SFEBES2008 Oral Communications Thyroid (8 abstracts)
Direct actions of T3 in proliferating chondrocytes regulate endochondral ossification and linear growth
Nicholas D Bernstein 1 , Rowan Swinhoe 1 , Monique HA Kester 2 , Marta Archanco 1 , Yan Lu 1 , Patrick J O’Shea 1 , Theo J Visser 2 , JH Duncan Bassett 1 & Graham R Williams 1
1Molecular Endocrinology Group, Imperial College London, London, UK; 2Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
Hypothyroidism causes delayed ossification and growth retardation. T3 stimulates hypertrophic chondrocyte differentiation whereas unliganded T3 receptors (TRs) repress gene expression and maintain cell proliferation in the absence of hormone. During development the type 3 deiodinase enzyme (D3) inactivates thyroid hormones and prevents T3-access to the fetus. At birth diminishing D3 activity and increasing T3 availability triggers the onset of cell differentiation and correlates with accelerated post-natal growth. Thus, the TR functions as a developmental switch that regulates the timing of organ maturation. To determine the role of the TR in endochondral ossification we generated (i) chondrogenic ATDC5 cell lines that stably over-express D3 and (ii) transgenic mice in which D3 over-expression is restricted to proliferating chondrocytes. ATDC5 cells expressing low (3.4 fmol/min per milligram) and high (89.7 fmol/min per milligram) D3 activities were compared with control cells stably transfected with vector alone that lacked D3 activity. T3 inhibited cell proliferation by up to 50% in control cells (P<0.05) but this effect was blocked in cells with both low and high D3 activity. In untreated control cells basal alkaline phosphatase (ALP) activity increased during chondrogenesis but was markedly enhanced by T3 treatment (0.1–10 nM, P<0.05–0.001). In cells with low D3 activity basal ALP activity did not increase and the response to 0.1 nM T3 was inhibited. In cells with high D3 activity responses to all concentrations of T3 were attenuated. Thus, T3 stimulates chondrogenesis in a concentration dependent manner in vitro and the level of D3 activity regulates chondrocyte T3 responsiveness. Preliminary analysis of mice over-expressing D3 in proliferating chondrocytes revealed severe growth retardation at post-natal day 21 (tail length (mm) 60.5±1.0 vs 53.1±0.9, control (n=15) versus chondrocyte D3 over-expressing littermates (n=10), P<0.001; tibia length (mm) 13.25±0.14 vs 12.41±0.11, P<0.01), indicating local availability of T3 in growth plate chondrocytes is essential for normal endochondral ossification in vivo.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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