Department of Clinical and Translational Science, Creighton University School of Medicine, CRISS II Room 510, 2500 California Plaza, Omaha, NE, 68178, USA.
Department of Orthopedic Surgery, Creighton University School of Medicine, Omaha, NE, 68178, USA.
Mol Cell Biochem. 2017 Oct;434(1-2):171-179. doi: 10.1007/s11010-017-3047-4. Epub 2017 May 4.
Osteoarthritis (OA) is a chronic disease that degrades the joints and is often associated with increasing age and obesity. The two most common sites of OA in adults are the knee and hip joints. Increased mechanical stress on the joint from obesity can cause the articular cartilage to degrade and release damage-associated molecular patterns (DAMPs). These DAMPs are involved in various molecular pathways that interact with nuclear factor-kappa B and result in the transcription of inflammatory cytokines and activation of matrix metalloproteinases that progressively destroy cartilage. This review focuses on the interactions and contribution to the pathogenesis and progression of OA through the DAMPs: high-mobility group box 1 (HMGB-1), the receptor for advanced glycation end-products (RAGE), the alarmin proteins S100A8 and S100A9, and heparan sulfate. HMGB-1 is released from damaged or necrotic cells and interacts with toll-like receptors (TLRs) and RAGE to induce inflammatory signals, as well as behave as an inflammatory cytokine to activate innate immune cells. RAGE interacts with HMGB-1, advanced glycation end-products, and innate immune cells to increase local inflammation. The alarmin proteins are released following cell damage and interact through TLRs to increase local inflammation and cartilage degradation. Heparan sulfate has been shown to facilitate the binding of HMGB-1 to RAGE and could play a role in the progression of OA. Targeting these DAMPs may be the potential therapeutic strategies for the treatment of OA.
骨关节炎（OA）是一种慢性疾病，会导致关节退化，通常与年龄增长和肥胖有关。成年人中最常见的 OA 发生部位是膝关节和髋关节。肥胖导致关节承受的机械压力增加，会使关节软骨退化并释放损伤相关分子模式（DAMPs）。这些 DAMPs 参与各种分子途径，与核因子-κB 相互作用，导致炎症细胞因子的转录和基质金属蛋白酶的激活，从而逐渐破坏软骨。本文重点讨论 DAMPs（高迁移率族蛋白 B1（HMGB-1）、晚期糖基化终产物受体（RAGE）、警报素蛋白 S100A8 和 S100A9 以及硫酸乙酰肝素）在 OA 发病机制和进展中的相互作用和贡献。HMGB-1 从受损或坏死细胞中释放出来，与 Toll 样受体（TLRs）和 RAGE 相互作用，诱导炎症信号，并作为炎症细胞因子激活固有免疫细胞。RAGE 与 HMGB-1、晚期糖基化终产物和固有免疫细胞相互作用，增加局部炎症。警报素蛋白在细胞损伤后释放，并通过 TLRs 相互作用增加局部炎症和软骨降解。硫酸乙酰肝素已被证明可促进 HMGB-1 与 RAGE 的结合，并可能在 OA 进展中发挥作用。针对这些 DAMPs 可能是治疗 OA 的潜在治疗策略。
