**2.3. Role of TSH on bone**

Thyroid stimulating hormone (TSH) is a ligand hormone between hypothalamic-pituitary axis and the thyroid gland. TSH has long been recognized to act on the thyroid gland to control follicle development and thyroid hormone production and secretion. Beyond thyroid, TSH has also been shown to have additional effects on other tissues. TSH can exert a direct effect on bone metabolism independently of the peripheral thyroid hormone (thyroxine, T4, and triiodothyronine, T3) levels. This effect is mediated through the receptor for binding the thyroid-stimulating hormone (TSH-R), which is a pituitary G proteincoupled transmembrane receptor. Its expression has been demonstrated on osteoblast and osteoclast precursors. The TSH-R haploinsufficient mice display osteoporosis and focal osteosclerosis and thyroid hormone replacement did not restore bone mass but corrected growth deficiency in these animals (Abe et al, 2003). It has been suggested that the effects of TSH on the skeleton are independent of thyroid hormone levels.

*In vitro* and *in vivo* studies have provided evidence that TSH has negative effects on both osteoclasts and osteoblasts (Abe et al, 2003; Hase et al, 2006; Sun et al, 2006; Ma et al, 2011). TSH inhibits osteoclastogenesis by attenuating Janus N-terminal kinase (JNK) and NF-KB signaling. The osteoclast-inhibitory actions of TSH are partially mediated also through effects on tumor necrosis factor (TNF)-alpha production as it has been demonstrated in murine models (Abe et al, 2003). Mice lacking the TSHR present osteoporosis, early in embryogenesis, due to increased osteoclast formation (Abe et al, 2003; Hase et al 2006; Ma et al, 2009). These observations have not been confirmed in double-null mice of TSHR and TNF-alpha supporting thus the role of TNF-alpha in increased osteoclastogenesis (Abe et al, 2003; Hase et al 2006; Ma et al, 2009). Yamoah et al (2008) have recently described RANKLresponsive elements on the TNF alpha gene providing new insights into regulation of TNF transcription in osteoclast formation. The role of TSH on RANKL remains controversial since the administration of the exogenous recombinant TSH in animal models and humans has been shown to increase and in other series to decrease RANKL serum levels (Martini et al, 2008; Sampath et al, 2007; Abe et al, 2003). Role of TSH in osteoblastogenesis seems to be mediated through attenuation of Wnt and VEGF signaling (Abe et al, 2003). Enhanced osteoblastogenesis in TSHR deficiency was found to be associated with increased expression of low-density lipoprotein receptor–like protein-5 and Flk-1 proteins (Abe et al, 2003). Expression of these receptors, but not that of osteoblastic transcription factors, was inhibited by rhTSH. Altogether, these observations suggest that TSH negatively modulates bone turnover, however, further research is warranted to explain in detail the regulatory pathways.

254 Thyroid Hormone

et al, 1992; Britto et al, 1994).

**2.3. Role of TSH on bone** 

osteoclasts are secondary to the actions of T3 in osteoblasts.

TSH on the skeleton are independent of thyroid hormone levels.

Furthermore, T3 is involved in local signaling pathways by stimulating osteoblast responses to IGF1-I, PTH and fibroblast growth factors. T3 is a critical regulator of the Ihh - bone morphogenetic protein (BMP) – PTHrP feedback loop (Stevens et al, 2000). Hypothyroidism is marked by increased PTHrP expression and impaired hypertrophic chondrocyte differentiation (Stevens et al, 2000). In hyperthyroidism, reduced expression of PTHrP associated with augmentation of BMP enhances hypertrophic chondrocyte differentiation (Lassova et al, 2009; Stevens et al, 2000). It has also been shown that T3 regulates terminal differentiation of growth plate chondrocytes in part through controlling cell cycle progression at the G1/S restriction point (Ballock et al, 2000). T3 mediates osteoclastic bone resorption through activation of osteoblasts, which then release receptor activator for NF-κB ligand (RANKL), a member of the TNF cytokine family. RANKL is a ligand for osteoprotegerin, a cytokine that regulates osteoclastic differentiation, and functions as a key factor for osteoclast differentiation and activation by inhibiting osteoclasts apoptosis (Allain

Overall, T3 seems to enhance activity of osteoblasts by various mechanisms and signaling loops. Although the effects of thyrotoxicosis in adult bone are characterized by increased bone resorption, it is not known whether T3 acts directly in osteoclasts or whether effects on

Thyroid stimulating hormone (TSH) is a ligand hormone between hypothalamic-pituitary axis and the thyroid gland. TSH has long been recognized to act on the thyroid gland to control follicle development and thyroid hormone production and secretion. Beyond thyroid, TSH has also been shown to have additional effects on other tissues. TSH can exert a direct effect on bone metabolism independently of the peripheral thyroid hormone (thyroxine, T4, and triiodothyronine, T3) levels. This effect is mediated through the receptor for binding the thyroid-stimulating hormone (TSH-R), which is a pituitary G proteincoupled transmembrane receptor. Its expression has been demonstrated on osteoblast and osteoclast precursors. The TSH-R haploinsufficient mice display osteoporosis and focal osteosclerosis and thyroid hormone replacement did not restore bone mass but corrected growth deficiency in these animals (Abe et al, 2003). It has been suggested that the effects of

*In vitro* and *in vivo* studies have provided evidence that TSH has negative effects on both osteoclasts and osteoblasts (Abe et al, 2003; Hase et al, 2006; Sun et al, 2006; Ma et al, 2011). TSH inhibits osteoclastogenesis by attenuating Janus N-terminal kinase (JNK) and NF-KB signaling. The osteoclast-inhibitory actions of TSH are partially mediated also through effects on tumor necrosis factor (TNF)-alpha production as it has been demonstrated in murine models (Abe et al, 2003). Mice lacking the TSHR present osteoporosis, early in embryogenesis, due to increased osteoclast formation (Abe et al, 2003; Hase et al 2006; Ma et al, 2009). These observations have not been confirmed in double-null mice of TSHR and TNF-alpha supporting thus the role of TNF-alpha in increased osteoclastogenesis (Abe et al,
