Histidine decarboxylase-stimulating and inflammatory effects of alendronate in mice: Involvement of mevalonate pathway, TNFα, macrophages, and T-cells

Xue, Ding; Yu, Zhiqian; Funayama, Hiromi; Yamaguchi, Kohei; Sasano, Takashi; Sugawara, Shunji; Endo, Yasuo

doi:10.1016/j.intimp.2006.09.009

Cited by 30 publications

(31 citation statements)

References 54 publications

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“…Indeed, a transient early acute-phase reaction [39] mediated by stimulated Vγ9Vδ2 T cells occurs after the first NBP administration, but not after subsequent infusions [40]. NBPs may act on cells other than Vγ9Vδ2 T cells, through sustained inhibition of farnesyl diphosphate synthase, a key enzyme in the mevalonate pathway [41]. Mevalonate inhibition would induce the production and release of IFNγ by monocytes and macrophages [42], followed by TNF-α and IL-1β [41,43].…”

Section: Discussionmentioning

confidence: 99%

“…NBPs may act on cells other than Vγ9Vδ2 T cells, through sustained inhibition of farnesyl diphosphate synthase, a key enzyme in the mevalonate pathway [41]. Mevalonate inhibition would induce the production and release of IFNγ by monocytes and macrophages [42], followed by TNF-α and IL-1β [41,43]. NBPs also induce leukocyte adherence to endothelial cells and transendothelial migration of mononuclear cells [44], mediated by increased ICAM-1 expression by monocytes through TNF-α stimulation; this occurs preferentially following intravenous administration [43].…”

Section: Discussionmentioning

confidence: 99%

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Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

Lesclous

Najm

Carrel

et al. 2009

Bone

192

140

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Osteonecrosis of the jaw (ONJ) can be associated with nitrogen-containing bisphosphonates (NBPs) therapy. Various mechanisms of NBP-associated ONJ have been proposed and there is currently no consensus of the underlying pathogenesis. The detailed medical and dental histories of 30 ONJ patients treated with NBPs for malignant diseases (24) or osteoporosis (6) were analyzed. The necrotic bone was resected and analyzed histologically after demineralization. In 10 patients the perinecrotic bone was also resected and processed without demineralization. Alveolar bone samples from 5 healthy patients were used as controls. In 14 ONJ patients, serial technetium-99m-methylene diphosphonate scintigraphic scans were also available and confronted to the other data. Strong radionuclide uptake was detected in some patients several months before clinical diagnosis of ONJ. The medullary spaces of the necrotic bone were filled with bacterial aggregates. In the perinecrotic bone, the bacteria-free bone marrow characteristically showed an inflammatory reaction. The number of medullary inflammatory cells taken as an index of inflammation allowed us to discriminate two inflammation grades in the ONJ samples. Low-grade inflammation, characterized by marrow fibrosis and low inflammatory cells infiltration, increased numbers of TRAP + monoand multineacleated cells was seen in patients with bone exposure b 2 cm 2 . High-grade inflammation, associated with larger lesions, showed amounts of tartrate-resistant acid phosphatase + /calcitonin receptor − mono-and multinucleated cells, osteocyte apoptosis, hypervascularization and high inflammatory cell infiltration. The clinical extent of ONJ was statistically linked to the numbers of inflammatory cell. Taken together these data suggest that bone necrosis precedes clinical onset and is an inflammation-associated process. We hypothesize that from an initial focus, bone damage spreads centrifugally, both deeper into the jaw and towards the mucosa before the oral bone exposure and the clinical diagnosis of ONJ.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

Lesclous

Najm

Carrel

et al. 2009

Bone

192

140

View full text Add to dashboard Cite

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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.…”

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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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“…ALN's effects are controversial in in vivo studies. Deng et al (59) reported that an i.p. injection of 40 mmol/kg (13 mg/kg) ALN induced IL-1-dependent inflammatory reactions in the spleen, lung, and liver.…”

Section: Discussionmentioning

confidence: 99%

Alendronate Attenuates Eosinophilic Airway Inflammation Associated with Suppression of Th2 Cytokines, Th17 Cytokines, and Eotaxin-2

Sasaki

Imamura

Yamazumi

et al. 2013

The Journal of Immunology

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Bisphosphonates (BPs) have been widely used to treat osteoporosis. They act by inhibiting farnesyl diphosphate synthase in the mevalonate pathway. This resembles the action of statins, whose immune-modulating effect has recently been highlighted. In contrast, the effect of BPs on immune responses has not been elucidated well. In this study, we examined the effect of alendronate (ALN), a nitrogen-containing BP, on allergic airway inflammation in a mouse model. BALB/c mice were sensitized twice with OVA and challenged three times with nebulized OVA to induce eosinophilic airway inflammation. ALN was administered by an intragastric tube before each inhalation. ALN strongly suppressed airway eosinophilia and Th2, as well as Th17 cytokine production in the lung. ALN also attenuated eotaxin-2 production in the lung. Immunohistochemistry demonstrated that the major cell source of eotaxin-2 was peribronchial/perivascular macrophages, and flow cytometrical studies confirmed that ALN decreased eotaxin-2 expression in these macrophages. Furthermore, ALN attenuated eotaxin-2 production from mouse pleural macrophages and human monocyte/macrophage-like THP-1 cells in vitro. These results suggest that ALN suppressed Ag-induced airway responses in the mouse model. The suppression of eotaxin-2 production from macrophages appears to be one of ALN’s immunomodulatory effects, whereas the mechanism by which ALN suppressed Th2 and Th17 responses could not be fully elucidated in this study. Although a clinical study should be conducted, ALN could be a novel therapeutic option for asthma.

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Histidine decarboxylase-stimulating and inflammatory effects of alendronate in mice: Involvement of mevalonate pathway, TNFα, macrophages, and T-cells

Cited by 30 publications

References 54 publications

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

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

Alendronate Attenuates Eosinophilic Airway Inflammation Associated with Suppression of Th2 Cytokines, Th17 Cytokines, and Eotaxin-2

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