Expanding the Role of Thyroid-Stimulating Hormone in Skeletal Physiology

Abstract

The dogma that thyroid-stimulating hormone (TSH) solely regulates the production of thyroid hormone from the thyroid gland has hampered research on its wider physiological roles. The action of pituitary TSH on the skeleton has now been well described; in particular, its action on osteoblasts and osteoclasts. It has also been recently discovered that the bone marrow microenvironment acts as an endocrine circuit with bone marrow-resident macrophages capable of producing a novel TSH-β subunit variant (TSH-βv), which may modulate skeletal physiology. Interestingly, the production of this TSH-βv is positively regulated by T3 accentuating such modulation in the presence of thyroid overactivity. Furthermore, a number of small molecule ligands acting as TSH agonists, which allosterically modulate the TSH receptor have been identified and may have similar modulatory influences on bone cells suggesting therapeutic potential. This review summarizes our current understanding of the role of TSH, TSH-β, TSH-βv, and small molecule agonists in bone physiology.

Keywords: TSH-receptor; TSH-β; TSH-βv; macrophage; osteoblast; osteoclast.

Figure 1

The hypothalamic–pituitary–thyroid–bone axis. This simplified figure illustrates the interactions of the pituitary hormone thyroid-stimulating hormone (TSH) and thyroid hormones T3 and T4 with bone. A negative feedback loop with origins in the thyroid and projections to the pituitary and hypothalamus is depicted. T3 and T4 hormone levels are maintained by such a loop. The role of TSH on bone has been hampered by the dogma that TSH exerts functions exclusively within the thyroid. However, within the past few decades, TSH has been show to exert physiologic effects on both osteoblasts and osteoclasts.

Figure 2

(A) A schematic comparison of the mouse native TSH-β and novel TSH-βv. Of note is a missing exon IV in the splice variant resulting in a smaller peptide of 8 vs 17 kDa for the full length. The intronic region is marked in black. Copyright (2013) Endocrinology and reproduced with permission from Oxford University Press (2). (B) A similar schematic outlining the human native TSH-β and novel TSH-βv gene arrangement [adapted from Baliram et al. (3)]. Copyright (2013) Endocrinology and reproduced with permission from Oxford University Press (2).

Figure 3

Small molecule MS 438 enhanced collagen gene expression in human osteoblast cells. The hFOB 1.19 cells were transformed into osteoblasts by treating with osteogenic stimulation/differentiation factors—20 μm of beta-glycerophosphate, 50 μg/ml of ascorbic acid, and 10⁻⁷M dexamethasone in refreshed media every 3 days along with or without 10 μM of MS 438 and 10 μM of PKA inhibitor (H 89). On day 10, cultures were terminated and gene expression analyzed by quantitative PCR and showed enhanced collagen gene expression.

Figure 4

Histologic staining of the thyroid-stimulating hormone receptor (TSHR)-KO mouse thyroid gland. Hematoxylin/eosin stained sections of WT (A,C) and TSHR-KO (B,D) thyroids. Fluorescent imaging of heterozygous (E) and TSHR-KO (F) green fluorescent protein reporter gene expression in the thyroid. Scanning electron micrographs for WT (G) and TSHR-KO (H) thyroid follicles [magnification: (A,B) 100; (C–F) 400; (G,H) 1,500]. Note the small but present thyroid cells in the TSHR-KO mouse, which has been used in a number of studies elucidating thyroid-stimulating hormone actions on bone. Copyright (2002) National Academy of Sciences, U.S.A (71).

Figure 5

(A) Thyroid hormone regulation of mouse thyroid-stimulating hormone (TSH)-βv in bone marrow cells. Here, bone marrow cells from mouse WT mice subcutaneously treated with T4 hormone pellets for 21 days showed greatly increased TSH-βv gene expression. Copyright (2016) Endocrinology and reproduced with permission from Oxford University Press (3). (B) Thyroid hormone regulation of mouse TSH-βv in the pituitary. The pituitary tissue from WT mice administered subcutaneous T4 pellets for 21 days showed suppression of both wild-type TSH-β and TSH-βv. This is in contrast to the bone marrow cells shown in (B). Copyright (2016) Endocrinology and reproduced with permission from Oxford University Press (3).

Figure 6

Schematic showing a collaborative effort among pituitary, thyroid, and macrophages in the local bone marrow microenvironment in regulating osteoclast and osteoblast activity through the release of thyroid-stimulating hormone (TSH)-β and TSH-βv. SM 438 is a small molecule agonist at the thyroid-stimulating hormone receptor. Solid dark arrows indicate modulatory effects of TSH-β, TSH-βv, and SM 438 on bone cells and the broken arrows indicate that such effects still need to be mapped.