Department of Lipid Science and Technology, The Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, 500007, India.
Division of Applied Biology, The Indian Institute of Chemical Technology, Tarnaka, Hyderabad, India.
Cell Commun Signal. 2024 Mar 22;22(1):189. doi: 10.1186/s12964-024-01547-4.
The proinflammatory cytokines and arachidonic acid (AA)-derived eicosanoids play a key role in cartilage degeneration in osteoarthritis (OA). The lysophosphatidylcholine acyltransferase 3 (LPCAT3) preferentially incorporates AA into the membranes. Our recent studies showed that MALT1 [mucosa-associated lymphoid tissue lymphoma translocation protein 1]) plays a crucial role in propagating inflammatory signaling triggered by IL-1β and other inflammatory mediators in endothelial cells. The present study shows that LPCAT3 expression was up-regulated in both human and mice articular cartilage of OA, and correlated with severity of OA. The IL-1β-induces cell death via upregulation of LPCAT3, MMP3, ADAMTS5, and eicosanoids via MALT1. Gene silencing or pharmacological inhibition of LPCAT3 or MALT1 in chondrocytes and human cartilage explants notably suppressed the IL-1β-induced cartilage catabolism through inhibition of expression of MMP3, ADAMTS5, and also secretion of cytokines and eicosanoids. Mechanistically, overexpression of MALT1 in chondrocytes significantly upregulated the expression of LPCAT3 along with MMP3 and ADAMTS5 via c-Myc. Inhibition of c-Myc suppressed the IL-1β-MALT1-dependent upregulation of LPCAT3, MMP3 and ADAMTS5. Consistent with the in vitro data, pharmacological inhibition of MALT1 or gene silencing of LPCAT3 using siRNA-lipid nanoparticles suppressed the synovial articular cartilage erosion, pro-inflammatory cytokines, and eicosanoids such as PGE, LTB, and attenuated osteoarthritis induced by the destabilization of the medial meniscus in mice. Overall, our data reveal a previously unrecognized role of the MALT1-LPCAT3 axis in osteoarthritis. Targeting the MALT1-LPCAT3 pathway with MALT1 inhibitors or siRNA-liposomes of LPCAT3 may become an effective strategy to treat OA by suppressing eicosanoids, matrix-degrading enzymes, and proinflammatory cytokines.
促炎细胞因子和花生四烯酸（AA）衍生的类二十烷酸在骨关节炎（OA）中的软骨退化中起关键作用。溶血磷脂酰胆碱酰基转移酶 3（LPCAT3）优先将 AA 掺入膜中。我们最近的研究表明，MALT1[黏膜相关淋巴组织淋巴瘤易位蛋白 1]）在 IL-1β和其他炎症介质在血管内皮细胞中引发炎症信号的传播中起着至关重要的作用。本研究表明，LPCAT3 在 OA 的人关节软骨和小鼠关节软骨中均上调，并与 OA 的严重程度相关。IL-1β 通过上调 LPCAT3、MMP3、ADAMTS5 和类二十烷酸来诱导细胞死亡通过 MALT1。在软骨细胞和人软骨外植体中，LPCAT3 或 MALT1 的基因沉默或药物抑制显著抑制了 IL-1β 诱导的软骨分解代谢，通过抑制 MMP3、ADAMTS5 的表达以及细胞因子和类二十烷酸的分泌。从机制上讲，在软骨细胞中过表达 MALT1 通过 c-Myc 显著上调 LPCAT3 的表达以及 MMP3 和 ADAMTS5。c-Myc 的抑制抑制了 IL-1β-MALT1 依赖性的 LPCAT3、MMP3 和 ADAMTS5 的上调。与体外数据一致，使用 MALT1 抑制剂或 siRNA-脂质纳米颗粒抑制 LPCAT3 的基因沉默抑制了滑膜关节软骨侵蚀、促炎细胞因子和类二十烷酸，如 PGE、LTB，并减轻了内侧半月板不稳定引起的骨关节炎在小鼠中。总体而言，我们的数据揭示了 MALT1-LPCAT3 轴在骨关节炎中的一个以前未被认识到的作用。用 MALT1 抑制剂或 LPCAT3 的 siRNA-脂质体靶向 MALT1-LPCAT3 途径可能成为通过抑制类二十烷酸、基质降解酶和促炎细胞因子来治疗 OA 的有效策略。
