Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, South Korea.
Department of Microbiology, Wonkwang University School of Medicine, Iksan, South Korea.
Cell Biochem Funct. 2018 Oct;36(7):366-376. doi: 10.1002/cbf.3356. Epub 2018 Sep 27.
Even though increasing evidence indicates the importance of peroxisomal lipid metabolism in regulating biological and pathological events, its involvement in cartilage development has not been well studied. Here, we identified the importance of peroxisomal function, particularly the functional integrity of ABCD2, in the pathogenesis of osteoarthritis (OA). Knockdown of ABCD2 in OA chondrocytes induced the accumulation of very long chain fatty acids (VLCFAs) and apoptotic cell death. Moreover, knockdown of ABCD2 altered profiles of miRNAs that affect the expression level of ACSL4, a known direct regulator of lipid metabolism. Suppression of ACSL4 in human chondrocytes-induced VLCFA accumulation, MMP-13 expression, and apoptotic cell death. In vivo morph-down of the ACSL4 homologue in zebrafish resulted in significant defects in cartilage development and in vivo knockdown of ACSL4 in cartilage tissue of an OA model mice promoted severe cartilage degradation. In summary, to the best of our knowledge, this is the first report suggesting that the regulatory network among peroxisomal ABCD2:ACSL4:VLCFA serves as a novel regulator of cartilage homeostasis, and these data may provide novel insights into the role of peroxisomal fatty acid metabolism in pathogenesis of human OA. SIGNIFICANCE OF THE STUDY: Our study indicates that peroxisomal dysfunction is closely related to OA pathogenesis. Particularly, the functional integrity of ABCD2 may play an important role in OA pathogenesis via the accumulation of VLCFAs and stimulation of apoptotic death through altering profiles of miRNAs that target ACSL4. Our findings suggest that targeting the regulatory network among the peroxisomal ABCD2:ACSL4:VLCFA axis may provide a new potential therapeutic strategy for OA pathogenesis.
尽管越来越多的证据表明过氧化物酶体脂质代谢在调节生物和病理事件中的重要性，但它在软骨发育中的作用尚未得到很好的研究。在这里，我们确定了过氧化物酶体功能的重要性，特别是 ABCD2 的功能完整性，在骨关节炎（OA）发病机制中的重要性。在 OA 软骨细胞中敲低 ABCD2 会导致超长链脂肪酸（VLCFA）的积累和细胞凋亡。此外，敲低 ABCD2 改变了影响 ACSL4 表达水平的 miRNA 谱，ACSL4 是已知的脂质代谢直接调节因子。在人软骨细胞中抑制 ACSL4 会导致 VLCFA 积累、MMP-13 表达和细胞凋亡。在斑马鱼中抑制 ACSL4 同源物的体内形态会导致软骨发育的显著缺陷，而在 OA 模型小鼠的软骨组织中体内敲低 ACSL4 会促进严重的软骨降解。总之，据我们所知，这是第一项表明过氧化物酶体 ABCD2：ACSL4：VLCFA 调节网络作为软骨稳态的新型调节剂的报告，这些数据可能为过氧化物酶体脂肪酸代谢在人类 OA 发病机制中的作用提供新的见解。研究意义：我们的研究表明，过氧化物酶体功能障碍与 OA 发病机制密切相关。特别是，ABCD2 的功能完整性可能通过 VLCFA 的积累和通过改变针对 ACSL4 的 miRNA 谱来刺激细胞凋亡死亡，在 OA 发病机制中发挥重要作用。我们的发现表明，靶向过氧化物酶体 ABCD2：ACSL4：VLCFA 轴的调节网络可能为 OA 发病机制提供一种新的潜在治疗策略。
