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AB0067 Chondroitin sulfate regulates two anti-angiogenic factors in human osteoarthritic synovial fibroblasts
  1. J. Martel-Pelletier1,
  2. F. Mineau1,
  3. E. Montell2,
  4. J. Vergés2,
  5. J.-P. Pelletier1
  1. 1Osteoarthritis Research Unit, Hospital Research Centre (CRCHUM), Notre-Dame Hospital. University of Montreal, Montreal, Canada
  2. 2Pre-Clinical R&D Area. Pharmascience Division, BIOIBERICA, Barcelona, Spain

Abstract

Background The symptomatic slow acting drug for osteoarthritis (SYSADOA), chondroitin sulfate, has attracted much interest as a biological agent for its use in the effective relief of disease symptoms. This is likely due to its capacity for reducing joint swelling and effusion which may be explained by its anti-inflammatory effects. However, the factors involved in this latter effect are yet to be fully identified. Angiogenesis is an important event of synovial inflammation and it is suggested to contribute to the joint symptoms in OA.

Objectives We thus elected to determine the effect of chondroitin sulfate on the levels of two well-known anti-angiogenic factors previously demonstrated to be involved in OA: the vascular endothelial growth inhibitor (VEGI) and thrombospondin-1 (TSP-1). Furthermore, we explored the signaling pathways by which chondroitin sulfate exerts its effects on these factors.

Methods Human OA synovial fibroblasts were obtained from sequential enzymatic digestion. Cells were pre-incubated for 18 hours with chondroitin sulfate (200 µg/ml; CSbBio-Active®, Bioibérica, Spain) and then incubated with IL-1ß (10 and 100 pg/ml) in the absence or presence of chondroitin sulfate for increasing periods of time. Cells were processed for protein expression determination using quantitative PCR, protein production using ELISAs, and for signaling pathways using Western blotting.

Results Both VEGI and TSP-1 expression were dose-dependently decreased by IL-1ß at both concentrations tested. Chondroitin sulfate significantly increased the expression and synthesis levels of the two anti-angiogenic factors VEGI and TSP-1 under basal conditions as well as under IL-1ß treatment. The signaling pathways through which chondroitin sulfate increased the levels of VEGI and TSP-1 in the presence of IL-1ß were further investigated by measuring the phosphorylated levels of three MAP kinases, namely ERK1/2, p38, and JNK, and other cascades including NF-κB, Akt, and STAT-3. Data revealed that the effects occurred through two main pathways, Akt and STAT-3. Additional experiments with specific inhibitors of Akt phosphorylation (SH-6, Santa Cruz) and STAT-3 translocation (Stat3 inhibitor VIII, 5,15-DPP, Santa Cruz) confirmed these data.

Conclusions This study showed that chondroitin sulfate increased the levels of two important anti-angiogenic factors, which could provide a possible new mechanism of action of this SYSADOA. These findings may explain, in part, how chondroitin sulfate reduces the severity of synovitis in knee OA. In addition, these data bring to light that anti-angiogenic factors could be targeted as a specific therapeutic approach in disease modifying OA drug development.

Disclosure of Interest None Declared

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