Lovastatin inhibits adipogenic and stimulates osteogenic differentiation by suppressing PPARgamma2 and increasing Cbfa1/Runx2 expression in bone marrow mesenchymal cell cultures.

Abstract

The mechanism whereby lovastatin can counteract steroid-induced osteonecrosis and osteoporosis is poorly understood. We assessed the effect of lovastatin on a multipotential cell line, D1, which is capable of differentiating into either the osteoblast or the adipocyte lineage. The expression of bone cell and fat cell transcription factors Cbfa1/Runx2 and PPARgamma2, respectively, were determined. 422aP2 gene expression was analyzed. Osteocalcin promoter activity was measured by cotransfecting the cells with the phOC-luc and pSV beta-Gal plasmids. Lovastatin enhanced osteoblast differentiation as assessed by a 1.8x increase in expression of Cbfa1/Runx2 and by a 5x increase in osteocalcin promoter activity. Expression of PPARgamma2 was decreased by 60%. By enhancing osteoblast gene expression and by inhibiting adipogenesis, lovastatin may shunt uncommitted osteoprogenitor cells in marrow from the adipocytic to the osteoblastic differentiation pathway. Future evaluation of lovastatin and other lipid-lowering drugs will help determine their potential as therapeutic agents for osteonecrosis and osteoporosis.