Cecil Denise L, Johnson Kristen, Rediske John, Lotz Martin, Schmidt Ann Marie, Terkeltaub Robert
Veterans Affairs Medical Center, Department of Medicine, University of California, San Diego, CA 92161, USA.
J Immunol. 2005 Dec 15;175(12):8296-302. doi: 10.4049/jimmunol.175.12.8296.
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.
晚期糖基化终末产物（RAGE）的多配体受体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/钙粒蛋白，这是一类低分子量、钙结合多肽，其中几种由软骨细胞表达。在此，我们检验了以下假设：S100A11和RAGE信号传导通过调节软骨细胞分化向肥大的转变来调节骨关节炎（OA）的发病机制。我们分析了人类软骨和培养的人类关节软骨细胞，并使用重组人S100A11、可溶性RAGE和先前表征的RAGE特异性阻断抗体。正常人类膝关节软骨显示出组成性RAGE和S100A11表达，通过免疫组织化学研究发现，OA软骨中的RAGE和S100A11表达上调。CXCL8和肿瘤坏死因子-α（TNF-α）诱导培养的软骨细胞中S100A11的表达和释放。此外，S100A11在体外诱导细胞大小增加和X型胶原表达，这与软骨细胞肥大一致。用可溶性RAGE或RAGE特异性阻断抗体处理可抑制CXCL8诱导、白细胞介素-8（IL-8）诱导和TNF-α诱导但不是视黄酸诱导的软骨细胞肥大。最后，通过转染显性负性RAGE和显性负性丝裂原活化蛋白激酶3（MAPK激酶3），我们证明S100A11诱导的软骨细胞X型胶原表达依赖于RAGE介导的p38 MAPK途径激活。我们得出结论，OA软骨中RAGE配体S100A11的软骨细胞表达上调，以及通过p38 MAPK途径的RAGE信号传导，促进了与炎症相关的软骨细胞肥大。因此，RAGE信号传导有可能促进OA的进展。
