Mechanism of Action of Bisphosphonate Drugs

Dr Donald J Watts

• Sheffield 222 4196
• D.J.Watts@sheffield.ac.uk

Bisphosphonate drugs are used to treat conditions in which there is excessive bone resorption e.g. Paget's disease, tumoral bone disease. Most recently, the extremely potent nitrogen-containing bisphosphonate drugs have been adopted for clinical use and particularly for the treatment of osteoporosis which is common in elderly people and in patients treated with glucocorticoids to relieve the effects of severe arthritis.

The drugs act on the osteoclasts in bone but these cells are difficult to study in vitro. However, my research group found that the bisphosphonates also inhibit axenic growth of the amoeboid micro-organism Dictyostelium discoideum and determination of the structure-activity relationships for a wide variety of bisphosphonate drugs as inhibitors of bone resorption and as inhibitors of Dictyostelium growth indicated that the bisphosphonates have the same mechanism of action in Dictyostelium as in osteoclasts. Use of Dictyostelium as a convenient model system then allowed us to prove that the target for the nitrogen-containing bisphosphonates is the enzyme farnesyl diphosphate synthase and it has since been confirmed that this enzyme is also the target in osteoclasts. However, it appears that there may be further targets involved in the action of the nitrogen-containing bisphosphonate and we are currently seeking to identify these.

Recently, we have proved that farnesyl diphosphate synthase is a peroxisomal enzyme in Dictyostelium and this has led us to begin investigations of of the contribution of peroxisomes to further aspects of metabolism in Dictyostelium.

Figure Legend - Dictyostelium is also used as a model system for studies of development and differentiation since, on starvation, the amoebae form aggregates that transform into fruiting bodies in which the original amoebae have differentiated into stalk cells and spores. The scanning electron micrograph shows a group of aggregates.

Selected Publications

Farnesyl diphosphate synthase, the target for nitrogen-containing bisphosponate drugs, is a peroxisomal enzyme in the model system Dictyostelium discoideum. J.M. Nuttall, E.H. Hettema and D.J. Watts (2012) Biochemical Journal 447, 353-361.

Determination of the microscopic equilibrium dissociation constants for risedronate and its analogues reveals two distinct roles for the nitrogen atom in nitrogen-containing bisphosphonate drugs. A.M. Hounslow, J. Carran, R.J. Brown, D. Rejman, G.M. Blackburn and D.J. Watts (2008) Journal of Medicinal Chemistry 51, 4170-4178.

The intracellular target for the antiresorptive aminobisphosphonate drugs in Dictyostelium discoideum is the enzyme farnesyl diphosphate synthase. J.E.Grove, R.J.Brown and D.J.Watts (2000) Journal of Bone and Mineral Research 15, 971-981.

Structure-activity relationships of new heterocycle-containing bisphosphonates as inhibitors of bone resorption and as inhibitors of growth of Dictyostelium discoideum amoebae. M.J.Rogers, X.Xiong, R.J.Brown, D.J.Watts, R.G.G.Russell, A.V.Bayless and F.H.Ebetino (1995) Molecular Pharmacology 47, 398-402.

Inhibitory effects of bisphosphonates on growth of amoebae of the cellular slime mould Dictyostelium discoideum. M.J.Rogers, D.J.Watts, R.G.G.Russell, X.Ji, X.Xiong, G.M.Blackburn, A.V.Bayless and F.H.Ebetino (1994) Journal of Bone and Mineral Research 9, 1029-1039.