ATX-LPA1 axis contributes to proliferation of chondrocytes by regulating fibronectin assembly leading to proper cartilage formation

Abstract

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.

Fibroblasts derived from patients with opsismodysplasia display SHIP2-specific cell migration and adhesion defects

“…Mechanistically, LPA 1 signaling acts by promoting S‐phase entry and cell proliferation of chondrocytes by regulating fibronectin assembly. Loss of LPA 1 signaling in LPA 1 −/− mice leads to disorganization of chondrocytes similarly to what is observed in OPS (Nishioka et al., ). It is known that focal adhesion assembly involves the activation of β1‐integrin downstream of LPA 1 signaling; this is also decreased in LPA 1 −/− chondrocytes as compared to normal cells.…”

“…For column‐forming, chondrocytes require cell–cell adhesion mechanisms that influence cell spreading and rearrangement (Romereim et al., ). Cell adhesion also affects the proliferation and survival of chondrocytes (Nishioka et al., ). Our data suggest that the appropriate control of cell adhesion in normal chondrocytes, which have SHIP2, would not be present in OPS cells and this would disorganize dividing cells at the growth plate.…”

Fibronectin 1 promotes migration and invasion of papillary thyroid cancer and predicts papillary thyroid cancer lymph node metastasis

“…As an EMT marker, fibronectin is involved in cell adhesion and migration, including embryogenesis,17 wound healing,18 blood coagulation,19 osteogenesis,20 and metastasis 21,22. EMT is a process involved in embryonic development, during which cells lose their epithelial features and adopt characteristics of mesenchymal cells.…”

Autotaxin–lysophosphatidic acid– LPA 3 signaling at the embryo‐epithelial boundary controls decidualization pathways

“…LPA is mainly synthesized from lysophospholipids such as lysophosphatidylcholine (LPC) by a secretory enzyme autotaxin (ATX; Umezu‐Goto et al , 2002). Studies of knock‐out (KO) mice and human genetic diseases of these LPA‐related genes have shown that LPA has various pathophysiological roles including angiogenesis (Yukiura et al , 2011), hair follicle formation (Inoue et al , 2011; Hayashi et al , 2015), bone development (Nishioka et al , 2016), and neural development (Yung et al , 2015). We previously showed that LPA 3 , which is highly expressed in the uterine epithelium during the peri‐implantation period (Ye et al , 2005), has a critical role in the early pregnancy.…”