Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products
Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products
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DOI：
10.4049/jimmunol.175.12.8296
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发表时间：
2005-12-15
影响因子：
4.4
通讯作者：
Terkeltaub, R
中科院分区：
文献类型：
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作者：
Cecil, DL;Johnson, K;Terkeltaub, R
晚期糖基化终末产物多配体受体(RAGE)介导某些伴有低度炎症的慢性血管和神经退行性疾病。RAGE配体包括S100/钙颗粒蛋白，这是一类低分子质量的钙结合多肽，其中一些是软骨细胞表达的。在这里，我们验证了S100A11和RAGE信号通过调节软骨细胞分化向肥大的转变来调控骨关节炎(OA)发病机制的假设。我们分析了人软骨和培养的人关节软骨细胞，并使用了重组人S100A11、可溶性RAGE和先前鉴定的RAGE特异性阻断抗体。正常膝关节软骨呈结构性RAGE和S100A11表达，免疫组织化学研究发现OA软骨RAGE和S100A11表达上调。CXCL8和TNF-α诱导培养的软骨细胞表达和释放S100A11。此外，S100A11诱导的软骨细胞体积增大和X型胶原表达与软骨细胞肥大一致。可溶性RAGE或RAGE特异性阻断抗体可抑制CXCL8诱导的软骨细胞肥大、IL-8诱导的软骨细胞肥大和TNF-α诱导的软骨细胞肥大，但不能抑制维甲酸诱导的软骨细胞肥大。最后，通过显性-负性RAGE和显性-负性MAPK激酶3的转染，我们证明了S100A11诱导的软骨细胞X型胶原的表达依赖于RAGE介导的p38MAPK通路的激活。我们认为，骨关节炎软骨细胞RAGE配体S100A11的表达上调，并通过p38MAPK通路上调RAGE信号通路，促进炎症相关的软骨细胞肥大。因此，RAGE信号有可能促进骨性关节炎的进展。
The multiligand receptor for advanced glycation end products (RAGE) mediates certain chronic vascular and neurologic degenerative diseases accompanied by low-grade inflammation. RAGE ligands include S100/calgranulins, a class of low-molecular-mass, calcium-binding polypeptides, several of which are chondrocyte expressed. Here, we tested the hypothesis that S100A11 and RAGE signaling modulate osteoarthritis (OA) pathogenesis by regulating a shift in chondrocyte differentiation to hypertrophy. We analyzed human cartilages and cultured human articular chondrocytes, and used recombinant human S100A11, soluble RAGE, and previously characterized RAGE-specific blocking Abs. Normal human knee cartilages demonstrated constitutive RAGE and S100A11 expression, and RAGE and S100A11 expression were up-regulated in OA cartilages studied by immunohistochemistry. CXCL8 and TNF-alpha induced S100A11 expression and release in cultured chondrocytes. Moreover, S100A11 induced cell size increase and expression of type X collagen consistent with chondrocyte hypertrophy in vitro. CXCL8-induced, IL-8-induced, and TNF-alpha-induced but not retinoic acid-induced chondrocyte hypertrophy were suppressed by treatment with soluble RAGE or RAGE-specific blocking Abs. Last, via transfection of dominant-negative RAGE and dominant-negative MAPK kinase 3, we demonstrated that S100A11-induced chondrocyte type X collagen expression was dependent on RAGE-mediated p38 MAPK pathway activation. We conclude that up-regulated chondrocyte expression of the RAGE ligand S100A11 in OA cartilage, and RAGE signaling through the p38 MAPK pathway, promote inflammation-associated chondrocyte hypertrophy. RAGE signaling thereby has the potential to contribute to the progression of OA.