“…It is proposed that W9 and OP3-4 bind to RANKL expressed on cell surfaces of osteoblasts to induce retrograde signals [ 29 , 33 ]. Up-regulation of the alkaline phosphatase expression by these peptides was not clearly observed in osteoblasts derived from RANKL –/– mice in vitro [ 29 ].…”

“…Up-regulation of the alkaline phosphatase expression by these peptides was not clearly observed in osteoblasts derived from RANKL –/– mice in vitro [ 29 ]. W9 and OP3-4 have been demonstrated to stimulate mammalian target of rapamycin complex 1 (mTORC1) signaling in osteoblasts, which may be necessary for the RANKL-mediated retrograde signals [ 33 ]. It was also reported that RANK-coated beads enhanced OPG secretion by osteoblasts through the interaction between RANK expressed on beads and RANKL expressed on osteoblasts [ 37 ].…”

Bone Regeneration by Low-dose Recombinant Human Bone Morphogenetic Protein-2 Carried on Octacalcium Phosphate Collagen Composite

“…The clinical application of recombinant human bone morphogenetic protein-2 (rhBMP-2), which is one of the most important bone inductive proteins, has been expected, and it has been approved for clinical use in extraction socket preservation and maxillary sinus floor augmentation 5) . rhBMP-2 shows superior bone regeneration, however, several adverse events have been reported such as local edema, seroma, and cancer induction at high-dose rhBMP-2 [6][7][8] . Atelocollagen sponge (ACS) is presently used as a carrier of rhBMP-2; however, it is reported to release rh-BMP-2 instantaneously 9) .…”