Short communicationl-arginine prevents bone loss and bone collagen breakdown in cyclosporin A-treated rats.
Introduction
Cyclosporin A is a potent immunosuppressive agent that is widely used in the therapy of organ rejection in post-transplantation patients, and in the treatment of several autoimmune diseases. Unfortunately, this agent has major adverse effects, one of which is a dose- and duration-dependent high-turnover osteopenic state (Cvetkovic et al., 1994).
Despite the considerable attention that cyclosporin A's effects on bone metabolism have received, the mechanism by which cyclosporin A induces bone loss is not clearly understood.
A recent study by Oriji and Keiser (1998) has shown that the development of arterial hypertension associated to cyclosporin A treatment is characterized in the rat by inhibition of endothelial nitric oxide (NO) activity, an effect which can be overcome by parenteral administration of l-arginine. Moreover, it is well known that NO is a key signaling molecule in bone also, being produced by bone cells in response to various stimuli (Evans and Ralston, 1996).
This study aimed to investigate further the skeletal effects of cyclosporin A in the rat, endeavoring to determine whether l-arginine (a basic amino acid which can be converted to produce NO) could help maintain bone mass in cyclosporin A-treated animals.
Section snippets
Material and methods
Thirty-six 10-week-old Sprague–Dawley male rats, each weighing approximately 220±20 g were used in this study. All animals were housed under similar conditions (12/12 h light/dark cycle, ambient temperature 22°C) and maintained on a standard diet containing 0.97% Ca2+, 0.85% phosphorus, and 1045 IU/kg of vitamin D3, and deionized water ad libitum. All procedures conformed with the guidelines of the Animal Care and Use Committee of Catania University. Rats were randomly divided into six groups
Results
There were no significant differences in the baseline bone mineral content, at the three sites measured, among the six groups of rats studied (mean±S.E.). The changes in body weight of rats in each group is shown in Table 1. As expected, control rats increased the body weight throughout the study. Although food intake was almost identical in all groups over the whole study, there was a tendency to lose some weight in cyclosporin A+l-Name-treated rats. Rats receiving cyclosporin A alone,
Discussion
This study confirmed previous findings of an osteopenic state, involving both cortical and trabecular bone, induced by cyclosporin A administration to mature rats at a 15 mg/kg daily dose for 4 weeks. This is not due to impaired bone growth or loss of body weight. This experiment, like previous studies (Erben et al., 1998), did not show alterations in serum Ca2+, creatinine and alkaline phosphatase. Although pyridinoline is released more generally by remodeling tissues, the significant increase
Acknowledgements
This work was supported by funds from the Italian Ministry of Scientific Research (MURST).
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