Role of thyroid hormones in skeletal development and bone maintenance J.H. Duncan Bassett, Graham R. Williams Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, Hammersmith Campus, Du Cane Rd, London, W12 0NN, UK 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. Thyrotox- icosis 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 individual skeletal cell lineages will provide new insights into cell-specific molecular mechanisms and may ultimately identify novel therapeutic targets for chronic degenerative diseases such as osteoporosis and osteo- arthritis. This review provides a comprehensive analysis of the current state-of-the-art. I. Introduction don in 1878 linking cretinism, myxedema and cachexia strumipriva (decay due to lack of goiter) as a single entity. HE ESSENTIAL REQUIREMENT for thyroid hor- Indeed, in a lecture to the German Society of Surgery in T mones during linear growth and skeletal maturation 1883, the Swiss Nobel Laureate Theodor Kocher de- is well established and has been recognized for 125 years. scribed cachexia strumipriva as a specific disease that in- Indeed, the association between goiter, cretinism, devel- cluded “decreased growth in height” following removal of opmental retardation and short stature had been known the thyroid gland. Ultimately, these events led to the first for centuries, and the therapeutic use of burnt sponge and organotherapy for hypothyroidism by George Murray in seaweed in the treatment of goiter dates back to 1600 BC 1891, although the ancient Chinese had used animal thy- in China. Paracelcus provided the first clinical description roid tissue as a treatment for goiter as early as 643 AD of endemic goiter and congenital idiocy in 1603. Between (1–3). 1811–1813 Bernard Courtois discovered iodine, Joseph Alongside the emergence of hypothyroidism as a rec- Gay-Lussac identified it as an element and Humphrey ognized disease, Charles de Saint-Yves, Antonio Testa and Davy recognized it as a halogen (1). However Jean-Fran- Guiseppe Flajani reported the first cases of goiter, palpi- cois Coindet, in 1820, was the first to use iodine as a tations and exophthalmos between 1722–1802, although treatment for goiter and Gaspard Chatin, in the 1850’s, these features were not linked at that time. Caleb Parry had was the first to show that iodine in plants prevented cre- recognized in 1825, while Robert Graves independently tinism and goiter in endemic regions. Thomas Curling, in recognized and also published in 1835, the link between 1850, described cretinism in association with athyreosis, hypertrophic goiter and exophthalmos (1, 3). Carl Adolf while William Gull provided the causal link between lack von Basedow extended Graves’ description in 1840 by of a thyroid gland and cretinism in 1873. William Ord adding palpitations, weight loss, diarrhea, tremor, rest- extended Gull’s observations and chaired the first detailed lessness, perspiration, amenorrhea, myxedema of the report on hypothyroidism by the Clinical Society of Lon- lower leg and orbital tissue hypertrophy to describe the ISSN Print 0163-769X ISSN Online 1945-7189 Abbreviations: Printed in USA Copyright © 2016 by the Endocrine Society Received September 23, 2015. Accepted January 29, 2016. doi: 10.1210/er.2015-1106 Endocrine Reviews press.endocrine.org/journal/edrv 1 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 February 2016. at 05:18 For personal use only. No other uses without permission. All rights reserved. 2 Thyroid hormones and bone Endocrine Reviews syndrome more completely. In 1886, Paul Möbius pro- (fT3), free T4 (fT4) and TSH of 65% (14), and candidate posed the cause of these symptoms was increased thyroid function and Murray supported this view in 1891 at the Figure 1. time of his organotherapy for hypothyroidism (1, 3). Co- incidentally, in the same year of 1891, Friedrich Von Recklinghausen reported a patient with thyrotoxicosis and multiple fractures and was the first to identify the relationship between the thyroid and the adult skeleton (4, 5). Since then a role for thyroid hormones in bone and mineral metabolism has become well established. During the last 25 years the role of thyroid hormones in bone and cartilage biology has attracted considerable and growing attention, leading to important