IL-8 in chondrocalcinosis

描述（由申请人提供）：关节软骨中细胞周基质的钙化在骨关节炎（OA）和衰老中非常普遍。 焦磷酸钙二水合物（CPPD）和/或羟基磷灰石（HA）的沉积晶体可以从软骨基质中释放出来，并且可以引发炎症并促进结缔组织降解酶的表达，从而有助于进一步的软骨降解。近年来研究表明，C-X-C类趋化因子IL-8及其受体CXCR-1和CXCR-2在软骨细胞中表达，且在体内OA软骨中表达上调。我们的初步研究表明，IL-8诱导MMP-13，并促进肥大分化（X型胶原表达和转氨酶激活）与关节软骨细胞在体外基质钙化增高相关的特征。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信号传导如何通过CXCR 1和/或CXCR 2转导关节软骨细胞中的肥大和基质钙化。我们将检验以下假设模型：1）p38 MAPK的激活是IL-8诱导关节软骨细胞肥大分化、基质钙化和MMP-13特征的必要条件。2)Pyk 2酪氨酸激酶与Src家族酪氨酸激酶相关，在介导IL-8在关节软骨细胞中的这种作用中在p38 MAPK的激活中起核心作用。3)CXCR 1和CXCR 2的信号传导差异，以抑制IL-8的刺激作用。4)磷脂酶C（PLC）通过CXCR 1和CXCR 2信号转导诱导细胞内Ca 2+升高和蛋白激酶C（PKC）活化，进而分别激活Pyk 2和α 5 β 1整联蛋白。5)通过α 5-β 1整联蛋白激活的FAK和Pyk 2差异介导CXCR 1和CXCR 2信号传导，以诱导关节软骨细胞的肥大分化、基质钙化和MMP-13。这项研究的完成有可能为新的趋化因子和信号转导为基础的治疗策略，在OA和衰老的软骨钙质沉着症的治疗提供了基础。

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.