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Expression of Cyclin-Dependent Kinase Inhibitors in Epiphyseal Chondrocytes Induced to Terminally Differentiate with Thyroid Hormone

Pediatric Orthopedic Research Laboratory, Department of Orthopedics, Rainbow Babies and Childrens Hospital, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio 44106

Address all correspondence and requests for reprints to: R. Tracy Ballock, M.D., 11100 Euclid Avenue, Cleveland, Ohio 44106. E-mail: rtracy.ballock{at}uhhs.com

A growing body of evidence suggests that systemic hormones and peptide growth factors may exert their effects on cell growth and differentiation in part through regulation of the cell division cycle. We hypothesized that thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through controlling cell cycle progression at the G₁/S restriction point. Our results support this hypothesis by demonstrating that treatment of epiphyseal chondrocytes with thyroid hormone under chemically defined conditions results in the arrest of DNA synthesis and the onset of terminal differentiation, indicating that thyroid hormone is one factor capable of regulating the transition between cell growth and differentiation in these cells. This terminal differentiation process is associated with induction of the cyclin/cyclin-dependent kinase inhibitors p21^{cip-1, waf-1} and p27^kip1, suggesting that thyroid hormone may regulate terminal differentiation in part by arresting cell cycle progression through induction of cyclin-dependent kinase inhibitors.

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