title: Lysophosphatidic acid receptor type 1 (LPA1) plays a functional role in osteoclast differentiation and bone resorption activity.
abstract: Lysophosphatidic acid (LPA) is a natural bioactive lipid that acts through six different G protein-coupled receptors (LPA1-6) with pleiotropic activities on multiple cell types. We have previously demonstrated that LPA is necessary for successful in vitro osteoclastogenesis of bone marrow cells. Bone cells controlling bone remodeling (i.e. osteoblasts, osteoclasts, and osteocytes) express LPA1, but delineating the role of this receptor in bone remodeling is still pending. Despite Lpar1(-/-) mice displaying a low bone mass phenotype, we demonstrated that bone marrow cell-induced osteoclastogenesis was reduced in Lpar1(-/-) mice but not in Lpar2(-/-) and Lpar3(-/-) animals. Expression of LPA1 was up-regulated during osteoclastogenesis, and LPA1 antagonists (Ki16425, Debio0719, and VPC12249) inhibited osteoclast differentiation. Blocking LPA1 activity with Ki16425 inhibited expression of nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) and dendritic cell-specific transmembrane protein and interfered with the fusion but not the proliferation of osteoclast precursors. Similar to wild type osteoclasts treated with Ki16425, mature Lpar1(-/-) osteoclasts had reduced podosome belt and sealing zone resulting in reduced mineralized matrix resorption. Additionally, LPA1 expression markedly increased in the bone of ovariectomized mice, which was blocked by bisphosphonate treatment. Conversely, systemic treatment with Debio0719 prevented ovariectomy-induced cancellous bone loss. Moreover, intravital multiphoton microscopy revealed that Debio0719 reduced the retention of CX3CR1-EGFP(+) osteoclast precursors in bone by increasing their mobility in the bone marrow cavity. Overall, our results demonstrate that LPA1 is essential for in vitro and in vivo osteoclast activities. Therefore, LPA1 emerges as a new target for the treatment of diseases associated with excess bone loss.
authors.affiliation: INSERM, UMR1033, UCB Lyon 1, Faculté de Médecine Lyon Est, 69732 Lyon, France.
authors.forename: Marion
authors.initials: M
authors.lastname: David
authors.affiliation: CNRS, UMR5242, ENS, Équipe Biologie Cellulaire et Physiopathologie Osseuse, Institut de Génomique Fonctionnelle de Lyon, UCB Lyon 1, 69007 Lyon, France.
authors.forename: Irma
authors.initials: I
authors.lastname: Machuca-Gayet
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, 565-0871 Osaka, Japan; CREST, Japan Science and Technology Agency, 102-0076 Tokyo, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kikuta
authors.affiliation: Academic Unit of Clinical Oncology, University of Sheffield Medical School, Beech Hill Road, S10 2RX Sheffield, United Kingdom.
authors.forename: Penelope
authors.initials: P
authors.lastname: Ottewell
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, 565-0871 Osaka, Japan; CREST, Japan Science and Technology Agency, 102-0076 Tokyo, Japan.
authors.forename: Fuka
authors.initials: F
authors.lastname: Mima
authors.affiliation: INSERM, UMR1033, UCB Lyon 1, Faculté de Médecine Lyon Est, 69732 Lyon, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Leblanc
authors.affiliation: INSERM, UMR1033, UCB Lyon 1, Faculté de Médecine Lyon Est, 69732 Lyon, France.
authors.forename: Edith
authors.initials: E
authors.lastname: Bonnelye
authors.affiliation: INSERM, UMR1033, UCB Lyon 1, Faculté de Médecine Lyon Est, 69732 Lyon, France.
authors.forename: Johnny
authors.initials: J
authors.lastname: Ribeiro
authors.affiliation: Academic Unit of Clinical Oncology, University of Sheffield Medical School, Beech Hill Road, S10 2RX Sheffield, United Kingdom.
authors.forename: Ingunn
authors.initials: I
authors.lastname: Holen
authors.affiliation: Grup de Neuroplasticitat i Regeneració, Unitat de Fisiologia Mèdica, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain.
authors.forename: Rùben Lopez
authors.initials: RL
authors.lastname: Vales
authors.affiliation: CNRS, UMR5242, ENS, Équipe Biologie Cellulaire et Physiopathologie Osseuse, Institut de Génomique Fonctionnelle de Lyon, UCB Lyon 1, 69007 Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Jurdic
authors.affiliation: Department of Molecular Biology, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.affiliation: INSERM, UMR1033, UCB Lyon 1, Faculté de Médecine Lyon Est, 69732 Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Clézardin
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, 565-0871 Osaka, Japan; CREST, Japan Science and Technology Agency, 102-0076 Tokyo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishii
authors.affiliation: INSERM, UMR1033, UCB Lyon 1, Faculté de Médecine Lyon Est, 69732 Lyon, France. Electronic address: olivier.peyruchaud@inserm.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Peyruchaud
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D001862:Bone Resorption / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement; D005260:Female; D007555:Isoxazoles / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009829:Oleic Acids / Q000494:pharmacology; D010755:Organophosphates / Q000494:pharmacology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011422:Propionates / Q000494:pharmacology; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; C499636:DC-STAMP protein, mouse; D007555:Isoxazoles; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C494005:Nfatc1 protein, mouse; D009829:Oleic Acids; D010755:Organophosphates; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; C556086:phosphoric acid mono-(3-(4-benzyloxyphenyl)-2-octadec-9-enoylaminopropyl) ester
keywords: Bone; Differentiation; Lysophospholipid; Osteoclast; Osteoporosis; Receptors