Morici Luca, Allémann Eric, Jordan Olivier, Nikolić Ines
School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, Geneva 4, 1211, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, Rue Michel-Servet 1, Geneva 4, 1211, Switzerland.
School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, Geneva 4, 1211, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, Rue Michel-Servet 1, Geneva 4, 1211, Switzerland.
Pharmacol Res. 2025 Feb;212:107627. doi: 10.1016/j.phrs.2025.107627. Epub 2025 Jan 26.
Osteoarthritis (OA) is the most affected joint disease worldwide, touching millions of people every year. It is caused by a progressive degeneration of articular cartilage, causing pain and limited mobility. Among the pathways involved in cartilage homeostasis, "LOX" proteins (referring to three distinct protein families, very often confused in the literature) play a prominent role. The lipoxygenase enzyme family is involved in the inflammatory process of OA by inducing the production of several pro-inflammatory leukotrienes. Lectin-like oxidized low-density lipoprotein family are receptors located at the surface of chondrocytes, which interact with their ligand, ox-LDL, activating several catabolic pathways involved in OA pathophysiology. Finally, lysyl oxidase and lysyl oxidase-like are enzymes expressed intracellularly (in chondrocytes' cytoplasm) involved in elastin biosynthesis and collagen cross-linking in cartilage extracellular matrix. EMA and FDA have not yet approved any drug targeting the LOX proteins. In particular, today lysyl oxidase-like 2 is considered as a new promising target for OA modifying therapy. This review clarifies the main roles of different LOX proteins involved in the progression of OA. Potential LOX inhibitoion strategies for drug development in advanced OA therapy, particularly for local intraarticular delivery, were listed and discussed for each target type. This review, therefore, proposes promising strategies for future drug development in OA treatment.
骨关节炎（OA）是全球受影响最严重的关节疾病，每年影响数百万人。它是由关节软骨的进行性退变引起的，导致疼痛和活动受限。在参与软骨稳态的途径中，“LOX”蛋白（指三个不同的蛋白家族，在文献中常常混淆）发挥着重要作用。脂氧合酶家族通过诱导几种促炎白三烯的产生参与OA的炎症过程。凝集素样氧化低密度脂蛋白家族是位于软骨细胞表面的受体，它们与其配体氧化型低密度脂蛋白相互作用，激活参与OA病理生理学的几种分解代谢途径。最后，赖氨酰氧化酶和赖氨酰氧化酶样蛋白是在细胞内（软骨细胞的细胞质中）表达的酶，参与软骨细胞外基质中的弹性蛋白生物合成和胶原蛋白交联。欧洲药品管理局（EMA）和美国食品药品监督管理局（FDA）尚未批准任何针对LOX蛋白的药物。特别是，如今赖氨酰氧化酶样蛋白2被认为是OA改善治疗的一个新的有前景的靶点。本综述阐明了不同LOX蛋白在OA进展中所起的主要作用。针对晚期OA治疗，特别是局部关节内给药的药物开发，列出并讨论了每种靶点类型的潜在LOX抑制策略。因此，本综述为OA治疗的未来药物开发提出了有前景的策略。
