Transforming growth factor-β administration modifies cyclosporine A-induced bone loss

Abstract Cyclosporine A (CsA), a potent immunosuppressant used in transplantation, induces increased formation with excess resorption in the rat with resultant osteopenia. These findings are confirmed in the human model. Transforming growth factor-β (TGF-β) is reported to be involved in the coupling of bone formation with resorption and in vivo and in vitro stimulates osteoblasts, and in vitro inhibits osteoclasts. CsA stimulates secretion of TGF-β1 in humans, which, while improving immunosuppression, may also contribute to renal toxicity. This study was performed determine whether exogenously administered TGF-β would modify the bone effects of CsA. Male Sprague-Dawley rats, 6 months of age, were randomized to receive: TGF-β and CsA vehicle (group A); TGF-β 5 μg/kg three times per week and CsA vehicle (group B); TGF-β vehicle and CsA 10 mg/kg (group C); or TGF-β 5 μg/kg three times per week and CsA 10 mg/kg (group D). These were compared with control over 28 days. CsA, but not TGF-β, increased serum 1,25(OH) 2 D levels throughout the study. CsA increased osteocalcin (BGP), but TGF-β negated this effect. Histomorphometry confirmed the known effects of CsA, whereas TGF-β alone had no effect. However, in combination, TGF-β blocked CsA’s effect and increased osteoblast recruitment and activity, as reflected by increased percent mineralizing surface, percent osteoid perimeter, bone formation rate (bone volume referent), and activation frequency. Thus, it appears as if TGF-β administration may have potential in modulating the deleterious bone effects of CsA.