Boning Up (or Down) on Statins

Abstract

The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mediates cholesterol biosynthesis by converting HMG-CoA to mevalonic acid. Although the focus has been on its effects on cholesterol, because mevalonic acid is also required for isoprenoid synthesis, it may also affect other important biological processes. Isoprenoids are converted by transferases to farnesyl and geranylgeranyl pyrophosphate, which are used for protein prenylation, a post-translational modification consisting of covalent addition of the isoprenoid side chains at or near the carboxyl terminus of certain proteins. Prenylation directs proteins to associate with membranes and mediates protein-protein interactions, thus contributing to a wide variety of general cell functions, particularly signal transduction. Not all the proteins that undergo prenylation have been identified. See article, page 1636 It has been suggested that inhibitors of HMG-CoA reductase (statins), widely used for treatment of hyperlipidemia, may have pleiotropic effects through inhibition of protein prenylation. This may account for effects of statins that are independent of lipid lowering.1,2 However, there is also evidence that the mevalonate pathway is so tightly regulated that prenylation could not be significantly affected without toxic doses of statins.3 The report by Maritz et al4 in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology addresses one of the possible pleiotropic effects of statins: modulation of bone metabolism. This possibility was brought to attention when Mundy et al5 reported that statins promote bone formation in rats and in calvarial fragments maintained in an organ culture. Although the …