title: Lysophosphatidic acid receptor inhibition as a new multipronged treatment for rheumatoid arthritis.
abstract: OBJECTIVE
  To investigate the effect of lysophosphatidic acid (LPA) receptor inhibition in a mouse model of autoantibody-mediated arthritis.
  
  
  METHODS
  Arthritis was induced in C57BL/6 mice by K/BxN serum transfer. Arthritic mice were treated with the LPA receptor antagonist, Ki16425 and arthritis severity was assessed clinically and histologically. Expression of inflammatory mediators in joints was identified by a mouse cytokine array and validated by western blot and real-time PCR assays. Effects of treatment with LPA receptor antagonist or with small interfering RNA on bone metabolism were assessed by in vitro assays of osteoclastogenesis, bone resorption, osteoblasts differentiation and bone mineralisation.
  
  
  RESULTS
  Mice treated with the LPA receptor antagonist Ki16425 showed attenuated arthritis characterised by reduction of synovial inflammation, cartilage damage and, more markedly, bone erosion. We detected increased apoptosis, reduction of inflammatory mediators and of bone remodelling proteins in arthritic joints from mice treated with Ki16425. In addition, we demonstrated that inhibition or suppression of LPA1 receptor reduces osteoclast differentiation and bone resorption and, on the contrary, it promotes differentiation of osteoblasts and bone mineralisation.
  
  
  CONCLUSIONS
  Pharmacological inhibition of LPA1 receptor in the K/BxN serum-transfer arthritis model led to reduction of severity of arthritis involving multiple mechanisms, increased apoptosis, reduced inflammatory mediators and proteins involved in bone remodelling, that show LPA1 as a very promising target in rheumatoid arthritis treatment.
authors.affiliation: Laboratorio de Investigación 8 y Servicio de Reumatología, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario de Santiago de Compostela (CHUS), SERGAS, , Santiago de Compostela, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Orosa
authors.forename: Samuel
authors.initials: S
authors.lastname: García
authors.forename: Paula
authors.initials: P
authors.lastname: Martínez
authors.forename: Antonio
authors.initials: A
authors.lastname: González
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Gómez-Reino
authors.forename: Carmen
authors.initials: C
authors.lastname: Conde
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D007555:Isoxazoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology*; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors*; D013585:Synovitis / Q000188:drug therapy* / Q000276:immunology
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D001323:Autoantibodies; D007555:Isoxazoles; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid
keywords: Arthritis; Autoimmune Diseases; Rheumatoid Arthritis