The Nicolas Andry award. The pathogenesis and prevention of steroid-induced osteonecrosis

The effects of steroids on a cloned pluripotential cell from bone marrow stroma were examined in vitro in culture and in vivo after the cells were transfected with a traceable gene and transplanted into host mice. Bipedal chickens were treated with steroids to establish a model for osteonecrosis. The effects of a lipid lowering agent, lovastatin, on the prevention of steroid induced adipogenesis in vitro in cell culture, and on adipogenesis and osteonecrosis in vivo in chickens, were evaluated. On treatment with dexamethasone, cloned pluripotential cells began to differentiate into adipocytes and expressed a fat specific gene, whereas the expression of Type I collagen and osteocalcin messenger ribonucleic acid decreased. Addition of lovastatin in culture inhibited steroid induced fat gene expression and counteracted the inhibitory effect of steroids on osteoblastic gene expression. Cloned pluripotential cells were transduced with a traceable retrovirus vector encoding the beta-galactosidase and neomycin resistance genes. The transfected cells were administered to mice either by tail vein or by direct intramedullary injection. Half of the animals in each group were treated with steroids. Histologic sections showed the appearance of transplanted cells in the marrow. Analysis of marrow blowouts by flow cytometry revealed that steroid treatment produced adipogenesis in transplanted cells. Evidence of osteonecrosis was observed in steroid treated chickens, whereas sections from animals treated with steroids and lovastatin showed less adipogenesis and no bone death. The results indicate that steroid induced adipogenesis in the marrow may contribute to osteonecrosis and that lovastatin may be helpful in preventing the development of steroid induced osteonecrosis.