title: Inhibition of phosphate transporters ameliorates the inflammatory and necrotic side effects of the nitrogen-containing bisphosphonate zoledronate in mice.
abstract: Bisphosphonates (BPs) are pyrophosphate analogs. They are widely used against enhanced bone-resorption in various diseases. Nitrogen-containing BPs (N-BPs) exhibit strong anti-bone-resorptive effects but have inflammatory and necrotic side effects. The non-nitrogen-containing BPs (non-N-BPs) etidronate and clodronate lack such side effects, but their anti-bone-resorptive effects are weak. In mice, etidronate and clodronate reduce the inflammatory/necrotic effects of N-BPs, even those of zoledronate, the N-BP with the strongest anti-bone-resorptive effect yet reported and the highest risk of inflammation/necrosis. Here, to explore the mechanisms underlying this protection, we used a mouse model in which a single reagent or a mixture of two reagents was injected subcutaneously into ear-pinnas. These reagents included zoledronate, four non-N-BPs, pyrophosphate, and inhibitors of various organic-anion-transporters. Pyrophosphate and two of the four non-N-BPs (not etidronate or clodronate) had inflammatory/necrotic effects. These effects were reduced by etidronate and clodronate, but not by phosphonoformate, an inhibitor of two of the three known phosphate-transporter families. Phosphonoformate reduced the inflammatory/necrotic effects of zoledronate, but not those of pyrophosphate or of non-N-BPs. Conversely, pyrophosphate, at non-inflammatory/necrotic concentrations, reduced the inflammatory/necrotic effects of non-N-BPs, but not those of zoledronate. The efficacies of the protective effects against the inflammatory/necrotic effects of zoledronate were clodronate > etidronate > phosphonoformate. These findings suggest that (i) the N-BP zoledronate may enter soft-tissue cells via phosphonoformate-inhibitable phosphate-transporters, (ii) other phosphate-transporters may carry pyrophosphate and inflammatory/necrotic non-N-BPs into such cells, and (iii) etidronate and clodronate inhibit all these transporters, and they ameliorate the side effects of zoledronate by inhibiting phosphonoformate-inhibitable phosphate-transporters.
authors.affiliation: Division of Oral Molecular Regulation, Graduate School of Dentistry, Tohoku University.
authors.forename: Satoru
authors.initials: S
authors.lastname: Okada
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kiyama
authors.forename: Eri
authors.initials: E
authors.lastname: Sato
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Takefumi
authors.initials: T
authors.lastname: Oizumi
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Kuroishi
authors.forename: Tetsu
authors.initials: T
authors.lastname: Takahashi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Sasaki
authors.forename: Shunji
authors.initials: S
authors.lastname: Sugawara
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Endo
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control*; D004002:Clodronic Acid / Q000737:chemistry / Q000494:pharmacology; D004164:Diphosphonates / Q000009:adverse effects* / Q000737:chemistry; D012968:Etidronic Acid / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D017245:Foscarnet / Q000737:chemistry / Q000378:metabolism; D007093:Imidazoles / Q000009:adverse effects* / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009336:Necrosis / Q000139:chemically induced* / Q000188:drug therapy; D010000:Osteitis / Q000139:chemically induced* / Q000188:drug therapy; D028061:Phosphate Transport Proteins / Q000037:antagonists & inhibitors*; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D028061:Phosphate Transport Proteins; D004002:Clodronic Acid; D017245:Foscarnet; D000077211:Zoledronic Acid; D012968:Etidronic Acid