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The Thyroid Hormone Receptor (TR) β-Selective Agonist GC-1 Inhibits Proliferation But Induces Differentiation and TR β mRNA Expression in Mouse and Rat Osteoblast-Like Cells

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Abstract

Previous studies showed anabolic effects of GC-1, a triiodothyronine (T3) analogue that is selective for both binding and activation functions of thyroid hormone receptor (TR) β1 over TRα1, on bone tissue in vivo. The aim of this study was to investigate the responsiveness of rat (ROS17/2.8) and mouse (MC3T3-E1) osteoblast-like cells to GC-1. As expected, T3 inhibited cellular proliferation and stimulated mRNA expression of osteocalcin or alkaline phosphatase in both cell lineages. Whereas equimolar doses of T3 and GC-1 equally affected these parameters in ROS17/2.8 cells, the effects of GC-1 were more modest compared to those of T3 in MC3T3-E1 cells. Interestingly, we showed that there is higher expression of TRα1 than TRβ1 mRNA in rat (~20–90%) and mouse (~90–98%) cell lineages and that this difference is even higher in mouse cells, which highlights the importance of TRα1 to bone physiology and may partially explain the modest effects of GC-1 in comparison with T3 in MC3T3-E1 cells. Nevertheless, we showed that TRβ1 mRNA expression increases (~2.8- to 4.3-fold) as osteoblastic cells undergo maturation, suggesting a key role of TRβ1 in mediating T3 effects in the bone forming cells, especially in mature osteoblasts. It is noteworthy that T3 and GC-1 induced TRβ1 mRNA expression to a similar extent in both cell lineages (~2- to 4-fold), indicating that both ligands may modulate the responsiveness of osteoblasts to T3. Taken together, these data show that TRβ selective T3 analogues have the potential to directly induce the differentiation and activity of osteoblasts.

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Acknowledgments

The authors are grateful to Dr. Maria Luiza Barreto-Chaves and Dr. Anselmo S. Moriscot (Institute of Biomedical Sciences, University of Sao Paulo) for making their laboratories available for some experiments. This work was supported by a grant (CHAG) from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Brazil (05/52910-4), and a grant (TSS) from the NIH (DK52798). E.H.B., L.P.C., T.L.F., and C.C.C. were recipients of fellowships from CAPES and FAPESP (03/07327-3, 05/59557-8, and 06/52982-8).

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Authors and Affiliations

  1. Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes 2415, Sao Paulo, SP, 05508-000, Brazil

    Eduardo H. Beber, Tatiana L. Fonseca, Cristiane C. Costa, Claudimara F. Lotfi & Cecilia H. A. Gouveia

  2. Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil

    Luciane P. Capelo

  3. Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR, 97239, USA

    Thomas S. Scanlan

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  1. Eduardo H. Beber
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  2. Luciane P. Capelo
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Correspondence to Cecilia H. A. Gouveia.

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Beber, E.H., Capelo, L.P., Fonseca, T.L. et al. The Thyroid Hormone Receptor (TR) β-Selective Agonist GC-1 Inhibits Proliferation But Induces Differentiation and TR β mRNA Expression in Mouse and Rat Osteoblast-Like Cells. Calcif Tissue Int 84, 324–333 (2009). https://doi.org/10.1007/s00223-009-9230-1

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