The mevalonate pathway in bone biology
Bone Biology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
The mevalonate pathway, necessary for the biosynthesis of cholesterol, is a conserved and ubiquitous process in eukaryotic organisms. It works via a step-wise condensation of isoprene units to form longer-chain isoprenoid lipids. It has two branches: one leads to the synthesis of sterols, and the other to the synthesis of isoprenoid lipids tags required for the post-translational modification of proteins known as prenylation. It is estimated that at least 300 proteins of the human proteome are prenylated, particularly signaling proteins such as Ras, Rho and Rab small GTPases. During prenylation, farnesyl or geranylgeranyl isoprenoid moieties are irreversibly added to a cysteine residue at the protein’s carboxy terminus, enabling subcellular membrane localisation and protein:protein interactions, and hence adequate signal transduction and regulation. The importance of the mevalonate pathway in bone biology emerged from the discovery that most bisphosphonate drugs, used worldwide to treat common diseases of excessive bone destruction such as osteoporosis, act by blocking protein prenylation in bone-degrading osteoclasts. Bisphosphonates (BPs) are non-hydrolysable analogues of naturally-occurring pyrophosphate. Having high avidity for calcium ions, BPs bind rapidly to bone mineral and are preferentially internalised by osteoclasts. Once in the cytosol, BPs lock farnesyl diphosphate synthase in an inactive state, thereby blocking the synthesis of farnesyl and geranylgeranyl isoprenoid tags and preventing protein prenylation. In this way, bisphosphonates interfere with cellular processes governed by prenylated small GTPases that are essential for bone resorption, such as cell polarisation, cytoskeletal organisation and vesicular trafficking. We are now using the tools developed to study the actions of bisphosphonates to provide new advances in the diagnosis and pathophysiology of a human autoinflammatory disease caused by defective protein prenylation.