Nishioka Tatsuji, Arima Naoaki, Kano Kuniyuki, Hama Kotaro, Itai Eriko, Yukiura Hiroshi, Kise Ryoji, Inoue Asuka, Kim Seok-Hyung, Solnica-Krezel Lilianna, Moolenaar Wouter H, Chun Jerold, Aoki Junken
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan.
Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO), Kawaguchi City, Saitama 332-0012, Japan.
Sci Rep. 2016 Mar 23;6:23433. doi: 10.1038/srep23433.
The lipid mediator lysophosphatidic acid (LPA) signals via six distinct G protein-coupled receptors to mediate both unique and overlapping biological effects, including cell migration, proliferation and survival. LPA is produced extracellularly by autotaxin (ATX), a secreted lysophospholipase D, from lysophosphatidylcholine. ATX-LPA receptor signaling is essential for normal development and implicated in various (patho)physiological processes, but underlying mechanisms remain incompletely understood. Through gene targeting approaches in zebrafish and mice, we show here that loss of ATX-LPA1 signaling leads to disorganization of chondrocytes, causing severe defects in cartilage formation. Mechanistically, ATX-LPA1 signaling acts by promoting S-phase entry and cell proliferation of chondrocytes both in vitro and in vivo, at least in part through β1-integrin translocation leading to fibronectin assembly and further extracellular matrix deposition; this in turn promotes chondrocyte-matrix adhesion and cell proliferation. Thus, the ATX-LPA1 axis is a key regulator of cartilage formation.
脂质介质溶血磷脂酸（LPA）通过六种不同的G蛋白偶联受体发出信号，介导独特和重叠的生物学效应，包括细胞迁移、增殖和存活。LPA由自分泌运动因子（ATX）在细胞外产生，ATX是一种从溶血磷脂酰胆碱分泌的溶血磷脂酶D。ATX-LPA受体信号传导对正常发育至关重要，并涉及各种（病理）生理过程，但其潜在机制仍未完全了解。通过在斑马鱼和小鼠中采用基因靶向方法，我们在此表明，ATX-LPA1信号缺失会导致软骨细胞紊乱，从而在软骨形成中造成严重缺陷。从机制上讲，ATX-LPA1信号传导通过促进软骨细胞在体外和体内进入S期和细胞增殖来发挥作用，至少部分是通过β1整合素易位导致纤连蛋白组装和进一步的细胞外基质沉积来实现的；这反过来又促进软骨细胞与基质的粘附和细胞增殖。因此，ATX-LPA1轴是软骨形成的关键调节因子。
