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

Abstract

BackgroundNot 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).MethodsFemale 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.ResultsGradual 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.ConclusionsMuscle wasting might exacerbate joint swelling in a collagen-induced arthritis model of cynomolgus monkeys.

Compensatory anabolic signaling in the sarcopenia of experimental chronic arthritis

“…We observed an elevated serum CRP together with a significant decrease in body weight and muscle size. While RC in humans is widely reported to be associated with stable weight or weight gain, our results are consistent with previous animal models of inflammatory arthritis in rabbits 33 , rats 34 , mice 35 and monkeys 36 . Similarly, our findings of reduced muscle CSA, CSD and weight is reflected in previous models across a range of species 36–38 .…”

“…While RC in humans is widely reported to be associated with stable weight or weight gain, our results are consistent with previous animal models of inflammatory arthritis in rabbits 33 , rats 34 , mice 35 and monkeys 36 . Similarly, our findings of reduced muscle CSA, CSD and weight is reflected in previous models across a range of species 36–38 . The loss in muscle size and weight, and the heterogenous myofibre size observed in AiA rabbits may reflect our qualitative observation of preferential wasting of type II muscle fibres, an established phenomenon described in experimental arthritis in other species 36 .…”

“…Similarly, our findings of reduced muscle CSA, CSD and weight is reflected in previous models across a range of species 36–38 . The loss in muscle size and weight, and the heterogenous myofibre size observed in AiA rabbits may reflect our qualitative observation of preferential wasting of type II muscle fibres, an established phenomenon described in experimental arthritis in other species 36 .…”

“…recently demonstrated elevated myostatin expression in synovial membranes of patients with RA, it is not known whether these patients were also affected by RC 54 . Furthermore, of the seven previous models of inflammatory arthritis that we found in the literature, only three reported increased myostatin mRNA or protein 36, 45, 54 . A number of the conflicting reports may originate from myostatin mRNA-protein discordance.…”

Role of regeneration in tissue repairing and therapies

“…For this purpose an efficient genome manipulation technology is followed by using RNA-guided DNase Cas9. This clustered and regularly interspaced short palindromic repeats (CRISPR) system is found highly efficient and useful for genome engineering of human iPS cells [51]. However, to obtain organotypic cells pluripotent stem cells can be selected on the basis of expressing green fluorescent protein and puromycin resistance under control of the Oct4 promoter.…”