TSH and Thyroid Hormones Both Regulate Bone Mass (original) (raw)

Thyroid-stimulating hormone, thyroid hormones, and bone loss

Current Osteoporosis Reports, 2009

It has become accepted by virtue of rich anecdotal experience and clinical research that thyrotoxicosis is associated with high-turnover osteoporosis. The bone loss, primarily due to accelerated resorption that is not compensated by a coupled increase in bone formation, has been attributed solely to elevated thyroid hormone levels. Evidence using mice lacking the thyroid hormone receptors α and β establishes a role for thyroid hormones in regulating bone remodeling but does not exclude an independent action of thyroid-stimulating hormone (TSH), levels of which are low in hyperthyroid states, even when thyroid hormones are normal, as after thyroxine supplementation and in subclinical hyperthyroidism. We show that TSH directly suppresses bone remodeling and that TSH receptor null mice have profound bone loss, suggesting that reduced TSH signaling contributes to hyperthyroid osteoporosis. TSH and its receptor could become valuable drug targets in treating bone loss.

Role of thyroid hormones in skeletal development and bone maintenance

Endocrine reviews, 2016

The skeleton is an exquisitely sensitive and archetypal T3-target tissue that demonstrates the critical role for thyroid hormones during development, linear growth, and adult bone turnover and maintenance. Thyrotoxicosis is an established cause of secondary osteoporosis, and abnormal thyroid hormone signaling has recently been identified as a novel risk factor for osteoarthritis. Skeletal phenotypes in genetically modified mice have faithfully reproduced genetic disorders in humans, revealing the complex physiological relationship between centrally regulated thyroid status and the peripheral actions of thyroid hormones. Studies in mutant mice also established the paradigm that T3 exerts anabolic actions during growth and catabolic effects on adult bone. Thus, the skeleton represents an ideal physiological system in which to characterize thyroid hormone transport, metabolism, and action during development, adulthood and in response to injury. Future analysis of T3 action in individua...

The regulatory role of thyroid hormones in bone cell growth and differentiation

The Journal of nutrition, 1995

The clinical effects of thyroid hormones on bone in hypo- and hyperthyroidism are well known but their fundamental role in the regulation of bone remodeling is still poorly understood. In this review the current literature is summarized and experimental data from our laboratory are presented. The direct stimulation of bone resorption by thyroid hormones in organ culture, which in part is mediated by prostaglandins and TGF-beta, and the effect of different agents thereon are reviewed. More recent data concerning thyroid hormone action in the osteoblastic cell line MC3T3E1, are summarized. From their effect on proliferation and alkaline phosphatase activity, we conclude that thyroid hormones accelerate osteoblastic differentiation. The regulation of the transcriptional expression of certain genes by nuclear T3 receptors and their effect on osteoblastic target genes like IGF-I are reviewed. In addition a novel role of triiodothyronine as inhibitor of growth factor induced transcription...

Intermittent recombinant TSH injections prevent ovariectomy-induced bone loss

Proceedings of the National Academy of Sciences, 2008

We recently described the direct effects of thyroid-stimulating hormone (TSH) on bone and suggested that the bone loss in hyperthyroidism, hitherto attributed solely to elevated thyroid hormone levels, could at least in part arise from accompanying decrements in serum TSH. Recent studies on both mice and human subjects provide compelling evidence that thyroid hormones and TSH have the opposite effects on the skeleton. Here, we show that TSH, when injected intermittently into rodents, even at intervals of 2 weeks, displays a powerful antiresorptive action in vivo. By virtue of this action, together with the possible anabolic effects shown earlier, TSH both prevents bone loss and restores the lost bone after ovariectomy. Importantly, the osteoclast inhibitory action of TSH persists ex vivo even after therapy is stopped for 4 weeks. This profound and lasting antiresorptive action of TSH is mimicked in cells that genetically overexpress the constitutively active ligand-independent TSH receptor (TSHR). In contrast, loss of function of a mutant TSHR (Pro 3 Leu at 556) in congenital hypothyroid mice activates osteoclast differentiation, confirming once again our premise that TSHRs have a critical role in regulating bone remodeling.

TNFα mediates the skeletal effects of thyroid-stimulating hormone

Proceedings of the National Academy of Sciences, 2006

We have shown recently that by acting on the thyroid-stimulating hormone (TSH) receptor (TSHR), TSH negatively regulates osteoclast differentiation. Both heterozygotic and homozygotic TSHR null mice are osteopenic with evidence of enhanced osteoclast differentiation. Here, we report that the accompanying elevation of TNFα, an osteoclastogenic cytokine, causes the increased osteoclast differentiation. This enhancement in TSHR −/− and TSHR +/− mice is abrogated in compound TSHR −/− /TNFα −/− and TSHR +/− /TNFα +/− mice, respectively. In parallel studies, we find that TSH directly inhibits TNFα production, reduces the number of TNFα-producing osteoclast precursors, and attenuates the induction of TNFα expression by IL-1, TNFα, and receptor activator of NF-κB ligand. TSH also suppresses osteoclast formation in murine macrophages and RAW-C3 cells. The suppression is more profound in cells that overexpress the TSHR than those transfected with empty vector. The overexpression of ligand-ind...

Thyroid Status during Skeletal Development Determines Adult Bone Structure and Mineralization

Molecular Endocrinology, 2007

Childhood hypothyroidism delays ossification and bone mineralization, whereas adult thyrotoxicosis causes osteoporosis. To determine how effects of thyroid hormone (T 3) during development manifest in adult bone, we characterized TR␣1 ؉/m ␤ ؉/؊ mice, which express a mutant T 3 receptor (TR) ␣1 with dominant-negative properties due to reduced ligand-binding affinity. Remarkably, adult TR␣1 ؉/m ␤ ؉/؊ mice had osteosclerosis with increased bone mineralization even though juveniles had delayed ossification. This phenotype was partially normalized by transient T 3 treatment of juveniles and fully reversed in compound TR␣1 ؉/m ␤ ؊/؊ mutant mice due to 10-fold elevated hormone levels that allow the mutant TR␣1 to bind T 3. By contrast, deletion of TR␤ in TR␣1 ؉/؉ ␤ ؊/ ؊ mice, which causes a 3-fold increase of hormone levels, led to osteoporosis in adults but advanced ossification in juveniles. T 3-target gene analysis revealed skeletal hypothyroidism in TR␣1 m/؉ ␤ ؉/؊ mice, thyrotoxicosis in TR␣1 ؉/؉ ␤ ؊/؊ mice, and euthyroidism in TR␣1 ؉/ ␤ ؊/؊ double mutants. Thus, TR␣1 regulates both skeletal development and adult bone maintenance, with euthyroid status during development being essential to establish normal adult bone structure and mineralization. (Molecular Endocrinology