Pro-IL-1β accumulation in macrophages by alendronate and its prevention by clodronate

Shikama, Yosuke; Nagai, Yoshinori; Okada, Satoru; Oizumi, Toru; Shimauchi, Hidetoshi; Sugawara, Shunji; Endo, Yasuo

doi:10.1016/j.toxlet.2010.08.013

Cited by 23 publications

(34 citation statements)

References 29 publications

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“…[6][7][8][9][10] Actually, etidronate and clodronate are protective against the inflammatory/necrotic effects of N-BPs. 8,[10][11][12][13] Concerning the mechanism underlying this protective effect, we hypothesized that (i) N-BPs enter soft-tissue cells via phosphate transporters, and (ii) etidronate and clodronate can inhibit the entry of N-BPs into cells. These hypotheses were supported by our recent finding in mice that among various BP-related substances and inhibitors of various transporters, only etidronate, clodronate, and phosphonoformate (a well-known inhibitor of the phosphate-transporter families SLC34 and/or SLC20) dronate (a cyclic-type N-BP that has the highest reported risk of side effects among N-BPs).…”

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confidence: 99%

Phosphonocarboxylates Can Protect Mice against the Inflammatory and Necrotic Side Effects of Nitrogen-Containing Bisphosphonates by Inhibiting Their Entry into Cells <i>via</i> Phosphate Transporters

Kiyama

Tsuchiya

Okada

et al. 2016

Biological & Pharmaceutical Bulletin

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Bisphosphonates (BPs) are used against diseases involving increased bone-resorption. Among BPs, nitrogencontaining BPs (N-BPs) have much stronger anti-bone-resorptive effects than non-nitrogen-containing BPs (non-N-BPs). However, N-BPs carry the risk of inflammatory/necrotic effects, including osteonecrosis of jawbones. When injected into mouse ear-pinnas, N-BPs induce inflammatory/necrotic effects within the ear-pinna. We previously found that (a) the non-N-BPs clodronate and etidronate can reduce such side effects of N-BPs, and (b) phosphonoformate (an inhibitor of the phosphate transporters SLC20 and SLC34) can reduce the inflammatory/necrotic effects of zoledronate (the N-BP with the highest reported risk of side effects). However, it is not clear (i) whether phosphonoformate can reduce the side effects of other N-BPs, too, and (ii) whether other phosphonocarboxylates have such inhibitory effects. Here, using the mouse ear-pinna model, we compared the effects of etidronate, clodronate, and four phosphonocarboxylates on the inflammatory/necrotic effects of N-BPs of the alkyl type (alendronate) or cyclic type (zoledronate and minodronate). Like phosphonoformate, the other three phosphonocarboxylates protected against the inflammatory/necrotic effects of all the N-BPs. The protective potencies were clodronate>etidronate>phosphonoacetate>phosphonoformate> phosphonopropionate>phosphonobutyrate. With a similar order of potencies, these agents reduced the amount of 3 H-alendronate retained within the ear-pinna after its injection therein. The mRNAs of SLC20 and SLC34 were detected in untreated ear-pinnas. These findings suggest that the inhibition of phosphate transporters by phosphonocarboxylates, as well as by etidronate and clodronate, might be a useful preventive strategy against the side effects of both alkyl-and cyclic-type N-BPs.

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confidence: 99%

Phosphonocarboxylates Can Protect Mice against the Inflammatory and Necrotic Side Effects of Nitrogen-Containing Bisphosphonates by Inhibiting Their Entry into Cells <i>via</i> Phosphate Transporters

Kiyama

Tsuchiya

Okada

et al. 2016

Biological & Pharmaceutical Bulletin

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“…This suggests a common involvement of IL-1 in the inflammatory effects of N-BPs. Although Deng et al (2006) found that alendronate did not induce any detectable elevation in the serum level of IL-1 (or mature IL-1), we later reported that alendronate stimulates the synthesis of pro-IL-1 (but not mature IL-1) in macrophages (Shikama et al 2010). We have also shown that the elevation of serum IL-1 levels induced by lipopolysaccharide (a surface component of gram-negative bacteria) is greatly augmented by alendronate (Sugawara et al 1998;Yamaguchi et al 2000).…”

Section: Involvement Of Il-1 In Inflammatory Effects Of N-bpsmentioning

confidence: 78%

“…Concerning the INSEs of N-BPs in mice, we have reported that clodronate and etidronate can reduce or prevent the systemic and local INSEs of various N-BPs (Endo et al 1999;Funayama et al 2005;Oizumi et al 2009Oizumi et al , 2010Shikama et al 2010). In the present study, clodronate prevented the INSEs of minodronate, too, suggesting that the protective effect of clodronate is widely exerted against the INSEs of various N-BPs.…”

Section: Protective Effect Of Clodronate (A Non-n-bp) Against Minodromentioning

confidence: 99%

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Inflammatory and Necrotic Effects of Minodronate, a Nitrogen-Containing Bisphosphonate, in Mice

Kiyama

Okada

Tanaka

et al. 2013

Tohoku J. Exp. Med.

