TERMINAL DIFFERENTIATION OF GROWTH PLATE CHONDROCYTES

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DESCRIPTION (Adapted from the Applicant's Abstract): Deficiency of thyroid hormone in children results in delayed skeletal maturation, disorganization of the cartilage columns of the growth plates, and impaired differentiation of growth plate chondrocytes into hypertrophic cells. These abnormalities are often clinically manifested as severe growth retardation and mechanical failure of the growth plates of the hips (slipped capital femoral epiphyses). Despite exciting advances in the understanding of how systemic hormones and peptide growth factors regulate growth and differentiation in a number of target tissues, the molecular mechanisms by which thyroid hormone exerts these profound effects on bone growth and development have remained an enigma. Evidence is accumulating to suggest that systemic hormones and peptide growth factors in general, and thyroid hormone in particular, may regulate cell growth and differentiation, in part through control of the cell cycle. A chemically-defined model of growth plate chondrocyte differentiation has been developed which is not only exquisitely sensitive to thyroid hormone, but also results in morphogenesis of chondrocytes into a columnar pattern similar to the in vivo growth plate. This model will be used to determine if thyroid hormone regulates the transition between chondrocyte growth and differentiation, in part through inhibiting progression of cells through the cell cycle. The Specific Aims of this project are: 1) to define the role of thyroid hormone in regulating the transition from cell growth to cell differentiation in this chemically-defined model of growth plate chondrocyte differentiation; 2) to characterize the cell cycle response to thyroid hormone-induced terminal differentiation in this system; and 3) to overexpress specific cell cycle proteins in growth plate chondrocytes, by transient transfection, to determine their effect on thyroid hormone signalling.