title: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan.
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Nishioka
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Arima
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan.
authors.forename: Kuniyuki
authors.initials: K
authors.lastname: Kano
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hama
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Itai
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yukiura
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Kise
authors.affiliation: 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.
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Seok-Hyung
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Lilianna
authors.initials: L
authors.lastname: Solnica-Krezel
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Moolenaar
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA-92037, USA.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki-aza, Aoba-ku, Sendai, 980-8578, Japan.|Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Chiyoda-ku, Tokyo 100-0004 Japan.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
mesh_terms: D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D018390:Gene Targeting; D019012:Integrin beta1 / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D000099189:Lysophospholipase D
chemical_list: D005353:Fibronectins; D019012:Integrin beta1; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid