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Synergistic Effects of FGF-2 With Insulin or IGF-I on the Proliferation of Human Auricular Chondrocytes

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Chondrocyte preparation with the safety and efficiency is the first step in cartilage regenerative medicine. To prepare a chondrocyte proliferation medium that does not contain fetal bovine serum (FBS) and that provides more than a 1000-fold increase in cell numbers within approximately 1 month, we attempted to use the medium containing 5% human serum (HS), but it exerted no more than twofold increase in 2 weeks. To compensate for the limited proliferation ability in HS, we investigated the combinational effects of 12 factors [i.e., fibroblast growth factor(FGF)-2, insulin-like growth factor(IGF)-I, insulin, bone morphogenetic protein-2, parathyroid hormone, growth hormone, dexamethasone, 1α25-dihydroxy vitamin D3, L-3,3′,5′-triodothyronine, interleukine-1 receptor antagonist, 17-estradiol, and testosterone] on the proliferation of human auricular chondrocytes by analysis of variance in fractional factorial design. As a result, FGF-2, dexamethasone, insulin, and IGF-I possessed promotional effects on proliferation, while the combination of FGF-2 with insulin or IGF-I synergistically enhanced the proliferation. Actually, the chondrocytes increased 7.5-fold in number in 2 weeks in a medium containing 5% HS with 10 ng/ml FGF-2 , while the cell number synergistically gained a 10–12-fold increase with 5 g/ml insulin or 100 ng/ml IGF-I in the same period. The proliferation effects were more enhanced at a concentration of 100 ng/ml for FGF-2, and especially for the combination of 100 ng/ml FGF-2 and 5 g/ml insulin (approximately 16-fold within 2 weeks). In the long-term culture with repeated passaging, this combination provided more than 10,000-fold within 8 weeks (i.e., passage 4). Thus, we concluded that such a combination of FGF-2 with insulin or IGF-I may be useful for promotion of auricular chondrocyte proliferation in a clinical application for cartilage regeneration.

Keywords: Chondrocyte; Fractional factorial design; Medium; Proliferation; Regenerative medicine; Soluble factor

Document Type: Research Article


Affiliations: 1: Department of Clinical Bioinformatics, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-Ku, Tokyo 113-0033, Japan 2: Department of Plastic & Reconstructive Surgery, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-Ku, Tokyo 113-0033, Japan 3: Department of Plastic & Reconstructive Surgery, Saitama Medical School, Kerohongo 38, Moroyama-cho, Iruma, Saitama 350-0495, Japan 4: Department of Plastic & Reconstructive Surgery, Kitasato University, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan 5: Division of Tissue Engineering, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-Ku, Tokyo 113-0033, Japan

Publication date: 2005-09-01

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