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.
Highlights
(d,e) Loss of ATX-LPA1 signaling in zebrafish embryos leads to mislocalization of chondrocytes in cartilage tissues. (d) EGFP is expressed in chondrocytes in col2:egfp transgenic zebrafish at 120 hpf
Since chondrocytes in cartilage tissues are surrounded by and are in contact with extracellular matrix (ECM), which mainly consists of Col II and fibronectin (FN), we examined the effect of ECM on Lysophosphatidic acid (LPA)-induced cell proliferation
Previous reports indicated that loss of LPA1 signaling resulted in impaired differentiation of osteoclasts and osteoblasts in vitro[7,24,25]
Summary
(d,e) Loss of ATX-LPA1 signaling in zebrafish embryos leads to mislocalization of chondrocytes in cartilage tissues. (d) EGFP is expressed in chondrocytes in col2:egfp transgenic zebrafish at 120 hpf. (d,e) Loss of ATX-LPA1 signaling in zebrafish embryos leads to mislocalization of chondrocytes in cartilage tissues. (d) EGFP is expressed in chondrocytes in col2:egfp transgenic zebrafish at 120 hpf. (e) In zebrafish embryos treated with LPA1 or ATX morpholinos, chondrocytes are unevenly distributed in Meckel’s and ceratohyal cartilages at 120 hpf. ATX is expressed in various normal tissues and is present at high concentration in various biological fluids. We show that ATX-LPA-LPA1 signaling promotes the G0/G1-phase to S-phase transition in chondrocytes by enhancing integrin-dependent fibronectin assembly. These changes contribute to the normal development of cartilage tissues, based on analyses of both fish and mice
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