title: Lysophosphatidic acid mediates fibrosis in injured joints by regulating collagen type I biosynthesis.
abstract: OBJECTIVE
  Articular cartilage is a highly specialized tissue which forms the surfaces in synovial joints. Full-thickness cartilage defects caused by trauma or microfracture surgery heal via the formation of fibrotic tissue characterized by a high content of collagen I (COL I) and subsequent poor mechanical properties. The goal of this study is to investigate the molecular mechanisms underlying fibrosis after joint injury.
  
  
  METHODS
  Rat knee joint models were used to mimic cartilage defects after acute injury. Immunohistochemistry was performed to detect proteins related to fibrosis. Human fetal chondrocytes and bone marrow stromal cells (BMSCs) were used to study the influence of the lipid lysophosphatidic acid (LPA) on COL I synthesis. Quantitative PCR, ELISA and immunohistochemistry were performed to evaluate the production of COL I. Chemical inhibitors were used to block LPA signaling both in vitro and in vivo.
  
  
  RESULTS
  After full-thickness cartilage injury in rat knee joints, stromal cells migrating to the injury expressed high levels of the LPA-producing enzyme autotaxin (ATX); intact articular cartilage in rat and humans expressed negligible levels of ATX despite expressing the LPA receptors LPAR1 and LPAR2. LPA-induced increases in COL I production by chondrocytes and BMSCs were mediated by the MAP kinase and PI3 Kinase signaling pathways. Inhibition of the ATX/LPA axis significantly reduced COL I-enriched fibrocartilage synthesis in full-thickness cartilage defects in rats in favor of the collagen II-enriched normal state.
  
  
  CONCLUSIONS
  Taken together, these results identify an attractive target for intervention in reducing the progression of post-traumatic fibrosis and osteoarthritis.
authors.affiliation: Department of Orthopaedic Surgery, Orthopedic Hospital Research Center, David Geffen School of Medicine (DGSOM), University of California at Los Angeles, Los Angeles, CA 90095, USA. Electronic address: lingwu@mednet.ucla.edu.
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Orthopaedic Surgery, Orthopedic Hospital Research Center, David Geffen School of Medicine (DGSOM), University of California at Los Angeles, Los Angeles, CA 90095, USA. Electronic address: FPetrigliano@mednet.ucla.edu.
authors.forename: F A
authors.initials: FA
authors.lastname: Petrigliano
authors.affiliation: Department of Orthopaedic Surgery, Orthopedic Hospital Research Center, David Geffen School of Medicine (DGSOM), University of California at Los Angeles, Los Angeles, CA 90095, USA; State Key Laboratory for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, 610041, China. Electronic address: k.ba@msn.com.
authors.forename: K
authors.initials: K
authors.lastname: Ba
authors.affiliation: Department of Orthopaedic Surgery, Orthopedic Hospital Research Center, David Geffen School of Medicine (DGSOM), University of California at Los Angeles, Los Angeles, CA 90095, USA. Electronic address: siyounglee@mednet.ucla.edu.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Orthopaedic Surgery, Orthopedic Hospital Research Center, David Geffen School of Medicine (DGSOM), University of California at Los Angeles, Los Angeles, CA 90095, USA. Electronic address: j.bogdanov@ucla.edu.
authors.forename: J
authors.initials: J
authors.lastname: Bogdanov
authors.affiliation: Department of Orthopaedic Surgery, Orthopedic Hospital Research Center, David Geffen School of Medicine (DGSOM), University of California at Los Angeles, Los Angeles, CA 90095, USA. Electronic address: dmcallister@mednet.ucla.edu.
authors.forename: D R
authors.initials: DR
authors.lastname: McAllister
authors.affiliation: Department of Orthopaedic Surgery, Orthopedic Hospital Research Center, David Geffen School of Medicine (DGSOM), University of California at Los Angeles, Los Angeles, CA 90095, USA; UCLA Broad Stem Cell Institute for Regenerative Medicine and Stem Cell Research, USA; UCLA Jonsson Comprehensive Cancer Center, USA. Electronic address: JSAdams@mednet.ucla.edu.
authors.forename: J S
authors.initials: JS
authors.lastname: Adams
authors.affiliation: Division of Rheumatology, Department of Medicine, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee WI 53226, USA. Electronic address: Ann.Rosenthal@va.gov.
authors.forename: A K
authors.initials: AK
authors.lastname: Rosenthal
authors.affiliation: Novogenix Laboratories, LLC, Los Angeles, CA 90033, USA. Electronic address: bvanhandel@novogenixlabs.com.
authors.forename: B
authors.initials: B
authors.lastname: Van Handel
authors.affiliation: UCLA Broad Stem Cell Institute for Regenerative Medicine and Stem Cell Research, USA; UCLA Jonsson Comprehensive Cancer Center, USA; Department of Pathology and Laboratory Medicine, DGSOM, UCLA, USA. Electronic address: GCrooks@mednet.ucla.edu.
authors.forename: G M
authors.initials: GM
authors.lastname: Crooks
authors.affiliation: State Key Laboratory for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, 610041, China. Electronic address: yunfenglin@scu.edu.cn.
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Orthopaedic Surgery, Orthopedic Hospital Research Center, David Geffen School of Medicine (DGSOM), University of California at Los Angeles, Los Angeles, CA 90095, USA; UCLA Broad Stem Cell Institute for Regenerative Medicine and Stem Cell Research, USA; UCLA Jonsson Comprehensive Cancer Center, USA. Electronic address: devseenko@mednet.ucla.edu.
authors.forename: D
authors.initials: D
authors.lastname: Evseenko
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000293:injuries* / Q000473:pathology*; D024042:Collagen Type I / Q000096:biosynthesis*; D005355:Fibrosis / Q000209:etiology; D006801:Humans; D008246:Lysophospholipids / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013264:Stifle / Q000293:injuries*
chemical_list: D024042:Collagen Type I; D008246:Lysophospholipids; C032881:lysophosphatidic acid
keywords: Autotaxin; Cartilage injury; Chondrocytes; Collagen type I; Fibrosis; Lysophosphatidic acid