IL-8 in chondrocalcinosis

描述(申请人提供)：关节软骨中细胞周围基质的钙化在骨关节炎(OA)和衰老中非常普遍。沉积的二水焦磷酸钙(CPPD)和/或羟基磷灰石(HA)晶体可以从软骨基质中释放出来，引发炎症，促进结缔组织降解酶的表达，从而促进软骨的进一步降解。最近在软骨细胞中发现了包括IL-8及其受体CXCR-1和CXCR-2在内的C-X-C趋化因子的表达，并且这些介质在体内的骨性关节炎软骨中表达上调。我们的初步研究表明，IL-8诱导了基质金属蛋白酶-13，并促进了关节软骨细胞肥大分化的特征(X型胶原表达和转谷氨酰胺酶激活)与体外高水平的基质钙化相关。根据我们关于白细胞和关节软骨细胞中IL-8信号和功能的最新数据，我们建议进一步了解IL-8信号如何通过CXCR1和/或CXCR2转导在关节软骨细胞中肥大和基质钙化。我们将验证以下假设模型：1)p38MAPK的激活是IL-8诱导软骨细胞肥大分化、基质钙化和基质金属蛋白酶-13特征所必需的。2)与Src家族酪氨酸激酶相关的PYK2酪氨酸激酶在p38MAPK的激活中起核心作用，p38MAPK介导IL-8对关节软骨细胞的影响。3)CXCR1和CXCR2信号不同，转导IL-8的刺激效应。4)磷脂酶C(PLC)转导CXCR1和CXCR2信号，诱导细胞内钙离子升高和蛋白激酶C(PKC)激活，进而分别激活PYK2和α5beta1整合素。5)通过α5-β1整合素激活的FAK和PYK2不同地介导CXCR1和CXCR2信号，诱导关节软骨细胞肥大分化、基质钙化和基质金属蛋白酶-13。这项研究的完成有可能为新的基于趋化因子和信号转导的治疗策略提供基础，用于治疗骨性关节炎和衰老的软骨钙质沉着症。

DESCRIPTION (provided by applicant): Calcification of the pericellular matrix in articular cartilage is highly prevalent in osteoarthritis (OA) and aging. The deposited crystals of calcium pyrophosphate dihydrate (CPPD) and/or hydroxyapatite (HA) can be released from the cartilage matrix and can trigger inflammation and promote the expression of connective tissue degrading enzymes, thereby contributing to further cartilage degradation. The expression of C-X-C chemokines including IL-8 and its receptors CXCR-1 and CXCR-2 has recently been demonstrated in chondrocytes, and these mediators all are up regulated in OA cartilage in vivo. Our preliminary studies demonstrated that IL-8 induces MMP-13, and promotes features of hypertrophic differentiation (type X collagen expression and transglutaminase activation) associated with heightened matrix calcification in vitro in articular chondrocytes. Base on our new data on IL-8 signaling and function in leukocytes and articular chondrocytes, we propose to advance understanding of how IL-8 signaling via CXCR1 and/or CXCR2 transduces hypertrophy and matrix calcification in articular chondrocytes. We will test the following hypothetical model: 1) Activation of p38 MAPK is essential for induction of the features of hypertrophic differentiation, matrix calcification and MMP-13 by IL-8 in articualr chondrocytes. 2) Pyk2 tyrosine kinase, associated with a Src family tyrosine kinase, plays a central role in activation of p38 MAPK in mediating such effects of IL-8 in articular chondrocytes. 3) CXCR1 and CXCR2 signal differentially to transduce the stimulatory effect of IL-8. 4) Phospholipase C (PLC) transduces CXCR1 and CXCR2 signaling to induce intracellular Ca2+ increase and protein kinase C (PKC) activation, which in turn, activate Pyk2 and alpha5beta1 integrin, respectively. 5) FAK, activated through alpha5-beta1 integrin, and Pyk2 differentially mediate CXCR1 and CXCR2 signaling to induce hypertrophic differentiation, matrix calcification and MMP-13 in articular chondrocytes. The completion of this study has the potential to provide a foundation for novel chemokine and signal transduction-based therapeutic strategies for treatment of chondrocalcinosis in OA and aging.