Thyroid Hormone Actions and Bone Remodeling – The Role of the Wnt Signaling Pathway

Abstract

Thyroid hormones are indispensable for bone development and growth. Also in adults, bone mass maintenance is under the control of thyroid hormones. Preclinical and clinical studies established untreated hyperthyroidism as a cause for secondary osteoporosis with increased fracture risk. Thus, normal thyroid function is essential for bone health. Mechanistically, thyroid hormone excess accelerates bone turnover with predominant bone resorption. How thyroid hormones affect osteoblast and osteoclast functions, however, still remains ill-defined. The Wnt signaling pathway is a major determinant of bone mass and strength as it promotes osteoblastogenesis and bone formation, while inhibiting bone resorption. So far, only few studies investigated a possible link between thyroid hormones, bone metabolism and the Wnt pathway. In this review, we summarize the literature linking thyroid hormones to bone homeostasis through Wnt signaling and discuss its potential as a therapeutic approach to treat hyperthyroidism-induced bone loss.

Key words

thyroid hormones - thyroid disease - bone - bone turnover - Wnt signaling - sclerostin - dickkopf-1

Publication History

Received: 07 September 2019
Received: 16 December 2019

Accepted: 02 January 2020

Article published online:
20 January 2020

• References

• 1 Waung JA, Bassett JHD, Williams GR. Thyroid hormone metabolism in skeletal development and adult bone maintenance. Trends Endocrinol Metab 2012; 23: 155-162
• 2 Bassett JHD, Williams GR. Role of thyroid hormones in skeletal development and bone maintenance. Endocr Rev 2016; 37: 135-187
• 3 Tsourdi E, Lademann F, Siggelkow H. Auswirkungen von Schilddrüsenfunktionsstörungen auf den Knochen. Internist (Berl) 2018; 59: 661-667
• 4 Vestergaard P, Mosekilde L. Hyperthyroidism, bone mineral, and fracture risk—a meta-analysis. Thyroid 2003; 13: 585-593
• 5 Vestergaard P, Rejnmark L, Mosekilde L. Influence of hyper- and hypothyroidism, and the effects of treatment with antithyroid drugs and levothyroxine on fracture risk. Calcif Tissue Int 2005; 77: 139-144
• 6 Nicholls JJ, Brassill MJ, Williams GR. et al. The skeletal consequences of thyrotoxicosis. J Endocrinol 2012; 213: 209-221
• 7 Tsourdi E, Rijntjes E, Köhrle J. et al. Hyperthyroidism and hypothyroidism in male mice and their effects on bone mass, bone turnover, and the Wnt inhibitors sclerostin and dickkopf-1. Endocrinology 2015; 156: 3517-3527
• 8 Siddiqi A, Parsons MP, Lewis JL. et al. TR expression and function in human bone marrow stromal and osteoblast-like cells. J Clin Endocrinol Metab 2002; 87: 906-914
• 9 Gruber R, Czerwenka K, Wolf F. et al. Expression of the vitamin D receptor, of estrogen and thyroid hormone receptor alpha- and beta-isoforms, and of the androgen receptor in cultures of native mouse bone marrow and of stromal/osteoblastic cells. Bone 1999; 24: 465-473
• 10 Allain TJ, Yen PM, Flanagan AM. et al. The isoform-specific expression of the tri-iodothyronine receptor in osteoblasts and osteoclasts. Eur J Clin Invest 1996; 26: 418-425
• 11 Krieger NS, Stappenbeck TS, Stern PH. Characterization of specific thyroid hormone receptors in bone. J Bone Miner Res 1988; 3: 473-478
• 12 Kasono K, Sato K, Han DC. et al. Stimulation of alkaline phosphatase activity by thyroid hormone in mouse osteoblast-like cells (MC3T3-E1): a possible mechanism of hyperalkaline phosphatasia in hyperthyroidism. Bone Miner 1988; 4: 355-363
• 13 Capelo LP, Beber EH, Huang SA. et al. Deiodinase-mediated thyroid hormone inactivation minimizes thyroid hormone signaling in the early development of fetal skeleton. Bone 2008; 43: 921-930
• 14 Williams AJ, Robson H, Kester MHA. et al. Iodothyronine deiodinase enzyme activities in bone. Bone 2008; 43: 126-134
• 15 Klaushofer K, Hoffmann O, Gleispach H. et al. Bone-resorbing activity of thyroid hormones is related to prostaglandin production in cultured neonatal mouse calvaria. J Bone Miner Res 2009; 4: 305-312
