Inhibition of mevalonate pathway is involved in alendronate-induced cell growth inhibition, but not in cytokine secretion from macrophages in vitro

Töyräs, Anu; Ollikainen, Jouko; Taskinen, Markku; Mönkkönen, Jukka

doi:10.1016/s0928-0987(03)00108-8

Cited by 35 publications

(13 citation statements)

References 42 publications

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“…Statistical significance was evaluated using a one-tailed t test for unpaired data. used to rescue the mevalonate pathway inhibition in cellular models (8,17). The compounds were first used in ALD/MDPtreated mice, at the same concentration (250 mg/kg) and timing (days 0 and 1) chosen for GOH (Fig.…”

Section: Resultsmentioning

confidence: 99%

Natural Isoprenoids are Able to Reduce Inflammation in a Mouse Model of Mevalonate Kinase Deficiency

et al. 2008

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Mevalonate kinase deficiency (MKD) is a rare disorder characterized by recurrent inflammatory episodes and, in most severe cases, by psychomotor delay. Defective synthesis of isoprenoids has been associated with the inflammatory phenotype in these patients, but the molecular mechanisms involved are still poorly understood, and, so far, no specific therapy is available for this disorder. Drugs like aminobisphosphonates, which inhibit the mevalonate pathway causing a relative defect in isoprenoids synthesis, have been also associated to an inflammatory phenotype. Recent data asserted that cell inflammation could be reversed by the addition of some isoprenoids, such as geranylgeraniol and farnesyl pyrophosphate. In this study, a mouse model for typical MKD inflammatory episode was obtained treating BALB/c mice with aminobisphosphonate alendronate and bacterial muramyldipeptide. The effect of exogenous isoprenoids-geraniol, farnesol, and geranylgeraniol-was therefore evaluated in this model. All these compounds were effective in preventing the inflammation induced by alendronate-muramyldipeptide, suggesting a possible role for these compounds in the treatment of MKD in humans. (Pediatr Res 64: 177-182, 2008)

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Section: Resultsmentioning

confidence: 99%

Natural Isoprenoids are Able to Reduce Inflammation in a Mouse Model of Mevalonate Kinase Deficiency

et al. 2008

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“…In previous studies, Aln inhibited cellular proliferation at high dose in MG-63 osteoblastic cells (10 −4 M) [7] and primary human osteoblasts (<10 −5 M) [5]. The toxic doses of Aln were usually greater than 1 µM in differentiated cells, such as chondrosacrcoma cell [21], epidermal cell [22], endothelial cell [23], fibroblast [24], intestinal epithelial cell [25], or macrophage [3], [26], [27]. In this study, the results showed that treatment with 10 µM Aln in group A inhibited the viability of hBMSCs (Figure 3, group A), but only 5 µM Aln reduced its cell viability in groups B and C (Figure 3, group B and group C).…”

Section: Discussionmentioning

confidence: 99%

The Susceptive Alendronate-Treatment Timing and Dosage for Osteogenesis Enhancement in Human Bone Marrow-Derived Stem Cells

et al. 2014

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Recent studies indicated that alendronate enhanced osteogenesis in osteoblasts and human bone marrow-derived stem cells. However, the time- and dose-dependent effects of Aln on ostegenic differentiation and cytotoxicity of hBMSCs remain undefined. In present study, we investigated the effective dose range and timing of hBMSCs. hBMSCs were treated with various Aln doses (1, 5 and 10 µM) according to the following groups: group A was treated with Aln during the first five days of bone medium, groups B, C and D were treated during the first, second, and final five days of osteo-induction medium and group E was treated throughout the entire experiment. The mineralization level and cytotoxicity were measured by quantified Alizarin Red S staining and MTT assay. In addition, the reversal effects of farnesyl pyrophosphate and geranylgeranyl pyrophosphate replenishment in group B were also investigated. The results showed that Aln treatment in groups A, B and E enhanced hBMSC mineralization in a dose-dependent manner, and the most pronounced effects were observed in groups B and E. The higher dose of Aln simultaneously enhanced mineralization and caused cytotoxicity in groups B, C and E. Replenishment of FPP or GGPP resulted in partial or complete reverse of the Aln-induced mineralization respectively. Furthermore, the addition of FPP or GGPP also eliminated the Aln-induced cytotoxicity. We demonstrated that hBMSCs are susceptible to 5 µM Aln during the initiation stage of osteogenic differentiation and that a 10 µM dose is cytotoxic.

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“…The inhibition of mevalonate pathway with alendronate is able to induce in monocytes the secretion of IL-1b in the presence of a second stimulus (Figure 1) as previously reported for RAW 264 murine macrophage cells and J774.1 cells. 8,9 Expression data obtained in ALD-, LPS-and ALD/LPS-treated HPBMCs were compared with those acquired using untreated cells (R) ( Supplementary Table A1), and the results obtained in a representative experiment are reported in Figure 1.…”

Section: Resultsmentioning

confidence: 99%

The inhibition of mevalonate pathway induces upregulation of NALP3 expression: new insight in the pathogenesis of mevalonate kinase deficiency

2010

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Mevalonate kinase deficiency (MKD) is a rare hereditary auto-inflammatory syndrome due to mutations in mevalonate kinase, the second enzyme of mevalonate pathway of cholesterol, and nonsterol-isoprenoids biosynthesis. The shortage of mevalonatederived intermediates, and in particular of geranylgeranyl pyrophosphate (GGPP), has been linked with the activation of caspase-1 and thereby with the production of IL-1b, but the true concatenation of these two events has not been clarified yet. We hypothesized that inflammasomes could mediate the activation of caspase-1 due to the shortage of GGPP. We monitored the expression of the principal proteins (NALP1, NALP3 and IPAF) of the three known inflammasomes, first in a cellular model of MKD and then in two MKD patients, after bacterial lipopolysaccharide (LPS) stimulation. In healthy subjects, alendronate alone induced the expression of NALP1 and NALP3, and then together with LPS it induced a dramatic increase in NALP3 expression. In MKD patients, NALP3 expression was higher than in untreated healthy controls. Our results, although preliminary, showed that the inhibition of the mevalonate pathway led to a hyper-expression of NALP3, suggesting a possible involvement of NALP3-inflammasome in the activation of caspase-1 consequent to GGPP decrement. This is the first time that the involvement of the inflammasome complexes was shown in MKD pathogenesis.

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Inhibition of mevalonate pathway is involved in alendronate-induced cell growth inhibition, but not in cytokine secretion from macrophages in vitro

Cited by 35 publications

References 42 publications

Natural Isoprenoids are Able to Reduce Inflammation in a Mouse Model of Mevalonate Kinase Deficiency

Natural Isoprenoids are Able to Reduce Inflammation in a Mouse Model of Mevalonate Kinase Deficiency

The Susceptive Alendronate-Treatment Timing and Dosage for Osteogenesis Enhancement in Human Bone Marrow-Derived Stem Cells

The inhibition of mevalonate pathway induces upregulation of NALP3 expression: new insight in the pathogenesis of mevalonate kinase deficiency

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