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High bone turnover state under osteoporotic changes induces pain-like behaviors in mild osteoarthritis model mice

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Abstract

Introduction

Our previous studies demonstrated that a high bone turnover state under osteoporotic changes decreased the threshold of skeletal pain. Recent studies reported that the incidence of joint pain due to osteoarthritis (OA) in postmenopausal women was higher than that in males even with the same radiographic OA grade. The aim of this study was to evaluate whether a high bone turnover state affects the induction of pain-like behaviors in mild OA model mice.

Materials and Methods

We established mild OA model mice with accompanying osteoporotic changes by monosodium iodoacetate injection after ovariectomy. We assessed pain-like behaviors by von Frey test and paw-flick test; histological changes in OA joints; the expression of Runx2, Osterix, Osteocalcin, and Rankl; bone micro-architecture by μCT and measured serum tartrate-resistant acid-phosphatase 5b levels in the model mice.

Results

Pain-like behaviors in mice with OA and osteoporotic changes were significantly increased in comparison with those in OA mice without osteoporotic changes. The severity of histological OA changes did not differ significantly between the OA mice with and without osteoporotic changes. Bisphosphonate significantly improved pain-like behaviors accompanied with improvement in the high bone turnover state in the OA mice with osteoporosis, while it had no significant effect on pain-like behaviors in the OA mice without osteoporosis. In addition, the improvement was maintained for more than 4 weeks even after the discontinuation of bisphosphonate treatment.

Conclusion

These results indicated that a high bone turnover state under osteoporotic changes could affect the induction of pain-like behaviors in mild OA model mice.

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Acknowledgements

We thank Drs. Yasutaka Murahashi, Takashi Matsumura (Department of Orthopedic surgery, Sapporo Medical University School of Medicine, Sapporo, Japan), Kanna Nagaishi and Mineko Fujimiya (Department of Anatomy, Sapporo Medical University School of Medicine) for their helpful advice and invaluable contributions to this study.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan

    Kenta Kiyomoto, Kousuke Iba, Megumi Hanaka, Koji Ibe, Hikaru Hayakawa, Atsushi Teramoto, Makoto Emori & Toshihiko Yamashita

  2. Division of Occupational Therapy, Department of Rehabilitation, Japan Health Care College, 17-3, West-6 Megumino, Eniwa, 061-1373, Japan

    Kenta Kiyomoto

  3. Division of Occupational Therapy, Department of Orthopedic Trauma Center, Sapporo Tokushukai Hospital, 1-1, Oyachi East-1, Atsubetsu-ku, Sapporo, 004-0041, Japan

    Koji Ibe

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Contributions

KK performed all the experiments and data analysis. KI advised and supervised the data analysis and helped to draft the manuscript. MH, KI and HH assisted with the behavioral study. AT assisted with the histological analysis of knee osteoarthritis. ME assisted with the bone morphometry and bone metabolic markers. TY participated in coordinating the study and helped to draft the manuscript. All authors read and approved the final submitted manuscript.

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Correspondence to Kousuke Iba.

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Supplementary Fig.

 1. Study design. The 8-week-old mice were bilaterally ovariectomized (OVX), and monosodium iodoacetate (MIA) was administrated to the left knee joint at 6 weeks after OVX. Pain-like behaviors were assessed at 0, 2, 4, 6, 7, 8, 9, 10, 11 and 12 weeks after OVX. Histological analysis was performed at 2, 6 and 10 weeks after MIA injection (8, 12 and 16 weeks after OVX). Bone micro-architectural changes (as assessed by μCT), serum levels of TRAP5b, and the expression of osteoblast and osteoclast differentiation regulators were evaluated at 6 weeks after MIA injection (12 weeks after OVX). Alendronate (ALN, 0.02 mg/kg of body weight) and Carprofen (5 mg/kg of body weight) were administered to the mice subcutaneously once a day from 6 to 8 weeks after OVX. (TIFF 469 kb)

Supplementary Fig.

 2. Histological evaluation of synovitis in the model mice. Synovial tissue around the anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) (boxed area) was evaluated for lining cell layer, synovial stroma and inflammatory infiltrates (arrows) (A). The synovitis scores in the OA (grey circles) and OA with osteoporosis (black squares) mice were significantly higher at 2 weeks after MIA injection (8 weeks after OVX) than those in the control (white triangles) and osteoporosis (white rhombuses) mice. At 6 and 10 weeks after MIA injection (12 weeks and 16 weeks after OVX), there were no significant differences in the scores among the control, OA, osteoporosis and OA with osteoporosis mice (B). * p < 0.05, OA versus control; † p < 0.05, OA with osteoporosis versus osteoporosis by one-way analysis of variance followed by Tukey’s post hoc test. The sham operation was performed in all control and OA mice. Right panels show higher magnification views of the boxed areas in the left panels. Bars in the left panels, 500 μm; in the right panels, 100 μm. (TIFF 2629 kb)

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Kiyomoto, K., Iba, K., Hanaka, M. et al. High bone turnover state under osteoporotic changes induces pain-like behaviors in mild osteoarthritis model mice. J Bone Miner Metab 38, 806–818 (2020). https://doi.org/10.1007/s00774-020-01124-y

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