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Analysis of Physiological Responses to Thyroid Hormones and Their Receptors in Bone

  • J. H. Duncan Bassett
  • Graham R. Williams
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1801)

Abstract

Thyroid hormone has profound effects on skeletal development and adult bone maintenance. Here, we review the current literature concerning thyroid hormone action in bone and cartilage in relation to human disease and animal models. We describe state-of-the-art imaging and biomechanical methods used to determine structural and functional parameters in the skeletal phenotyping of mouse models.

Key words

Thyroid hormone Thyroid hormone receptor Bone Skeleton Cartilage Chondrocyte Osteoblast Osteoclast X-ray microradiography Micro-CT Biomechanical testing Osteoporosis 

References

  1. 1.
    Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423(6937):332–336CrossRefPubMedGoogle Scholar
  2. 2.
    Zaidi M (2007) Skeletal remodeling in health and disease. Nat Med 13(7):791–801CrossRefPubMedGoogle Scholar
  3. 3.
    Long F (2012) Building strong bones: molecular regulation of the osteoblast lineage. Nat Rev Mol Cell Biol 13(1):27–38CrossRefGoogle Scholar
  4. 4.
    Bonewald LF, Johnson ML (2008) Osteocytes, mechanosensing and Wnt signaling. Bone 42(4):606–615CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Rice DP, Rice R (2008) Locate, condense, differentiate, grow and confront: developmental mechanisms controlling intramembranous bone and suture formation and function. Front Oral Biol 12:22–40CrossRefPubMedGoogle Scholar
  6. 6.
    Lassova L, Niu Z, Golden EB, Cohen AJ, Adams SL (2009) Thyroid hormone treatment of cultured chondrocytes mimics in vivo stimulation of collagen X mRNA by increasing BMP 4 expression. J Cell Physiol 219(3):595–605CrossRefPubMedGoogle Scholar
  7. 7.
    Jacenko O, LuValle PA, Olsen BR (1993) Spondylometaphyseal dysplasia in mice carrying a dominant negative mutation in a matrix protein specific for cartilage-to-bone transition. Nature 365(6441):56–61CrossRefPubMedGoogle Scholar
  8. 8.
    Bonjour JP, Chevalley T (2014) Pubertal timing, bone acquisition, and risk of fracture throughout life. Endocr Rev 35(5):820–847CrossRefPubMedGoogle Scholar
  9. 9.
    Raggatt LJ, Partridge NC (2010) Cellular and molecular mechanisms of bone remodeling. J Biol Chem 285(33):25103–25108CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bonewald LF (2011) The amazing osteocyte. J Bone Miner Res 26(2):229–238CrossRefPubMedGoogle Scholar
  11. 11.
    Heino TJ, Hentunen TA, Vaananen HK (2002) Osteocytes inhibit osteoclastic bone resorption through transforming growth factor-beta: enhancement by estrogen. J Cell Biochem 85(1):185–197CrossRefPubMedGoogle Scholar
  12. 12.
    Tolar J, Teitelbaum SL, Orchard PJ (2004) Osteopetrosis. N Engl J Med 351(27):2839–2849CrossRefPubMedGoogle Scholar
  13. 13.
    Baron R, Rawadi G (2007) Wnt signaling and the regulation of bone mass. Curr Osteoporos Rep 5(2):73–80CrossRefPubMedGoogle Scholar
  14. 14.
    Dallas SL, Prideaux M, Bonewald LF (2013) The osteocyte: an endocrine cell and more. Endocr Rev 34(5):658–690CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Murphy E, Gluer CC, Reid DM, Felsenberg D, Roux C, Eastell R, Williams GR (2010) Thyroid function within the upper normal range is associated with reduced bone mineral density and an increased risk of nonvertebral fractures in healthy euthyroid postmenopausal women. J Clin Endocrinol Metab 95(7):3173–3181CrossRefPubMedGoogle Scholar
