Expression of Type 2 Iodothyronine Deiodinase in Human Osteoblast Is Stimulated by Thyrotropin

Abstract

Thyroid hormones play important roles in bone growth, development, and turnover. To exert its biological activity, T(4) needs to be converted to T(3) by iodothyronine deiodinase. In human thyroid gland as well as rat brown adipose tissue, type 2 iodothyronine deiodinase (D2) expression is regulated by a TSH receptor-cAMP-mediated mechanism. TSH receptor knockout mice demonstrated the direct effects of TSH on bone via TSH receptors found on osteoblast and osteoclast precursors. In the present study we investigated the possible expression and function of iodothyronine deiodinase and TSH receptors in human osteoblast-like osteosarcoma (SaOS-2) cells and normal human osteoblast (NHOst) cells. Iodothyronine deiodinase activity was detected in SaOS-2 cells and NHOst cells, and all of the characteristics of deiodinating activity were compatible with those of D2. Northern analysis demonstrated D2 mRNA expression in SaOS-2 cells and NHOst cells. D2 mRNA levels as well as D2 activities were rapidly increased by dibutyryl cAMP or forskolin in SaOS-2 cells and NHOst cells. TSH receptor mRNA was demonstrated in SaOS-2 cells and NHOst cells, and D2 mRNA and D2 activity were stimulated by TSH in both cells. In addition, all T(3) receptor isoforms were detected by RT-PCR in SaOS-2 cells and NHOst cells. The present results indicate the expression of functional TSH receptors and D2 in human osteoblasts and suggest previously unrecognized roles of TSH receptors and local T(3) production by D2 in the pathophysiology of human osteoblasts.

Type 2 iodothyronine deiodinase is highly expressed in medullary thyroid carcinoma

“…Abnormal D2 expression and function have been described previously in other human neoplasms (Curcio et al, 2001;Dentice et al, 2007;Meyer et al, 2007;Morimura et al, 2005). Indeed, it is conceivable that thyroid status is linked to the development and growth of neoplastic tissues (Lemaire et al, 1981;Leuthauser et al, 1987).…”

The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density

“…In the context of conflicting data on a functional role for TSH in skeletal development, our data, which were corrected for serum TSH levels, outline the importance of local T 3 for bone metabolism. (13)(14)(15)(16)(17)(35)(36)(37)(38) Two recent papers by Bassett and colleagues, (18,19) who studied mice with complete or haploinsufficiency of TRa and -b, concluded that TRa regulates both skeletal development and adult bone maintenance.…”

“…(21) D2 is essential for the local production of T 3 through deiodination of triiodothyroxine (T 4 ). Although earlier studies on the role and functional expression of iodothyronine deiodinase enzymes in the skeleton have been equivocal, (12,14,(22)(23)(24)(25) a recent study reported normal growth in mice with deficiencies in D1 and D2, indicating that D2 may not be critical in skeletal development. (26) This notion was supported in a recent study that demonstrated that D2 activity is restricted to mature osteoblasts, suggesting a possible role for D2 in mature osteoblast function.…”

The Genetics of the Thyroid Stimulating Hormone Receptor: History and Relevance

“…Although the TSHR is highly expressed in the thyroid, it is also expressed in brain, bone, fibroblasts, and other sites (85)(86)(87), and mutations in the TSHR have been related to a variety of abnormalities. The TSHR gene has been associated with photoperiod control in birds (88) and polymorphisms in the TSHR gene may be related to the loss of seasonal reproduction cycles in domestic birds (89).…”