Molecular mechanisms of action of bisphosphonates
1999; Elsevier BV; Volume: 24; Issue: 5 Linguagem: Inglês
10.1016/s8756-3282(99)00070-8
ISSN8756-3282
AutoresMichael J. Rogers, Julie C. Frith, Steven P. Luckman, Fraser P. Coxon, Helena L. Benford, Jukka Mönkkönen, Seppo Auriola, Kathya Chilton, R.G.G. Russell,
Tópico(s)Protein Kinase Regulation and GTPase Signaling
ResumoBPs can be grouped into two general classes according to their chemical structure and the molecular mechanism by which they inhibit osteoclast-mediated bone resorption. The simple BPs can be metabolically incorporated into non-hydrolysable analogues of ATP that accumulate intracellularly in osteoclasts, causing osteoclast cell death by apoptosis. By contrast, the more potent N-BPs inhibit FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids that are required for the prenylation of small GTPase signalling proteins necessary for osteoclast function. Inhibition of FPP synthase in cells other than osteoclasts also appears to account for the adverse effects of N-BPs in vivo (including the acute phase reaction) and for the anti-tumour effects of N-BPs in vitro.
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