高迁移率族蛋白B1氧化还原状态在骨关节炎中的调控作用及靶向干预前景

Regulatory roles of high mobility group box 1 redox states in osteoarthritis and prospects for targeted intervention

摘要:

高迁移率族蛋白B1（HMGB1）作为典型的损伤相关分子模式（DAMP），在骨关节炎（OA）低度炎症、软骨基质降解及疼痛敏化过程中发挥重要作用。近年来研究发现，HMGB1的生物学效应并非单一促炎作用，而是受其氧化还原状态的严格调控：完全还原型HMGB1（fr-HMGB1）主要通过基质细胞衍生因子1（SDF-1/CXCL12）-趋化因子受体4（CXCR4）轴介导细胞趋化，二硫键型HMGB1（ds-HMGB1）则通过Toll样受体4（TLR4）/核因子κB（NF-κB）通路放大炎症反应。两者还可经高级糖基化终末产物受体（RAGE）/磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（Akt）轴协同促进软骨细胞分解代谢与疼痛敏化。OA特有的机械负荷、低氧、氧化应激及慢性滑膜炎微环境，可能促进HMGB1释放及其氧化还原状态转化，从而形成“状态-受体-通路-表型”的病理调控网络。该文围绕HMGB1不同氧化还原状态在OA炎症反应、软骨退变、疼痛敏化及潜在靶向干预中的作用进行综述，以期为OA分子分型和精准治疗提供理论依据。

Abstract:

High mobility group box 1 (HMGB1), a prototypical damage-associated molecular pattern (DAMP), plays an important role in low-grade inflammation, cartilage matrix degradation, and pain sensitization in osteoarthritis (OA). Recent studies indicate that the biological effects of HMGB1 are not uniformly proinflammatory but are strictly regulated by its redox state. Fully reduced HMGB1 (fr-HMGB1) primarily mediates chemotaxis through the stromal cell-derived factor 1 (SDF-1/CXCL12)-CXC chemokine receptor 4 (CXCR4) axis, whereas disulfide HMGB1 (ds-HMGB1) amplifies inflammatory responses through the toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway. Both redox forms may also synergistically promote chondrocyte catabolism and pain sensitization through the receptor for advanced glycation end products (RAGE)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) axis. The mechanical loading, hypoxia, oxidative stress, and chronic synovitis characteristic of the OA microenvironment may promote HMGB1 release and redox conversion, thereby forming a pathological regulatory network linking redox state, receptor, pathway, and phenotype. This article reviews the roles of different HMGB1 redox states in OA-associated inflammation, cartilage degeneration, pain sensitization, and potential targeted interventions, with the aim of providing a theoretical basis for molecular stratification and precision treatment of OA.