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Arthritis Res Ther. 2015 Sep 12;17:251. doi: 10.1186/s13075-015-0753-8.

The inhibitory effects of a RANKL-binding peptide on articular and periarticular bone loss in a murine model of collagen-induced arthritis: a bone histomorphometric study.

Author information

1
Department of Pharmacology, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan. kat-hpha@tmd.ac.jp.
2
Department of Orthodontic Science, Division of Oral Health Sciences, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan. y.shimizu.orts@tmd.ac.jp.
3
Department of Removable Partial Prosthodontics, Division of Oral Health Science, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan. y.arai.rpro@tmd.ac.jp.
4
Department of Removable Partial Prosthodontics, Division of Oral Health Science, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan. naturpro@tmd.ac.jp.
5
Department of Pharmacology, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan. sug-hpha@tmd.ac.jp.
6
Department of Pharmacology, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan. m.maeda@uke.de.
7
Present address: Department of Trauma-, Hand- and Reconstructive Surgery, Experimental Trauma Surgery, Molecular Skeletal Biology Laboratory, University Medical Center Hamburg-Eppendorf, Heisenberg Group, Martinistrasse 52, 20246, Hamburg, Germany. m.maeda@uke.de.
8
Department of Pharmacology, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan. takahashi.hpha@tmd.ac.jp.
9
Department of Pharmacology, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan. tamu.hpha@tmd.ac.jp.
10
Department of Removable Partial Prosthodontics, Division of Oral Health Science, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan. wakabayashi.rpro@tmd.ac.jp.
11
Department of Biomedical Sciences, Research Division of Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. Ramachandran.Murali@csmc.edu.
12
Department of Orthodontic Science, Division of Oral Health Sciences, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan. t.ono.orts@tmd.ac.jp.
13
Department of Pharmacology, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan. kohya.hpha@tmd.ac.jp.
14
Department of Pharmacology, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan. mis-hpha@tmd.ac.jp.
15
Department of Pharmacology, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan. kazu.hpha@tmd.ac.jp.

Abstract

INTRODUCTION:

We designed OP3-4 (YCEIEFCYLIR), a cyclic peptide, to mimic the soluble osteoprotegerin (OPG), and was proven to bind to RANKL (receptor activator of NF-κB ligand), thereby inhibiting osteoclastogenesis. We recently found that another RANKL binding peptide, W9, could accelerate bone formation by affecting RANKL signaling in osteoblasts. We herein demonstrate the effects of OP3-4 on bone formation and bone loss in a murine model of rheumatoid arthritis.

METHODS:

Twenty-four seven-week-old male DBA/1J mice were used to generate a murine model of collagen-induced arthritis (CIA). Then, vehicle or OP3-4 (9 mg/kg/day or 18 mg/kg/day) was subcutaneously infused using infusion pumps for three weeks beginning seven days after the second immunization. The arthritis score was assessed, and the mice were sacrificed on day 49. Thereafter, radiographic, histological and biochemical analyses were performed.

RESULTS:

The OP3-4 treatment did not significantly inhibit the CIA-induced arthritis, but limited bone loss. Micro-CT images and quantitative measurements of the bone mineral density revealed that 18 mg/kg/day OP3-4 prevented the CIA-induced bone loss at both articular and periarticular sites of tibiae. As expected, OP3-4 significantly reduced the CIA-induced serum CTX levels, a marker of bone resorption. Interestingly, the bone histomorphometric analyses using undecalcified sections showed that OP3-4 prevented the CIA-induced reduction of bone formation-related parameters at the periarticular sites.

CONCLUSION:

The peptide that mimicked OPG prevented inflammatory bone loss by inhibiting bone resorption and stimulating bone formation. It could therefore be a useful template for the development of small molecule drugs for inflammatory bone loss.

PMID:
26373710
PMCID:
PMC4570694
DOI:
10.1186/s13075-015-0753-8
[Indexed for MEDLINE]
Free PMC Article

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