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Diseases involving enhanced bone-resorption (e.g., osteoporosis) are widely treated with bisphosphonates (BPs). BPs are of two types: the nitrogen-containing BPs (N-BPs) and the non-nitrogen-containing BPs (non-N-BPs). N-BPs have much stronger anti-bone-resorptive effects than non-N-BPs, and N-BPs can exert inflammatory and necrotic effects, including osteonecrosis of jawbones. Minodronate, an N-BP, was approved in 2009 in Japan for osteoporosis. Its anti-bone-resorptive effect is comparable to that of zoledronate, the N-BP with the strongest anti-bone-resorptive effect and the highest risk of side effects yet reported. Unlike other N-BPs, minodronate has an analgesic effect, and no serious side effects have been documented. Here, to examine whether minodronate lacks inflammatory and/or necrotic effects, we used mice (since the N-BPs tested so far induce such effects in mice with potencies that parallel those reported in humans). To facilitate comparison with previous studies, we gave a single systemic (intraperitoneal) or local (ear pinna) injection of minodronate (or another N-BP). We measured the systemic responses (weight of thoracic exudate, number of inflammatory cells in the peritoneal cavity, and spleen weight) or local responses (area of inflamed skin and incidence of necrosis). Anti-bone-resorptive effects were evaluated by X-ray analysis of tibias following intraperitoneal injection. Minodronate's anti-bone-resorptive effect and its inflammatory and necrotic effects were as great as, or greater than those of zoledronate. Moreover, in cultured human periodontal ligament cells, the cytotoxicity of minodronate was significantly greater than that of zoledronate. These results suggest that caution may be needed with minodronate in clinical use, as with other N-BPs.

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“…14,37) Strangely, although we could not detect IL-1 in the blood after injection of an N-BP alone, we could detect IL-1β in the liver, spleen and lung. 38,39) The reason for IL-1β being undetectable in the blood seems to lie in our demonstration that although N-BPs increase pro-IL-1β within cells, activation of caspase-1 is insufficient for IL-1β to be released from the cells. 39) Fever occurs in about 30% of patients receiving an intravenous N-BP for the first time, 40) with fatalities occurring among children due to the fever.…”

Section: Il-1-producing Effectsmentioning

confidence: 94%

Underlying Mechanisms and Therapeutic Strategies for Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)

Endo

Kumamoto

Nakamura

et al. 2017

Biological & Pharmaceutical Bulletin

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Bisphosphonates (BPs), with a non-hydrolysable P-C-P structure, are cytotoxic analogues of pyrophosphate, bind strongly to bone, are taken into osteoclasts during bone-resorption and exhibit long-acting anti-bone-resorptive effects. Among the BPs, nitrogen-containing BPs (N-BPs) have far stronger anti-boneresorptive effects than non-N-BPs. In addition to their pyrogenic and digestive-organ-injuring side effects, BP-related osteonecrosis of jaws (BRONJ), mostly caused by N-BPs, has been a serious concern since 2003. The mechanism underlying BRONJ has proved difficult to unravel, and there are no solid strategies for treating and/or preventing BRONJ. Our mouse experiments have yielded the following results.

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Pro-IL-1β accumulation in macrophages by alendronate and its prevention by clodronate

Cited by 23 publications

References 29 publications

Phosphonocarboxylates Can Protect Mice against the Inflammatory and Necrotic Side Effects of Nitrogen-Containing Bisphosphonates by Inhibiting Their Entry into Cells <i>via</i> Phosphate Transporters

Phosphonocarboxylates Can Protect Mice against the Inflammatory and Necrotic Side Effects of Nitrogen-Containing Bisphosphonates by Inhibiting Their Entry into Cells <i>via</i> Phosphate Transporters

Inflammatory and Necrotic Effects of Minodronate, a Nitrogen-Containing Bisphosphonate, in Mice

Underlying Mechanisms and Therapeutic Strategies for Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)

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