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C Farquharson, J S Rennie, N Loveridge and C C Whitehead

Abstract

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is regarded as the most biologically active metabolite of cholecalciferol. It prevents tibial dyschondroplasia (TD) in chicks where inhibition of chondrocyte differentiation within the growth plate occurs. However, it is unclear whether its mode of action is through direct interaction with its chondrocyte receptor and its known regulatory role in cell differentiation or is mediated by increased calcium absorption and mobilisation. Synthetic analogues of 1,25(OH)2D3 such as 1,25-dihydroxy-16-ene-23-yne cholecalciferol (RO 23–7553) with increased differentiation properties but reduced calcaemic activity have been synthesised. In this study, the in vitro and in vivo effects of 1,25(OH)2D3 and RO 23–7553 on chick chondrocyte growth and differentiation were examined. In addition, the in vivo effectiveness of these steroids in preventing TD in chicks was assessed. 1,25(OH)2D3 and RO 23–7553 (10−12-10−7 m) displayed biphasic concentration effects and had similar potencies in vitro in regulating chondrocyte proliferation and differentiation. However, while the incidence of TD in birds dosed with 1,25(OH)2D3 was lower (10%) than in control chicks (55%), RO 23–7553 was ineffective (50%). This may be the result of its reduced affinity (1000 times less) for the plasma vitamin D binding protein (DBP) and the chondrocyte receptor in comparison to that of 1,25(OH)2D3. A reduction in calcium supply to the chondrocyte may also result in decreased chondrocyte differentiation but blood ionised and plasma total calcium were normal in birds dosed with RO 23–7553. These data suggest that RO 23–7553 and 1,25(OH)2D3 regulate chondrocyte proliferation and differentiation similarly in vitro but not in vivo. This may be caused by differences in DBP binding and clearance rates of the two steroids in vivo.

Journal of Endocrinology (1996) 148, 465–474

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C Farquharson, A S Law, E Seawright, D W Burt and C C Whitehead

Abstract

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) and transforming growth factor-β (TGF-β) are both important regulators of chondrocyte growth and differentiation. We report here that 1,25(OH)2D3 differentially regulates the expression of the genes for TGF-β1 to -β3 and the secretion of the corresponding proteins in cultured chick chondrocytes. Confluent growth plate chondrocytes were serum-deprived and cultured in varying concentrations of 1,25(OH)2D3. Cells were assayed for TGF-β mRNA and conditioned medium was assayed for TGF-β activity and isoform composition. Active TGF-β was only detected in 10−8 m 1,25(OH)2D3-treated cultures (8·37 ng active TGF-β/mg protein). There was a significant decrease in total (latent+active) TGF-β activity in conditioned medium of 10−12 m (23·4%; P<0·05) and 10−10 m (20·7%; P<0·05) 1,25(OH)2D3-treated cultures but 10−8 m 1,25(OH)2D3 significantly increased (30·9%; P<0·01) TGF-β activity. The amounts of TGF-β1, -β2 and -β3 isoforms produced were similar in control, 10−10 or 10−12 m 1,25(OH)2D3-treated cultures but the conditioned medium of 10−8 m 1,25(OH)2D3-treated cultures contained significantly higher amounts of all three isoforms. Quantification of TGF-β mRNA demonstrated differential control of TGF-β gene expression with TGF-β1 and -β3 mRNA levels reduced by all concentrations of 1,25(OH)2D3 examined (10−8, 10−10 and 10−12 m) whilst TGF-β2 mRNA concentrations were elevated. Our results indicated that 1,25(OH)2D3 regulates chick growth plate chondrocyte TGF-β secretion and mRNA expression in a concentration-dependent and isoform-specific manner. This interaction may be important in the regulation of chondrocyte metabolism and endochondral bone growth.

Journal of Endocrinology (1996) 149, 277–285

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J. Buyse, E. Decuypere, P. J. Sharp, L. M. Huybrechts, E. R. Kühn and C. Whitehead

ABSTRACT

Daily changes in the concentrations of plasma corticosterone, prolactin, thyroid hormones and somatomedin C were measured in 28-day-old fat and lean lines of broilers produced by selection for high and low concentrations of very low density lipoproteins (VLDL). The effects of daily injections of corticosterone on the concentrations of these hormones and on fattening were compared in the two lines. The selection procedure had no effect on the concentrations of any of the hormones. However, daily rhythms in concentrations of plasma corticosterone, tri-iodothyronine (T3) and prolactin were less often observed in the fat line than in the lean line. No differences were seen between lines in the daily rhythms in plasma thyroxine (T4) and somatomedin C. Daily injections of 2500 μg corticosterone/kg body weight, in both lines, depressed mean concentrations of plasma prolactin, T3 and somatomedin C and body weight. This dose of corticosterone also increased abdominal fat pad and liver weights expressed as a percentage of body weight. The liver and fat pad responses to 2500 μg corticosterone in both lines were greater when the steroid was injected at the end rather than towards the beginning of the 14-h daily photoperiod. There was no difference between the lines in the fattening response to corticosterone. Lower doses of 100 and 500 μg corticosterone per day did not induce fattening or affect concentrations of plasma prolactin. They did, however, depress concentrations of plasma T3. Concentrations of plasma T4 were increased in both lines treated with 2500, but not with 100 or 500 μg corticosterone, towards the beginning of the daily photoperiod. It is concluded that selection for low and high concentrations of VLDL does not affect mean levels of the hormones measured at 28 days of age or the fattening response to corticosterone. It does, however, alter the amplitude in the daily rhythm in concentrations of corticosterone, T3 and prolactin. The fattening response to corticosterone is associated with depressed concentrations of plasma prolactin, T3 and somatomedin C.

J. Endocr. (1987) 112, 229–237