Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Montreal, QC, Canada; Department of Medicine, University of Montreal, Montreal, QC, Canada.
Faculty of Veterinary Medicine, Clinical Science, University of Montreal, Saint-Hyacinthe, QC, Canada.
Osteoarthritis Cartilage. 2017 Oct;25(10):1719-1728. doi: 10.1016/j.joca.2017.07.001. Epub 2017 Jul 8.
12/15-Lipoxygenase (12/15-LOX) catalyzes the generation of various anti-inflammatory lipid mediators, and has been implicated in several inflammatory and degenerative diseases. However, there is currently no evidence that 12/15-LOX has a role in osteoarthritis (OA). The aim of this study was to investigate the role of 12/15-LOX in the pathogenesis of OA.
The development of aging-associated and destabilization of the medial meniscus (DMM)-induced OA were compared in 12/15-LOX-deficient (12/15-LOX-/-) and wild-type (WT) mice. The extent of cartilage damage was evaluated by histology. The expression of OA markers was evaluated by immunohistochemistry and RT-PCR. Cartilage explants were stimulated with IL-1α in the absence or presence of the 12/15-LOX metabolites, 15-hydroxyeicosatetraenoic acids (15-HETE), 13-hydroxyoctadecadienoic acid (13-HODE) or lipoxin A4 (LXA4), and the levels of matrix metalloproteinases-13 (MMP-13), Nitric oxide (NO) and prostaglandin E (PGE) were determined. The effect of LXA4 on the progression of OA was evaluated in wild type (WT) mice.
The expression of 12/15-LOX in cartilage increased during the progression of DMM-induced OA and with aging in WT mice. Cartilage degeneration was more severe in 12/15-LOX-/- mice compared to WT mice in both models of OA, and this was associated with increased expression of MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs, aggrecanases (ADAMTS5), inducible NO synthases (iNOS), and mPGES-1. Treatment of cartilage explants with 12/15-LOX metabolites, suppressed IL-1α-induced production of MMP-13, NO and PGE, with LXA4 being the most potent. Intra-peritoneal injection of LXA4 reduced the severity of DMM-induced cartilage degradation.
These data suggest an important role of 12/15-LOX in the pathogenesis of OA. They also suggest that activation of this pathway may provide a novel strategy for prevention and treatment of OA.
12/15-脂氧合酶（12/15-LOX）催化各种抗炎脂质介质的生成，并且与几种炎症和退行性疾病有关。然而，目前没有证据表明 12/15-LOX 在骨关节炎（OA）中起作用。本研究的目的是研究 12/15-LOX 在 OA 发病机制中的作用。
比较 12/15-LOX 缺陷（12/15-LOX-/-）和野生型（WT）小鼠中与年龄相关的发展和内侧半月板不稳定（DMM）诱导的 OA 的发展。通过组织学评估软骨损伤的程度。通过免疫组织化学和 RT-PCR 评估 OA 标志物的表达。用白细胞介素 1α（IL-1α）刺激软骨外植体，在不存在或存在 12/15-LOX 代谢物 15-羟基二十碳四烯酸（15-HETE）、13-羟基十八碳二烯酸（13-HODE）或脂氧素 A4（LXA4）的情况下，测定基质金属蛋白酶 13（MMP-13）、一氧化氮（NO）和前列腺素 E（PGE）的水平。在野生型（WT）小鼠中评估 LXA4 对 OA 进展的影响。
在 DMM 诱导的 OA 进展和 WT 小鼠衰老过程中，软骨中 12/15-LOX 的表达增加。与 WT 小鼠相比，12/15-LOX-/-小鼠在两种 OA 模型中软骨退变更严重，这与 MMP-13、解整合素和金属蛋白酶与血小板反应蛋白基序、聚集素酶（ADAMTS5）、诱导型一氧化氮合酶（iNOS）和 mPGES-1 的表达增加有关。用 12/15-LOX 代谢物处理软骨外植体，抑制了 IL-1α 诱导的 MMP-13、NO 和 PGE 的产生，其中 LXA4 的作用最强。腹腔内注射 LXA4 可减轻 DMM 诱导的软骨降解的严重程度。
这些数据表明 12/15-LOX 在 OA 的发病机制中起重要作用。它们还表明，激活该途径可能为 OA 的预防和治疗提供新策略。
