SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain.
International PhD School of the University of Santiago de Compostela (EDIUS), Doctoral Programme in Medicine Clinical Research, Santiago de Compostela, Spain.
Lab Invest. 2021 Dec;101(12):1550-1560. doi: 10.1038/s41374-021-00584-8. Epub 2021 Mar 25.
C-reactive protein (CRP) is an acute-phase protein that is used as an established biomarker to follow disease severity and progression in a plethora of inflammatory diseases. However, its pathophysiologic mechanisms of action are still poorly defined and remain elusive. CRP, in its pentameric form, exhibits weak anti-inflammatory activity. On the contrary, the monomeric isoform (mCRP) exhibits potent pro-inflammatory properties in endothelial cells, leukocytes, and platelets. So far, no data exists regarding mCRP effects in human or mouse chondrocytes. This work aimed to verify the pathophysiological relevance of mCRP in the etiology and/or progression of osteoarthritis (OA). We investigated the effects of mCRP in cultured human primary chondrocytes and in the chondrogenic ATDC5 mouse cell line. We determined mRNA and protein levels of relevant factors involved in inflammatory responses and the modulation of nitric oxide synthase type II (NOS2), an early inflammatory molecular target. We demonstrate, for the first time, that monomeric C reactive protein increases NOS2, COX2, MMP13, VCAM1, IL-6, IL-8, and LCN2 expression in human and murine chondrocytes. We also demonstrated that NF-kB is a key factor in the intracellular signaling of mCRP-driven induction of pro-inflammatory and catabolic mediators in chondrocytes. We concluded that mCRP exerts a sustained catabolic effect on human and murine chondrocytes, increasing the expression of inflammatory mediators and proteolytic enzymes, which can promote extracellular matrix (ECM) breakdown in healthy and OA cartilage. In addition, our results implicate the NF-kB signaling pathway in catabolic effects mediated by mCRP.
C-反应蛋白（CRP）是一种急性期蛋白，被用作评估多种炎症性疾病严重程度和进展的既定生物标志物。然而，其作用的病理生理机制仍未得到充分定义，仍然难以捉摸。五聚体形式的 CRP 表现出较弱的抗炎活性。相反，单体形式（mCRP）在血管内皮细胞、白细胞和血小板中表现出强烈的促炎特性。到目前为止，还没有关于 mCRP 在人类或小鼠软骨细胞中的作用的数据。本研究旨在验证 mCRP 在骨关节炎（OA）的病因和/或进展中的病理生理相关性。我们研究了 mCRP 对培养的人原代软骨细胞和软骨形成的 ATDC5 小鼠细胞系的影响。我们测定了参与炎症反应和一氧化氮合酶 II（NOS2）调节的相关因子的 mRNA 和蛋白水平，NOS2 是一个早期炎症分子靶点。我们首次证明，单体 C 反应蛋白增加了人源和鼠源软骨细胞中 NOS2、COX2、MMP13、VCAM1、IL-6、IL-8 和 LCN2 的表达。我们还证明，NF-kB 是 mCRP 驱动的促炎和分解代谢介质在软骨细胞中诱导的细胞内信号转导的关键因素。我们得出结论，mCRP 对人源和鼠源软骨细胞产生持续的分解代谢作用，增加了炎症介质和蛋白水解酶的表达，从而促进健康和 OA 软骨细胞外基质（ECM）的降解。此外，我们的结果表明 NF-kB 信号通路参与了 mCRP 介导的分解代谢作用。
