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Open Access Research article

Muscle wasting associated with pathologic change is a risk factor for the exacerbation of joint swelling in collagen-induced arthritis in cynomolgus monkeys

Naoto Horai12*, Takaharu Nagaoka2, Itsuro Higuchi3, Hayato Kasai2, Takako Yoshioka4, Yoshihisa Umekita5, Koichiro Fukuzaki2, Ryoichi Nagata2, Atsuro Miyata1 and Kazuhiro Abeyama6

Author Affiliations

1 Department of Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan

2 Shin Nippon Biomedical Laboratories, Ltd. Drug Safety Research Laboratories (SNBL DSR), 2438 Miyanoura, Kagoshima 891-1394, Japan

3 Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan

4 Department of Tumor Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan

5 Division of Organ Pathology, Faculty of Medicine, Tottori University, 86 Nishi-machi, Yonago, Tottori 683-8503, Japan

6 Department of Radiology, Morizono Hospital, 19-38 Oshoji-cho, Satsumasendai, Kagoshima 895-0076, Japan

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BMC Musculoskeletal Disorders 2013, 14:205  doi:10.1186/1471-2474-14-205

Published: 9 July 2013

Abstract

Background

Not only joint destruction but also muscle wasting due to rheumatoid cachexia has been problem in terms of quality of life of patients with rheumatoid arthritis (RA). In the present study, we performed histopathological examination and assessed relationships between characteristic parameters relating to muscle and joint swelling in a collagen-induced arthritis (CIA) model using cynomolgus monkeys (CMs).

Methods

Female CMs were used and CIA was induced by twice immunizations using bovine type II collagen with Freund’s complete adjuvant. Arthritis level was evaluated from the degree of swelling at the peripheral joints of the fore and hind limbs. Food consumption, body weight, and serum biochemical parameters were measured sequentially. Five or 6 animals per time point were sacrificed at 2, 3, 5 and 9 weeks after the first immunization to obtain quadriceps femoris specimens for histopathology. Pimonidazole hydrochloride was intravenously administered to determine tissue hypoxia in skeletal muscle.

Results

Gradual joint swelling was observed and the maximum arthritis score was noted at Week 5. In histopathology, necrosis of muscle fiber in the quadriceps femoris was observed only at Week 2 and the most significant findings such as degeneration, atrophy, and regeneration of muscle fiber were mainly observed at Week 5. Food consumption was decreased up to Week 4 but recovered thereafter. Body weight decreased up to Week 5 and did not completely recover thereafter. A biphasic increase in serum cortisol was also observed at Weeks 2 and 5. Histopathology showed that muscle lesions were mainly composed of degeneration and atrophy of the muscle fibers, and ATPase staining revealed that the changes were more pronounced in type II muscle fiber than type I muscle fiber. In the pimonidazole experiment, mosaic pattern in skeletal muscle was demonstrated in the intact animal, but not the CIA animal. Increased arthritis score was accompanied by a decrease in serum creatinine, a marker that reflects muscle mass.

Conclusions

Muscle wasting might exacerbate joint swelling in a collagen-induced arthritis model of cynomolgus monkeys.

Keywords:
Collagen-induced arthritis; Rheumatoid arthritis; Cynomolgus monkey; Muscle wasting; Hypoxia; Steroid; Histopathology; Muscle