title: Cyclic phosphatidic acid relieves osteoarthritis symptoms.
abstract: BACKGROUND
  Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator with a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. Natural cPA and its chemically stabilized cPA derivative, 2-carba-cPA (2ccPA), inhibit chronic and acute inflammation, and 2ccPA attenuates neuropathic pain. Osteoarthritis (OA) is a degenerative disease frequently associated with symptoms such as inflammation and joint pain. Because 2ccPA has obvious antinociceptive activity, we hypothesized that 2ccPA might relieve the pain caused by OA. We aimed to characterize the effects of 2ccPA on the pathogenesis of OA induced by total meniscectomy in the rabbit knee joint.
  
  
  RESULTS
  Intra-articular injection of 2ccPA (twice a week for 42 days) significantly reduced pain and articular swelling. Histopathology showed that 2ccPA suppressed cartilage degeneration in OA. We also examined the effects of 2ccPA on the inflammatory and catabolic responses of human OA synoviocytes and chondrosarcoma SW1353 cells in vitro. 2ccPA stimulated synthesis of hyaluronic acid and suppressed production of the metalloproteinases MMP-1, -3, and -13. However, it had no effect on the production of interleukin (IL)-6, an inflammatory cytokine. The suppressive effect of 2ccPA on MMP-1 and -3 production in synoviocytes and on MMP-13 production in SW1353 cells was not mediated by the lysophosphatidic acid receptor, LPA1 receptor (LPA1R).
  
  
  CONCLUSIONS
  Our results suggest that 2ccPA significantly reduces the pain response to OA by inducing hyaluronic acid production and suppressing MMP-1, -3, and -13 production in synoviocytes and chondrocytes.
authors.forename: Mari
authors.initials: M
authors.lastname: Gotoh
authors.forename: Aya
authors.initials: A
authors.lastname: Nagano
authors.forename: Ryoko
authors.initials: R
authors.lastname: Tsukahara
authors.forename: Hiromu
authors.initials: H
authors.lastname: Murofushi
authors.forename: Toshiro
authors.initials: T
authors.lastname: Morohoshi
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Otsuka
authors.affiliation: Endowed Research Division of Human Welfare Sciences, Ochanomizu University, 2-1-1 Ohtsuka, Bunkyo-ku, Tokyo 112-8610, Japan. murofushi.kimiko@ocha.ac.jp.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Murakami-Murofushi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004487:Edema / Q000188:drug therapy / Q000209:etiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D017746:Joint Capsule / Q000166:cytology; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D010147:Pain Measurement; D010712:Phosphatidic Acids / Q000627:therapeutic use*; D011422:Propionates / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D013583:Synovial Membrane / Q000187:drug effects; D013997:Time Factors
chemical_list: C558317:2-carba-cyclic phosphatidic acid; C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D007555:Isoxazoles; D010712:Phosphatidic Acids; D011422:Propionates; D012333:RNA, Messenger