advances in un- derstanding the consequences of thyroid disease on the developing and adult skeleton. Major progress in defining the mechanisms of thyroid hormone action in bone has followed and led to new insights into thyroid-related skel- etal disorders. As a result, the role of the hypothalamic- pituitary-thyroid (HPT) axis in skeletal pathophysiology has become a high profile subject. It is only now that ex- perimental tools are becoming available to allow deter- mination of the precise cellular and molecular mechanisms that underlie thyroid hormone actions in the skeleton. This review will discuss our current understanding by con- sidering the published literature up to December 31st 2015. II. Thyroid hormone physiology A. Hypothalamic-pituitary-thyroid axis Synthesis and release of the prohormone 3,5,3Ј,5Ј-L- tetraiodothyronine (thyroxine, T4) and the active thyroid hormone 3,5,3Ј-L-triiodothyronine (T3) are controlled by a negative feedback loop mediated by the HPT axis (Figure 1) (6). Thyrotropin releasing hormone (TRH) is secreted by the hypothalamic paraventricular nucleus and acts on pituitary thyrotrophs to stimulate release of thyrotropin (thyroid-stimulating hormone, TSH). TSH subsequently acts via the TSH receptor (TSHR) on thyroid follicular cells to stimulate cell proliferation and the synthesis and secretion of T4 and T3 (7). T3, derived predominantly from local metabolism of T4, acts via thyroid hormone receptors ␣ and ␤ (TR␣,TR␤) in the hypothalamus and pituitary to inhibit synthesis and secretion of TRH and TSH (8–11). Normal euthyroid status is maintained by a negative feedback loop that establishes a physiological in- verse relationship between TSH and circulating T3 and T4, thus defining the HPT axis set point (12, 13). Systemic Hypothalamic-pituitary-thyroid axis thyroid hormone and TSH concentrations vary signifi- cantly among individuals, indicating each person has a The thyroid gland secretes the prohormone T4 and the active hormone T3 and circulating concentrations are regulated by a classical endocrine unique set point (12). Twin studies indicate the set point negative feedback loop that maintains an inverse physiological is genetically determined with heritability for free T3 relationship between TSH, and T4 and T3. The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 February 2016. at 05:18 For personal use only. No other uses without permission. All rights reserved. doi: 10.1210/er.2015-1106 press.endocrine.org/journal/edrv 3 gene and genome wide association studies (GWAS) have transmembrane domains (Figure 2) (18). Although cAMP identified quantitative trait loci (15–17). is the major second messenger following activation of the TSHR in thyroid follicular cells, alternative downstream B. TSH action signaling pathways have been implicated in both thyroid The glycoprotein hormone TSH is composed of com- and extrathyroidal tissues (19–22). In the thyroid the mon ␣- and unique ␤-subunits. The TSHR is a G-protein TSHR associates with various G proteins (23), and G␣s coupled receptor consisting of ligand binding, ecto- and and G␣q are thought to compete for activation by the TSHR (20, 24). Figure 2. C. Extrathyroidal actions of TSH The TSHR has been proposed to have diverse functions in extrathy- roidal tissues, although their physi- ological importance has not been es- tablished. Thus, TSHR expression has been reported in anterior pitu- itary, brain, pars tuberalis, bone, or- bital preadipocytes and fibroblasts, kidney, ovary and testis, skin and hair follicles, heart, adipose tissue, as well as hematopoietic and immune cells (19, 25–28). These data suggest direct actions of TSH, for example, in the regulation of seasonal repro- duction (29–31), bone turnover (32), pathogenesis of Graves’ or- bitopathy (33–35), and immuno- modulatory responses in the bone marrow (36–43), gut (42, 43) and skeleton (38). D. Thyroid hormone transport Uptake of thyroid hormones into peripheral tissues and entry into tar- get cells is mediated by specific mem- brane transporter proteins (Figure 3) (44), including monocarboxylate transporters MCT8 and MCT10, the organic anion transporter pro- tein-1C1 (OATP1C1), and the non- specific L-type amino acid transport- ers 1 and 2 (LAT1, LAT2) (45). The best-characterized specific