The established function of thyroid stimulating hormone (TSH) is to promote thyroid follicle development and hormone secretion. The osteoporosis associated with hyperthyroidism is traditionally viewed as a secondary consequence of altered thyroid function. We provide evidence for direct effects of TSH on both components of skeletal remodeling, osteoblastic bone formation, and osteoclastic bone resorption, mediated via the TSH receptor (TSHR) found on osteoblast and osteoclast precursors. Even a 50% reduction in TSHR expression produces profound osteoporosis (bone loss) together with focal osteosclerosis (localized bone formation). TSH inhibits osteoclast formation and survival by attenuating JNK/c-jun and NFkappaB signaling triggered in response to RANK-L and TNFalpha. TSH also inhibits osteoblast differentiation and type 1 collagen expression in a Runx-2- and osterix-independent manner by downregulating Wnt (LRP-5) and VEGF (Flk) signaling. These studies define a role for TSH as a single molecular switch in the independent control of both bone formation and resorption.

The thyroid-stimulating hormone͞thyrotropin (TSH) is the most relevant hormone in the control of thyroid gland physiology in adulthood. TSH effects on the thyroid gland are mediated by the interaction with a specific TSH receptor (TSHR). We studied the role of TSH͞TSHR signaling on gland morphogenesis and differentiation in the mouse embryo using mouse lines deprived either of TSH (pit dw ͞pit dw ) or of a functional TSHR (tshr hyt ͞tshr hyt and TSHRknockout lines). The results reported here show that in the absence of either TSH or a functional TSHR, the thyroid gland develops to a normal size, whereas the expression of thyroperoxidase and the sodium͞iodide symporter are reduced greatly. Conversely, no relevant changes are detected in the amounts of thyroglobulin and the thyroid-enriched transcription factors TTF-1, TTF-2, and Pax8. These data suggest that the major role of the TSH͞TSHR pathway is in controlling genes involved in iodide metabolism such as sodium͞iodide symporter and thyroperoxidase. Furthermore, our data indicate that in embryonic life TSH does not play an equivalent role in controlling gland growth as in the adult thyroid. T he mouse thyroid gland begins to develop at embryonic day (E)8.5 as an endodermal thickening in the floor of the primitive pharynx. After loosing all connections with the pharynx, the thyroid bud migrates caudally, reaching its final position in front of the trachea ϷE13 (1). Only after completion of migration do thyroid follicular cells begin their differentiative program and express thyroid-specific genes such as thyroglobulin (Tg), thyroid-stimulating hormone͞thyrotropin (TSH) receptor (TSHR), thyroperoxidase (TPO), and the sodium͞iodide symporter (NIS) (2). Finally, primitive follicles appear, and the gland displays its final morphological organization. Since E8.5, thyroid precursor cells express a combination of transcription factors such as TTF-1 (encoded by the titf1͞nkx2.1 gene) (3), TTF-2 (encoded by the titf2͞foxe1 gene) (4), and Pax8 (5). Gene-targeting experiments demonstrated that all these factors are required for the early stages of thyroid development (6-8). However, it still is unclear what the mechanisms are that lead to the initiation of functional differentiation that only occurs at E14.TSH is known as the main regulator of the adult thyroid gland. Indeed, after binding to its receptor, TSH stimulates the thyroid cells in almost every aspect of their metabolism including synthesis and secretion of thyroid hormones (9). Several groups have demonstrated clearly that TSH regulates mRNA levels of several thyroid-specific genes such as Tg (10-13), TPO (13-15), and NIS (16,17).TSH also stimulates the aggregation of porcine thyroid cells in follicles (18), and its presence is necessary to maintain the follicular architecture (19). In the rat, there is a temporal correlation between the increased expression of TSHR and the formation of follicles. Indeed, TSHR mRNA is expressed by E15 (3, 20), and its expression increases on E17-E18. At this stage, thyroid-speci...

The thyrotropin (TSH) receptor (TSHR) is a member of the heterotrimeric G protein-coupled family of receptors whose main function is to regulate thyroid cell proliferation as well as thyroid hormone synthesis and release. In this study, we generated a TSHR knockout (TSHR-KO) mouse by homologous recombination for use as a model to study TSHR function. TSHR-KO mice presented with developmental and growth delays and were profoundly hypothyroid, with no detectable thyroid hormone and elevated TSH. Heterozygotes were apparently unaffected. Knockout mice died within 1 week of weaning unless fed a diet supplemented with thyroid powder. Mature mice were fertile on the thyroid-supplemented diet. Thyroid glands of TSHR-KO mice produced uniodinated thyroglobulin, but the ability to concentrate and organify iodide could be restored to TSHR-KO thyroids when cultured in the presence of the adenylate cyclase agonist forskolin. Consistent with this observation was the lack of detectable sodium-iodide symporter expression in TSHR-KO thyroid glands. Hence, by using the TSHR-KO mouse, we provided in vivo evidence, demonstrating that TSHR expression was required for expression of sodium-iodide symporter but was not required for thyroglobulin expression, suggesting that the thyroid hormone synthetic pathway of the mouse could be dissociated into TSHR-dependent and -independent steps.