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AB0066 Cyclic phosphatidic acid (cpa) stimulates hyaluronic acid production in human osteoarthritic articular chondrocytes, and intra-articular administration of cpa suppresses pain, swelling, and cartilage destruction in rabbit experimental osteoarthritis.
  1. I. Masuda1,2,
  2. K. Okada3,
  3. S. Momohara4
  1. 1Rheumatology, Sanno Hospital
  2. 2Rheumatology, Tokyo Women’s Medical University
  3. 3SANSHO Co. Ltd
  4. 4Joint Surgery, Tokyo Women’s Medical University, Tokyo, Japan

Abstract

Background Cyclic phosphatidic acid (cPA) is one of lipid mediators, has been shown various biological effects1. On human skin fibroblasts, cPA stimulates high molecular hyaluronic acid (HA) production through up-regulating HA synthase (HAS). cPA also have shown that antinociceptive effect on animal models of acute and chronic pain2.

Objectives The aim of this study was to evaluate the effects of cPA on articular chondrocytes HA synthesis in vitro, and its in vivo effect using a rabbit model of osteoarthritis.

Methods In vitro studies were performed using human osteoarthritic chondrocytes obtained at joint replacement surgery. cPA 0-50 microM was added to chondrocyte cultures and effects of cPA on chondrocyte HA metabolism were assessed at various time points (0-48hrs). Synthesized HA in culture media was measured by sandwich ELISA using bovine nasal HA binding protein. HAS expression in chondrocytes was examined by real time PCR using specific primers to HAS1, HAS2, and HAS3. Beta-actin was used as endogenous control. In vivo experimental OA was induced in the knee joints of 12 mature rabbit knee joints by partial medial menisectomy. They were divided into two groups, and cPA (10 micro gram/rabbit) or saline were injected intra-articularly twice a week immediately after the surgery. General health, weight, pain score {weight bearing % = (weight bearing of right leg) / (right + left leg) x100}, and swelling score {swelling % = (circumference of right knee – left knee) / (left knee+ left knee) x100} of rabbits were observed once a week. At 42 days after surgery, animals were painlessly sacrificed and degenerative changes in their femoral and tibial cartilages were graded histopathologically.

Results cPA stimulated HA synthesis of articular chondrocytes as time and dose-dependent manner in vitro. 50 microM cPA increased HA production three times more than control at 48 hours. HAS2 gene was up-regulated as dose–dependent manner and kept increased through the time. HAS1 and HAS3 up-regulated temporally at 2 hours after addition, but down at 4 hours. There was no difference from control on HYAL expression. In vivo study, cPA-treated rabbit showed significant less pain score (20% more weight bearing than control), and dramatic reduce of swelling score than control (p=0.0164). The histological score of cartilage degeneration was significantly less with cPA administration (cPA 8.33±2.51 vs. control 14.33±2.33; p=0.0649).

Conclusions These results indicated that cPA had stimulatory effects on HA synthesis by articular chondrocytes in vitro. In vivo study using rabbit experimental OA model indicated that cPA not only had stimulatory effects on endogenous HA synthesis, but also might have anti-nociceptive and anti-inflammatory effect, and was very effective in suppression of cartilage degeneration in early OA.

Molecular mechanism of cPA to prevent cartilage degeneration remains to be elucidated, however, further study should be warranted for cPA as a novel candidate for therapeutic agent of OA.

  1. Murakami-Murofushi K, et al. BBA-Mol Cell Biol Lipid 2002; 1582:1-7.

  2. Kakiuchi Y, et al. Mol Pain 2011; 7: 33-43.

Disclosure of Interest None Declared

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