• 16 Mundy GR, Shapiro JL, Bandelin JG. et al. Direct stimulation of bone resorption by thyroid hormones. J Clin Invest 1976; 58: 529-534
• 17 Allain TJ, Chambers TJ, Flanagan AM. et al. Tri-iodothyronine stimulates rat osteoclastic bone resorption by an indirect effect. J Endocrinol 1992; 133: 327-331
• 18 Siddiqi A, Burrin JM, Wood DF. et al. Tri-iodothyronine regulates the production of interleukin-6 and interleukin-8 in human bone marrow stromal and osteoblast-like cells. J Endocrinol 1998; 157: 453-461
• 19 Miura M, Tanaka K, Komatsu Y. et al. A novel interaction between thyroid hormones and 1,25(OH)2D3 in osteoclast formation. Biochem Biophys Res Commun 2002; 291: 987-994
• 20 Ernst M, Froesch ER. Triiodothyronine stimulates proliferation of osteoblast-like cells in serum-free culture. FEBS Lett 1987; 220: 163-166
• 21 Varga F, Rumpler M, Klaushofer K. Thyroid hormones increase insulin-like growth factor mRNA levels in the clonal osteoblastic cell line MC3T3-E1. FEBS Lett 1994; 345: 67-70
• 22 Fratzl-Zelman N, Hörandner H, Luegmayr E. et al. Effects of triiodothyronine on the morphology of cells and matrix, the localization of alkaline phosphatase, and the frequency of apoptosis in long-term cultures of MC3T3-E1 cells. Bone 1997; 20: 225-236
• 23 Cray JJ, Khaksarfard K, Weinberg SM. et al. Effects of thyroxine exposure on osteogenesis in mouse calvarial pre-osteoblasts. PLoS One 2013; 8: e69067
• 24 Varga F, Luegmayr E, Fratzl-Zelman N. et al. Tri-iodothyronine inhibits multilayer formation of the osteoblastic cell line, MC3T3-E1, by promoting apoptosis. J Endocrinol 1999; 160: 57-65
• 25 Luegmayr E, Varga F, Frank T. et al. Effects of triiodothyronine on morphology, growth behavior, and the actin cytoskeleton in mouse osteoblastic cells (MC3T3-E1). Bone 1996; 18: 591-599
• 26 Klaushofer K, Varga F, Glantschnig H. et al. The regulatory role of thyroid hormones in bone cell growth and differentiation. J Nutr 2018; 125: 1996S-2003S
• 27 Varga F, Rumpler M, Zoehrer R. et al. T3 affects expression of collagen I and collagen cross-linking in bone cell cultures. Biochem Biophys Res Commun 2010; 402: 180-185
• 28 Tokuda K, Otsuka T, Adachi S. et al. (-)-Epigallocatechin gallate inhibits thyroid hormone‑stimulated osteocalcin synthesis in osteoblasts. Mol Med Rep 2011; 4: 297-300
• 29 Banovac K, Koren E. Triiodothyronine stimulates the release of membrane-bound alkaline phosphatase in osteoblastic cells. Calcif Tissue Int 2000; 67: 460-465
• 30 Lerner UH, Ohlsson C. The WNT system: background and its role in bone. J Intern Med 2015; 277: 630-649
• 31 Duan P, Bonewald LF. The role of the wnt/β-catenin signaling pathway in formation and maintenance of bone and teeth. Int J Biochem Cell Biol 2016; 77: 23-29
• 32 Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: From human mutations to treatments. Nat Med 2013; 19: 179-192
• 33 Komori T. Regulation of osteoblast differentiation by transcription factors. J Cell Biochem 2006; 99: 1233-1239
• 34 Goldberg D, Polly P, Eisman JA. et al. Identification of an osteocalcin gene promoter sequence that binds AP1. J Cell Biochem 1996; 60: 447-457
• 35 Nishita M, Itsukushima S, Nomachi A. et al. Ror2/Frizzled Complex Mediates Wnt5a-Induced AP-1 Activation by Regulating Dishevelled Polymerization. Mol Cell Biol 2010; 30: 3610-3619
• 36 Bozec A, Bakiri L, Jimenez M. et al. Fra-2/AP-1 controls bone formation by regulating osteoblast differentiation and collagen production. J Cell Biol 2010; 190: 1093-1106
• 37 Martineau X, Abed É, Martel-Pelletier J. et al. Alteration of Wnt5a expression and of the non-canonical Wnt/PCP and Wnt/PKC-Ca2+ pathways in human osteoarthritis osteoblasts. PLoS One 2017; 12: e0180711
• 38 Kobayashi Y, Uehara S, Koide M. et al. The regulation of osteoclast differentiation by Wnt signals. Bonekey Rep 2015; 4: 713
