IL-8 in chondrocalcinosis

描述（申请人提供）：关节软骨细胞周基质钙化在骨关节炎（OA）和衰老中非常普遍。沉积的焦磷酸钙二水合物（CPPD）和/或羟基磷灰石（HA）晶体可从软骨基质中释放出来，并可引发炎症，促进结缔组织降解酶的表达，从而促进软骨进一步降解。C-X-C趋化因子包括IL-8及其受体CXCR-1和CXCR-2最近在软骨细胞中被证实表达，这些介质在体内OA软骨中都是上调的。我们的初步研究表明，IL-8诱导MMP-13，并促进增生性分化（X型胶原表达和转谷氨酰胺酶活化），与体外关节软骨细胞基质钙化增强相关。基于我们关于白细胞和关节软骨细胞中IL-8信号传导和功能的新数据，我们建议进一步了解IL-8信号如何通过CXCR1和/或CXCR2传导关节软骨细胞的肥大和基质钙化。我们将测试以下假设模型：1)激活p38 MAPK对于诱导关节软骨细胞中IL-8的肥大分化、基质钙化和MMP-13的特征至关重要。2) Pyk2酪氨酸激酶与Src家族酪氨酸激酶相关，在p38 MAPK激活介导IL-8在关节软骨细胞中的作用中起核心作用。3) CXCR1和CXCR2信号的差异介导IL-8的刺激作用。4)磷脂酶C （PLC）通过CXCR1和CXCR2信号转导，诱导细胞内Ca2+增加和蛋白激酶C （PKC）激活，进而激活Pyk2和alpha5beta1整合素。5) FAK通过α - 5- β - a1整合素激活，Pyk2差异介导CXCR1和CXCR2信号传导，诱导关节软骨细胞肥厚分化、基质钙化和MMP-13。这项研究的完成有可能为基于趋化因子和信号转导的新型治疗OA和衰老软骨钙化症的治疗策略提供基础。

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.