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1,25(OH)2D3 and Dihydrotestosterone Interact to Regulate Proliferation and Differentiation of Epiphyseal Chondrocytes

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Abstract

Growth plate chondrocytes are affected by 1,25(OH)2D3 and androgens, which may critically interact to regulate proliferation and differentiation during the male pubertal growth spurt. We investigated possible interactions of 1,25(OH)2D3 and the non-aromatizable androgen dihydrotestosterone (DHT) in primary chondrocyte cultures from young male rats. DHT and 1,25(OH)2D3 independently stimulated DNA synthesis and cell proliferation in a dose-dependent manner with maximally effective doses of [10-8 M] and [10-12 M], respectively. Both DHT and 1,25(OH)2D3 stimulated the expression and release of IGF-I, and the proliferative effects of each hormone were prevented by an IGF-I antibody. DHT and 1,25(OH)2D3 increased messenger RNAs (mRNAs) of their cognate receptors and of IGF-I receptor mRNA (IGF-I-R). 1,25(OH)2D3 also stimulated mRNA of the androgen receptor (AR), whereas DHT did not affect mRNA of the vitamin-D receptor (VDR). Coincubation with both steroid hormones did not stimulate receptor mRNAs more than either hormone alone. The proliferative effects of DHT and 1,25(OH)2D3 were completely inhibited by simultaneous incubation with both hormones, despite potentiation of IGF-I synthesis. In contrast, both hormones synergistically stimulated cell differentiation as judged by alkaline phosphatase activity, collagen X mRNA, and matrix calcification in long-term experiments. We conclude that DHT and 1,25(OH)2D3 interact with respect to chondrocyte proliferation and cell differentiation. The proliferative effects of both hormones are mediated by local IGF-I synthesis. Simultaneous coincubation with both hormones blunts the proliferative effect exerted by either hormone alone, in favor of a more marked stimulation of cell differentiation.

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Acknowledgements

Part of this work was presented at the 33rd Annual Meeting of the European Society for Paediatric Nephrology in Prague, Septemer 2–5, 1999, Czech Republic and at the 32nd Annual Meeting of the American Society of Nephrology in Miami Beach, Florida, November 4–8, 1999, USA

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Authors and Affiliations

  1. Divisions of Pediatric Nephrology, University Children’s Hospital, Heidelberg D-69120, and Marburg D-35033, Germany

    U. Hügel, R. Himmele, G. Klaus, O. Mehls & F. Schaefer

  2. Department of Pediatric Nephrology, Charité Hospital, Berlin, D-10117, Germany

    D. Haffner

  3. Department of Nutrition and Inborn Errors of Metabolism, University Children’s Hospital, Munich D-80337, Germany

    K. Krohn

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  1. K. Krohn
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Correspondence to F. Schaefer.

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Krohn, K., Haffner, D., Hügel, U. et al. 1,25(OH)2D3 and Dihydrotestosterone Interact to Regulate Proliferation and Differentiation of Epiphyseal Chondrocytes . Calcif Tissue Int 73, 400–410 (2003). https://doi.org/10.1007/s00223-002-2160-9

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