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首页> 外文期刊>Osteoarthritis and cartilage >Upregulated ank expression in osteoarthritis can promote both chondrocyte MMP-13 expression and calcification via chondrocyte extracellular PPi excess.
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Upregulated ank expression in osteoarthritis can promote both chondrocyte MMP-13 expression and calcification via chondrocyte extracellular PPi excess.

机译:骨关节炎中ank表达的上调可以促进软骨细胞MMP-13的表达和通过软骨细胞胞外PPi过量的钙化。

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OBJECTIVE: In idiopathic chondrocalcinosis and in osteoarthritis (OA), increased extracellular PP(i) (ecPP(i)) promotes calcification. In chromosome 5p-associated familial chondrocalcinotic degenerative arthropathy, certain mutations in the membrane protein ANK may chronically raise ecPP(i) via enhanced PP(i) channeling. Therefore, we assessed if dysregulated wild-type ANK expression could contribute to pathogenesis of idiopathic degenerative arthropathy through elevated ecPP(i). DESIGN: Using cells with genetic alterations in expression of ANK and the PP(i)-generating nucleotide pyrophosphatase phosphodiestrase (NPP) PC-1, we examined how increased ANK expression elevates ecPPI, testing for codependent effects with PC-1. We also evaluated the effects of ANK expression on chondrocyte growth, matrix synthesis, and MMP-13 expression and we immunohistochemically examined ANK expression in situ in human knee OA cartilages. RESULTS: Using cells expressing defective ANK, as well as PC-1 knockout cells, we demonstrated that ANK required PC-1 (and vice versa) to raise ecPP(i) and that the major ecPP(i) regulator TGFbeta required both ANK and PC-1 to elevate ecPP(i). Upregulation of wild-type ANK by transfection in normal chondrocytes not only raised ecPP(i) 5-fold to approximately 100nM but also directly stimulated matrix calcification and inhibited collagen and sulfated proteoglycans synthesis. In addition, upregulated ANK induced chondrocyte MMP-13, an effect that also was stimulated within 2h by treatment of chondrocytes with 100nM PP(i) alone. Finally, ANK expression was upregulated in situ in human knee OA cartilages. CONCLUSION: Elevation of ecPP(i) by ANK critically requires the fraction of cellular PP(i) generated by PC-1. The upregulation of ANK expression in OA cartilage and the capacity of increased ANK expression to induce MMP-13 and to promote matrix loss suggest that increased ANK expression and ecPP(i) exert noxious effects in degenerative arthropathies beyond stimulation of calcification.
机译:目的:在特发性软骨钙化病和骨关节炎(OA)中,细胞外PP(i)(ecPP(i))的增加会促进钙化。在与染色体5p相关的家族性软骨钙化变性性关节炎中,膜蛋白ANK中的某些突变可能通过增强的PP(i)通道长期升高ecPP(i)。因此,我们评估了野生型ANK表达失调是否可能通过ecPP(i)升高导致了特发性退行性关节炎的发病机理。设计:使用具有遗传改变的细胞表达ANK和产生PP(i)的核苷酸焦磷酸酶磷酸二酯(NPP)PC-1,我们研究了增加的ANK表达如何提高ecPPI,测试与PC-1的共依赖性作用。我们还评估了ANK表达对软骨细胞生长,基质合成和MMP-13表达的影响,并且我们通过免疫组织化学方法检测了人膝OA软骨中的ANK表达。结果:使用表达缺陷性ANK的细胞以及PC-1敲除细胞,我们证明ANK需要PC-1(反之亦然)才能提高ecPP(i),而主要的ecPP(i)调节剂TGFbeta则需要ANK和PC-1提升ecPP(i)。通过在正常软骨细胞中转染来上调野生型ANK不仅使ecPP(i)升高5倍至约100nM,而且还直接刺激基质钙化并抑制胶原蛋白和硫酸化蛋白聚糖的合成。此外,上调的ANK诱导软骨细胞MMP-13,仅用100nM PP(i)处理软骨细胞也可在2小时内刺激这种作用。最后,ANK表达在人膝OA软骨中原位上调。结论:ANK升高ecPP(i)至关重要地需要PC-1产生的细胞PP(i)的一部分。 OA软骨中ANK表达的上调以及ANK表达的增加诱导MMP-13和促进基质丢失的能力表明,增加的ANK表达和ecPP(i)在退化性关节病中起钙化刺激以外的有害作用。

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