In organ culture, also, some

BPs can inhibit the generation of mature osteoclasts, possibly by preventing the fusion of osteoclast precursors [5]. In contrast to their ability to induce apoptosis in osteoclasts, which contributes to the inhibition of selleck screening library resorptive activity, some experimental studies suggest that BPs may protect osteocytes and osteoblasts from apoptosis induced by glucocorticoids [9]. Since the early 1990s there has been a systematic effort Inhibitors,research,lifescience,medical to elucidate the molecular mechanisms of action of BPs, and, not surprisingly, it has been found that they could be divided into 2 structural subgroups [10, 11]. The first group comprises the nonnitrogen-containing bisphosphonates, such as CLO and ETI, that perhaps most closely resemble pyrophosphate. These Inhibitors,research,lifescience,medical can be metabolically incorporated into nonhydrolyzable analogues of adenosine triphosphate (ATP) methylene-containing (AppCp) nucleotides, by reversing the reactions of aminoacyl-transfer RNA synthetases [12]. The resulting metabolites contain the P–C–P moiety in place of the β,γ-phosphate groups of ATP [13]. Intracellular accumulation Inhibitors,research,lifescience,medical of these metabolites within osteoclasts inhibits their function and may cause osteoclast cell death, most likely by inhibiting ATP-dependent enzymes, such as the adenine nucleotide

translocase, a component of the mitochondrial permeability transition pore [14]. Induction of osteoclast apoptosis seems to be the primary mechanism by which the simple BPs inhibit bone resorption, since the Inhibitors,research,lifescience,medical ability of CLO and ETI to inhibit resorption in vitro can be overcome when osteoclast apoptosis is prevented using a caspase inhibitor [15]. In contrast, the second group, comprising the nitrogen-containing bisphosphonates (N-BPs), which are several orders of magnitude more potent at Inhibitors,research,lifescience,medical inhibiting bone resorption in vivo than the simple bisphosphonates, is not metabolized to toxic analogues of ATP [16]. N-BPs act by inhibiting farnesyl diphosphate (FPP) synthase, a

key enzyme of the mevalonate pathway (Figure 3). Figure 3 Isoprenoids are synthesized from the mevalonate pathway that starts from reaction catalyzed by the 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase (the rate-limiting reaction in cholesterol biosynthesis) which catalyzes the conversion of out HMG-CoA to … This enzyme is inhibited by nanomolar concentrations of N-BPs. ZOL and the structurally similar MIN are extremely potent inhibitors of FPP synthase [6] and inhibit the enzyme even at picomolar concentrations. Importantly, studies with recombinant human FPP synthase revealed that minor modifications to the structure and conformation of the R2 side chain that are known to affect antiresorptive potency also affect the ability to inhibit FPP synthase. These studies strongly suggest that FPP synthase is the major pharmacologic target of N-BPs in osteoclasts in vivo and help to explain the relationship between bisphosphonate structure and antiresorptive potency [6].