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Modulation of Commitment, Proliferation, and Differentiation of Chondrogenic Cells in Defined Culture Medium¹

Laboratorio di Differenziamento Cellulare (R.Q., G.C., R.C., B.D.), Istituto Nazionale per la Ricerca sul Cancro, Centro di Biotecnologie Avanzate; and Dipartimento di Oncologia Clinica e Sperimentale (R.C.), Universita’ di Genova, 16132 Genova, Italy

Address all correspondence and requests for reprints to: Beatrice Dozin, Ph.D., Laboratorio di Differenziamento Cellulare, Istituto Nazionale per la Ricerca sul Cancro, Centro di Biotecnologie Avanzate, Largo Rosanna Benzi n.10, 16132 Genova, Italy.

The factors regulating the growth and development of mesenchymal precursor cells toward chondrogenesis are not well identified. We have developed a defined serum-free culture system that allows the proliferation of chick embryo chondrogenic cells and their maturation toward hypertrophic chondrocytes. Proliferation is obtained in adhesion in medium supplemented with insulin (Ins), Dexamethasone (Dex), and either basic fibroblast growth factor (FGF-2), platelet-derived growth factor bb, epithelial growth factor, or GH; the highest mitogenic response is induced by FGF-2 in synergy with Ins. Ins can be substituted by Ins-like growth factor I. When these cells are transferred into suspension culture in Ins/Dex and T₃ without growth factor supplement, they undergo the complete chondrogenic development characterized by type X collagen synthesis and cellular hypertrophy. During differentiation, Ins cannot be substituted by Ins-like growth factor I. Chondrogenesis is also evidenced by the formation of hypertrophic cartilage when the medium is supplemented with ascorbic acid. If T₃ is introduced in the proliferation phase, the cells fail to differentiate to hypertrophy in suspension unless bone morphogenetic protein-2 is added. Assays of ectopic tissue formation in nude mice, with cells implanted sc after adsorption on collagen sponge or porous hydroxyapatite ceramics, indicate that cells grown in Ins/FGF-2 reform mainly cartilage in vivo, whereas expansion in Ins/T₃/Dex/FGF-2 leads to the formation of cartilage, bone, and adipose tissue.

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