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Antiinflammatory and Chondroprotective Effects of the Aminobisphosphonate Incadronate (YM175) in Adjuvant Induced Arthritis
ATSUSHI MATSUO, TOSHIHIDE SHUTO, GO HIRATA, HIDESHI SATOH, YOSHIHIRO MATSUMOTO, HONGPU ZHAO, and YUKIHIDE IWAMOTO
ABSTRACT. Objective. Incadronate is a third-generation bisphosphonate that suppresses bone resorption and is used to treat skeletal disorders and prevent bone loss in pathological conditions. We evaluated its therapeutic potential and antiinflammatory effects in established adjuvant induced arthritis (AIA), a rat model of rheumatoid arthritis (RA). Methods. Rats were administered incadronate subcutaneously at a dose of either 0.1 or 1.0 mg/kg/day, or 0.1 or 1.0 mg/kg/week, while a positive control group received phosphate buffered saline alone from Day 14 (after the onset of arthritis) to Day 42. The destruction of bone and cartilage and the antiinflammatory effects of incadronate in rats with established AIA were assessed during treatment, with reference to the arthritis index, hind paw volume, and radiological and histological examinations. To establish whether incadronate affects the migration of inflammatory cells, a chemotaxis assay was carried out using macrophage-like RAW 264.7 cells. Results. In vivo, incadronate suppressed the clinical manifestations of AIA in a dose-dependent manner. In vitro, the various concentrations of incadronate suppressed the migration of macrophages, but the viability and adhesion of these cells were not suppressed. Conclusion. Incadronate not only inhibits bone destruction but also reduces cartilage degeneration and joint inflammation in rats with established AIA. The mechanism underlying these antiinflammatory actions of incadronate may be attributable to the inhibition of macrophage migration to the site of inflammation. Bisphosphonates might be effective in preventing the progressive joint destruction and inflammation seen in patients with RA. (J Rheumatol 2003;30:1280-90) Key Indexing Terms:
BISPHOSPHONATES
From the Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. A. Matsuo, MD; T. Shuto, MD, PhD; G. Hirata, MD; H. Satoh, MD; Y. Matsumoto, MD, PhD; H. Zhao, MD, PhD; Y. Iwamoto, MD, PhD. Address reprint requests to Dr. T. Shuto, Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: shutot@ortho.med.kyushu-u.ac.jp Submitted April 29, 2002; revision accepted November 11, 2002. |