Wanner John, Subbaiah Roopashree, Skomorovska-Prokvolit Yelenna, Shishani Yousef, Boilard Eric, Mohan Sujatha, Gillespie Robert, Miyagi Masaru, Gobezie Reuben
Arthritis Res Ther. 2013 Nov 6;15(6):R180. doi: 10.1186/ar4369.
The development of effective treatments for osteoarthritis (OA) has been hampered by a poor understanding of OA at the cellular and molecular levels. Emerging as a disease of the 'whole joint', the importance of the biochemical contribution of various tissues, including synovium, bone and articular cartilage, has become increasingly significant. Bathing the entire joint structure, the proteomic analysis of synovial fluid (SF) from osteoarthritic shoulders offers a valuable 'snapshot' of the biologic environment throughout disease progression. The purpose of this study was to identify differentially expressed proteins in early and late shoulder osteoarthritic SF in comparison to healthy SF.
A quantitative 18O labeling proteomic approach was employed to identify the dysregulated SF proteins in early (n = 5) and late (n = 4) OA patients compared to control individuals (n = 5). In addition, ELISA was used to quantify six pro-inflammatory and two anti-inflammatory cytokines.
Key results include a greater relative abundance of proteins related to the complement system and the extracellular matrix in SF from both early and late OA. Pathway analyses suggests dysregulation of the acute phase response, liver x receptor/retinoid x receptor (LXR/RXR), complement system and coagulation pathways in both early and late OA. The network related to lipid metabolism was down-regulated in both early and late OA. Inflammatory cytokines including interleukin (IL) 6, IL 8 and IL 18 were up-regulated in early and late OA.
The results suggest a dysregulation of wound repair pathways in shoulder OA contributing to the presence of a 'chronic wound' that progresses irreversibly from early to later stages of OA. Protease inhibitors were downregulated in late OA suggesting uncontrolled proteolytic activity occurring in late OA. These results contribute to the theory that protease inhibitors represent promising therapeutic agents which could limit proteolytic activity that ultimately leads to cartilage destruction.
由于在细胞和分子水平上对骨关节炎（OA）的了解不足，有效的OA治疗方法的开发受到了阻碍。OA逐渐被视为一种“全关节”疾病，包括滑膜、骨骼和关节软骨在内的各种组织的生化作用的重要性日益凸显。对骨关节炎肩部滑液（SF）进行蛋白质组学分析，该滑液覆盖整个关节结构，能为疾病进展过程中的生物环境提供有价值的“快照”。本研究的目的是确定与健康SF相比，早期和晚期肩部骨关节炎SF中差异表达的蛋白质。
采用定量18O标记蛋白质组学方法，以确定早期（n = 5）和晚期（n = 4）OA患者与对照个体（n = 5）相比，SF中失调的蛋白质。此外，酶联免疫吸附测定（ELISA）用于定量六种促炎细胞因子和两种抗炎细胞因子。
关键结果包括早期和晚期OA的SF中与补体系统和细胞外基质相关的蛋白质相对丰度更高。通路分析表明，早期和晚期OA中急性期反应、肝X受体/视黄醇X受体（LXR/RXR）、补体系统和凝血通路均失调。早期和晚期OA中与脂质代谢相关的网络均下调。早期和晚期OA中促炎细胞因子包括白细胞介素（IL）6、IL 8和IL 18均上调。
结果表明，肩部OA中伤口修复通路失调，导致出现“慢性伤口”，该伤口从OA的早期到晚期不可逆地进展。蛋白酶抑制剂在晚期OA中下调，表明晚期OA中发生了不受控制的蛋白水解活性。这些结果支持了蛋白酶抑制剂代表有前景的治疗药物的理论，其可以限制最终导致软骨破坏的蛋白水解活性。
