Inflammatory Effects of Nitrogen-Containing Bisphosphonates (N-BPs): Modulation by Non-N-BPs

Shima, Kazuhiro; Tsuchiya, Masahiro; Oizumi, Toru; Takano‐Yamamoto, Teruko; Sugawara, Shunji; Endo, Yasuo

doi:10.1248/bpb.b16-00521

Cited by 15 publications

(19 citation statements)

References 36 publications

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“…1) also reduces Zol-induced inflammation, but its effect is much weaker than that of Eti. 10) In vitro experiments have confirmed the following. (i) One hundred micromol Ale directly stimulates RAW 264 cells (murine macrophage-like cells) to produce pro-IL-1β, and 1 µM Clo inhibits this effect.…”

Section: Effects Of Eti and Clo On The Inflam-matory/necrotic Effectsmentioning

confidence: 64%

“…28) Later, we found in various experiments that Eti and Clo inhibit not only the inflammation but also the necrosis induced by N-BPs, and that the inhibitory effect of Clo is more potent than that of Eti. [7][8][9][10]14,15,27,55,56) For example, although Zol (one of the most potent anti-bone-resorptive N-BPs) induces severe inflammation and necrosis in mouse ear-pinnas, such effects of 2 mM Zol are completely prevented by 8 mM Eti 14) and those induced by 4 mM Zol are completely prevented by 4 mM Clo.…”

Section: Effects Of Eti and Clo On The Inflam-matory/necrotic Effectsmentioning

confidence: 99%

“…These conclusions were supported by experiments using other N-BPs, too. 9,10,15) In brief, our view is that N-BPs enter cells via SLC20 and/or SLC34 phosphate transporters, and the non-N-BPs Eti and Clo inhibit this transport and thus reduce or prevent the inflammatory/necrotic effects of N-BPs (Fig. 5).…”

Section: Mechanism Underlying the Uptake Of N-bps Into Soft-tissue Cementioning

confidence: 99%

See 2 more Smart Citations

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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Section: Effects Of Eti and Clo On The Inflam-matory/necrotic Effectsmentioning

confidence: 64%

Section: Effects Of Eti and Clo On The Inflam-matory/necrotic Effectsmentioning

confidence: 99%

Section: Mechanism Underlying the Uptake Of N-bps Into Soft-tissue Cementioning

confidence: 99%

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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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“…They found that injection of etidronate (ETI) or clodronate, representative non‐N‐BPs, together with zoledronate (ZOL), an N‐BP, into mouse ear skin significantly reduced the inflammatory response caused by ZOL alone . Furthermore, mitigation of the effects of ZOL was also achieved by an inhibitor of the sodium‐dependent phosphate transporter family, thus they proposed that ETI competes with ZOL for uptake via phosphate transporters, resulting in decreased intracellular concentration of ZOL …”

Section: Introductionmentioning

confidence: 99%

“…1,13 Furthermore, mitigation of the effects of ZOL was also achieved by an inhibitor of the sodium-dependent phosphate transporter family, thus they proposed that ETI competes with ZOL for uptake via phosphate transporters, resulting in decreased intracellular concentration of ZOL. 14,15 The sodium-dependent phosphate transporter group, coded by SLC20A and SLC34A, is involved in active transport of phosphate into cells, with BP incorporation also considered to occur via its members. 14 The SLC34A family, composed of the SLC34A1, SLC34A2, and SLC34A3 isoforms, plays predominant roles in phosphate homeostasis.…”

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confidence: 99%

Suppressive effects of N‐bisphosphonate in osteoblastic cells mitigated by non‐N‐bisphosphonate but not by sodium‐dependent phosphate cotransporter inhibitor

