Basic research for the molecular mechanism of regeneration in bone and cartilage by the fibroblast-like synovial cells

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A. Purpose of Study: Fibroblast-like synovial cells (FLS) has similarity with mesenchymal stem cells, and cytokines regulate adipogenesis of mesenchymal stem cells. We examined here the multilineage differentiation potential of FLS, and the effect of cytokines during differentiation process of FLS.B.Methods : FLS were isolated from the synovial tissues at the time of orthopedic surgery in accordance with human experimental guidelines of our institution. Adipocyte-like cell differentiation from FLS was induced by PPARγ ligand, troglitazone. Differentiation of chondrocyte-like cells and osteoblast-like cells from FLS was also induced by each differentiation medium. Effect of IFN-γ, TNF-α, or IL-1β during the process was quantified by Oil red O staining (adipocyte-like cells), Alucian blue staining/Safranin O staining (chondrocyte-like cells), or von Kossa staining (osteoblast-like cells).C.Results : FLS expressed PPARy and C/EBP, key molecules for adipogenesis, and differentiated into ad … More ipocyte-like cells by troglitazone. NP-κB activity in adipocyte-like cells was diminished as compared with FLS, and the production of MMP-3, IL-6, and IL-8 from adipocyte-like cells was also inhibited. IFN-γ, TNF-α, and IL-β suppressed the expression of PPARy and C/EBP, resulting in inhibition of adipocyte-like cell differentiation from FLS. In addition to adipocyte-like cell differentiation, FLS succeeded in differentiation into chondrocyte-like cells and osteoblast-like cells by the use of each differentiation medium. The production of MMP-3, IL-6, and IL-8 from chondrocyte-like cells or osteoblast-like cells also tended to be diminished as compared with FLS.D.Discussion : FLS have the multilineage differentiation potential, and thought to be the local stem cells in synovial tissues. These results may indicate that FLS could be the candidate target cells of regeneration therapy. FLS are easy to be isolated from the patients, thus, the rejection during the inoculation is evaded. In addition, "the. inflammatory rheumatoid synovial microenviroments formed by cytokines" inhibits the differentiation process of FLS, and thus may suppress "the tissue repair of joints" in patients with rheumatoid arthritis. Less