Interferon-gamma causes loss of bone volume in vivo and fails to ameliorate cyclosporin A-induced osteopenia.

ABSTRACT

Interferon-gamma (IFN gamma) in vitro inhibits both bone resorption and bone formation, resulting in a net decrease in bone turnover. In vivo administration of cyclosporin A (CsA) produces accelerated bone remodeling with resultant bone loss. The aim of this study was to investigate whether administration of IFN gamma to rats would favorably modify the high turnover osteopenia caused by CsA. Thirty-six male Sprague-Dawley rats were randomized into 4 equal groups to receive either CsA (15 mg/kg.day) or vehicle by gavage and IFN gamma (10(6) IU/kg.day) or vehicle by ip injection for 8 days. Group 1 received CsA vehicle plus IFN gamma vehicle; group 2 received CsA plus IFN gamma vehicle; group 3 received CsA vehicle plus IFN-gamma; group 4 received CsA plus IFN gamma. Blood was sampled on days 0, 4, and 8 for measurement of ionized calcium (Ca2+), PTH, 1,25-dihydroxyvitamin D, and bone gla protein. Tibiae were removed on day 8 after double tetracycline labeling for histomorphometric analysis. Ca2+ and PTH levels were similar in all groups during the study period. Rats receiving CsA (groups 2 and 4) had elevated levels of 1,25-dihydroxyvitamin D and bone gla protein, whereas rats receiving IFN gamma alone (group 3) had no change in levels of these parameters. Bone histomorphometry revealed that treatment with CsA and/or IFN gamma (groups 2-4) caused an increase in bone resorption surface and a decrease in some parameters of bone formation, resulting in a net loss of bone volume. Thus, IFN gamma failed to influence the osteopenia caused by CsA and on its own had adverse effects on bone in vivo. These results demonstrate that immune-mediating agents have opposing actions in vitro as compared to in vivo.