Baba

Miyazaki

Ohara‐Nemoto

et al. 2019

Cell Biochemistry & Function

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There are two types of bisphosphonates (BPs), nitrogen‐containing (N‐BPs) and those free from nitrogen (non‐N‐BPs). Although N‐BPs show greater inhibition of bone resorption than non‐N‐BPs, their effects are likely accompanied with inflammation, which non‐N‐BPs mitigate. We examined the competitive effects of zoledronate (ZOL), an N‐BP, and etidronate (ETI), a non‐N‐BP, in osteoblasts. ZOL, but not ETI, markedly reduced alkaline phosphatase activity and cell viability in osteoblastic MC3T3‐E1 and Saos2 cells, while that inhibition was relieved by simultaneous administration of ETI, possibly because of competition with ZOL for cellular uptake. However, phosphonoformate, an inhibitor of the phosphonate transporters SLC20A and SLC34A, did not mitigate the reducing effects of ZOL, suggesting that those transporters are not involved in BP uptake in osteoblastic cells. Additionally, ZOL reduced fibroblastic NIH3T3 and C3H10T1/2 cell viability, which was relieved by administration of both ETI and phosphonoformate. Transporter gene expression levels were significantly lower in osteoblasts as compared with fibroblasts, which may account for the distinct effects of phosphonoformate with different cell types. Together, our results suggest existence of a common uptake route of N‐BPs and non‐N‐BPs into osteoblastic cells that is unrelated to the SLC20A and SLC34A families. Significance of the study N‐BP ZOL was shown to suppress differentiation and viability of osteoblasts. ZOL‐induced cell viability suppression was also observed in fibroblasts, which was markedly relieved by addition of the non‐N‐BP ETI. Additionally, mitigation of the effects of ZOL was achieved with phosphonoformate, a sodium‐phosphate cotransporter inhibitor, in fibroblastic cells but not osteoblasts. Expression levels of SLC20A and SLC34A family genes were significantly lower in osteoblasts as compared with fibroblasts. These observations suggest that incorporation of N‐BPs and non‐N‐BPs in osteoblasts is mediated via common transporters that appear to be distinct from SLC20A and 34A, which operate in fibroblasts.

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Nitrogen-containing bisphosphonates and lipopolysaccharide mutually augment inflammation via adenosine triphosphate (ATP)-mediated and interleukin 1β (IL-1β)-mediated production of neutrophil extracellular traps (NETs)

Bando

Kuroishi

Tada

et al. 2020

Journal of Bone and Mineral Research

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Among the bisphosphonates (BPs), nitrogen-containing BPs (N-BPs) have much stronger anti-bone-resorptive actions than non-N-BPs. However, N-BPs have various side effects such as acute influenza-like reactions after their initial administration and osteonecrosis of the jawbones after repeated administration. The mechanisms underlying such effects remain unclear.To overcome these problems, it is important to profile the inflammatory nature of N-BPs. Here, we analyzed the inflammatory reactions induced in mouse ear pinnae by the N-BPs alendronate (Ale) and zoledronate (Zol). We found the following: (i) Ale and Zol each induced two phases of inflammation (early weak and late strong ear swelling); (ii) both phases were augmented by lipopolysaccharides (LPSs; cell-surface constituent of gram-negative bacteria, including oral bacteria), but prevented by inhibitors of the phosphate transporters of solute carrier 20/34 (SLC20/SLC34); (iii) macrophages and neutrophils were involved in both phases of Ale+LPS-induced ear-swelling; (iv) Ale increased or tended to increase various cytokines, and LPS augmented these effects, especially that on interleukin 1β (IL-1β); (v) adenosine triphosphate (ATP) was involved in both phases, and Ale alone or Ale+LPS increased ATP in ear pinnae; (vi) the augmented late-phase swelling induced by Ale+LPS depended on both IL-1 and neutrophil extracellular traps (NETs; neutrophil-derived net-like complexes); (vii) neutrophils, together with macrophages and dendritic cells, also functioned as IL-1β-producing cells, and upon stimulation with IL-1β, neutrophils produced NETs; (viii) stimulation of the purinergic 2X7 (P2X7) receptors by ATP induced IL-1β in ear pinnae; (ix) NET formation by Ale +LPS was confirmed in gingiva, too. These results suggest that (i) N-BPs induce both early-phase and late-phase inflammation via ATP-production and P2X7 receptor stimulation; (ii) N-BPs and LPS induce mutually augmenting responses both early and late phases via ATP-mediated IL-1β production by neutrophils, macrophages, and/or dendritic cells; and (iii) NET production by IL-1β-stimulated neutrophils may mediate the late phase, leading to prolonged inflammation. These results are discussed in relation to the side effects seen in patients treated with N-BPs.

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Inflammatory Effects of Nitrogen-Containing Bisphosphonates (N-BPs): Modulation by Non-N-BPs

Cited by 15 publications

References 36 publications

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

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

Suppressive effects of N‐bisphosphonate in osteoblastic cells mitigated by non‐N‐bisphosphonate but not by sodium‐dependent phosphate cotransporter inhibitor

Nitrogen-containing bisphosphonates and lipopolysaccharide mutually augment inflammation via adenosine triphosphate (ATP)-mediated and interleukin 1β (IL-1β)-mediated production of neutrophil extracellular traps (NETs)

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