• 39 Wang L, Shao YY, Ballock RT. Thyroid hormone interacts With the Wnt/NL-catenin signaling pathway in the terminal differentiation of growth plate chondrocytes. J Bone Min Res 2007; 22: 1988-1995
• 40 Wang L, Shao YY, Ballock RT. Thyroid hormone-mediated growth and differentiation of growth plate chondrocytes involves IGF-1 modulation of β-catenin signaling. J Bone Miner Res 2010; 25: 1138-1146
• 41 Wang L, Shao YY, Ballock RT. Thyroid hormone interacts with the Wnt/beta-catenin signaling pathway in the terminal differentiation of growth plate chondrocytes. J Bone Miner Res 2007; 22: 1988-1995
• 42 Wang L, Shao YY, Ballock RT. Carboxypeptidase Z (CPZ) links thyroid hormone and Wnt signaling pathways in growth plate chondrocytes. J Bone Miner Res 2009; 24: 265-273
• 43 Fernández-Pernas P, Fafián-Labora J, Lesende-Rodriguez I. et al. 3, 3′, 5-triiodo-L-thyronine increases in vitro chondrogenesis of mesenchymal stem cells from human umbilical cord stroma through SRC2. J Cell Biochem 2016; 117: 2097-2108
• 44 O’Shea PJ, Kim DW, Logan JG. et al. Advanced bone formation in mice with a dominant-negative mutation in the thyroid hormone receptor β gene due to activation of Wnt/β-catenin protein signaling. J Biol Chem 2012; 287: 17812-17822
• 45 Furuya F, Hanover JA, Cheng S-y. Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone beta receptor. Proc Natl Acad Sci 2006; 103: 1780-1785
• 46 Guigon CJ, Zhao L, Lu C. et al. Regulation of -catenin by a novel nongenomic action of thyroid hormone receptor. Mol Cell Biol 2008; 28: 4598-4608
• 47 Skah S, Uchuya-Castillo J, Sirakov M. et al. The thyroid hormone nuclear receptors and the Wnt/β-catenin pathway: An intriguing liaison. Dev Biol 2017; 422: 71-82
• 48 Kress E, Skah S, Sirakov M. et al. Cooperation between the thyroid hormone receptor TRalpha1 and the WNT pathway in the induction of intestinal tumorigenesis. Gastroenterology 2010; 138: 1863-1874
• 49 Guigon CJ, Kim DW, Zhu X. et al. Tumor suppressor action of liganded thyroid hormone receptor beta by direct repression of beta-catenin gene expression. Endocrinology 2010; 151: 5528-5536
• 50 Sirakov M, Skah S, Lone IN. et al. Multi-Level Interactions between the Nuclear Receptor TRα1 and the WNT Effectors β-Catenin/Tcf4 in the Intestinal Epithelium. PLoS One 2012; 7: e34162
• 51 Dentice M, Luongo C, Ambrosio R. et al. β-catenin regulates deiodinase levels and thyroid hormone signaling in colon cancer cells. YGAST 2012; 143: 1037-1047
• 52 Fujita K, Otsuka T, Kawabata T. et al. Wnt3a downregulates thyroid hormone-induced osteocalcin expression in osteoblasts. Exp Ther Med 2019; 18: 1921-1927
• 53 Skowrońska-Jóźwiak E, Lewandowski KC, Adamczewski Z. et al. Mechanisms of normalisation of bone metabolism during recovery from hyperthyroidism: potential role for sclerostin and parathyroid hormone. Int J Endocrinol 2015; 2015: 1-5
• 54 Tsourdi E, Wallaschofski H, Rauner M. et al. Thyrotropin serum levels are differentially associated with biochemical markers of bone turnover and stiffness in women and men: results from the SHIP cohorts. Osteoporos Int 2016; 27: 719-727
• 55 Cosman F, Crittenden DB, Adachi JD. et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016; 375: 1532-1543
• 56 McClung MR, Grauer A, Boonen S. et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014; 370: 412-420
• 57 Witcher PC, Miner SE, Horan DJ et al. Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition. JCI insight. 2018; 3:
• 58 Florio M, Gunasekaran K, Stolina M. et al. A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nat Commun 2016; 7: 11505
• 59 Tsourdi E, Colditz J, Lademann F. et al. The role of Dickkopf-1 in thyroid hormone-induced changes of bone remodeling in male mice. Endocrinology 2019; 160: 664-674
• 60 Tsourdi E, Lademann F, Ominsky MS. et al. Sclerostin blockade and zoledronic acid improve bone mass and strength in male mice with exogenous hyperthyroidism. Endocrinology 2017; 158: 3765-3777