  16. 16.
    van Rijn LE, Pop VJ, Williams GR (2014) Low bone mineral density is related to high physiological levels of free thyroxine in peri-menopausal women. Eur J Endocrinol 170(3):461–468CrossRefPubMedGoogle Scholar
  17. 17.
    Leader A, Ayzenfeld RH, Lishner M, Cohen E, Segev D, Hermoni D (2014) Thyrotropin levels within the lower normal range are associated with an increased risk of hip fractures in euthyroid women, but not men, over the age of 65 years. J Clin Endocrinol Metab 99(8):2665–2673CrossRefPubMedGoogle Scholar
  18. 18.
    Svare A, Nilsen TI, Asvold BO, Forsmo S, Schei B, Bjoro T, Langhammer A (2013) Does thyroid function influence fracture risk? Prospective data from the HUNT2 study, Norway. Eur J Endocrinol 169(6):845–852CrossRefPubMedGoogle Scholar
  19. 19.
    Blum MR, Bauer DC, Collet TH, Fink HA, Cappola AR, da Costa BR, Wirth CD, Peeters RP, Asvold BO, den Elzen WP, Luben RN, Imaizumi M, Bremner AP, Gogakos A, Eastell R, Kearney PM, Strotmeyer ES, Wallace ER, Hoff M, Ceresini G, Rivadeneira F, Uitterlinden AG, Stott DJ, Westendorp RG, Khaw KT, Langhammer A, Ferrucci L, Gussekloo J, Williams GR, Walsh JP, Juni P, Aujesky D, Rodondi N, Thyroid Studies C (2015) Subclinical thyroid dysfunction and fracture risk: a meta-analysis. JAMA 313(20):2055–2065CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Huffmeier U, Tietze HU, Rauch A (2007) Severe skeletal dysplasia caused by undiagnosed hypothyroidism. Eur J Med Genet 50(3):209–215CrossRefPubMedGoogle Scholar
  21. 21.
    Rivkees SA, Bode HH, Crawford JD (1988) Long-term growth in juvenile acquired hypothyroidism: the failure to achieve normal adult stature. N Engl J Med 318(10):599–602CrossRefPubMedGoogle Scholar
  22. 22.
    Eriksen EF, Mosekilde L, Melsen F (1986) Kinetics of trabecular bone resorption and formation in hypothyroidism: evidence for a positive balance per remodeling cycle. Bone 7(2):101–108CrossRefPubMedGoogle Scholar
  23. 23.
    Abrahamsen B, Jorgensen HL, Laulund AS, Nybo M, Bauer DC, Brix TH, Hegedus L (2015) The excess risk of major osteoporotic fractures in hypothyroidism is driven by cumulative hyperthyroid as opposed to hypothyroid time: an observational register-based time-resolved cohort analysis. J Bone Miner Res 30(5):898–905CrossRefPubMedGoogle Scholar
  24. 24.
    Bassett JH, Williams GR (2016) Role of thyroid hormones in skeletal development and bone maintenance. Endocr Rev 37(2):135–187CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Segni M, Leonardi E, Mazzoncini B, Pucarelli I, Pasquino AM (1999) Special features of Graves' disease in early childhood. Thyroid 9(9):871–877CrossRefPubMedGoogle Scholar
  26. 26.
    Rasmussen SA, Yazdy MM, Carmichael SL, Jamieson DJ, Canfield MA, Honein MA (2007) Maternal thyroid disease as a risk factor for craniosynostosis. Obstet Gynecol 110(2 Pt 1):369–377CrossRefPubMedGoogle Scholar
  27. 27.
    Bours SP, van Geel TA, Geusens PP, Janssen MJ, Janzing HM, Hoffland GA, Willems PC, van den Bergh JP (2011) Contributors to secondary osteoporosis and metabolic bone diseases in patients presenting with a clinical fracture. J Clin Endocrinol Metab 96(5):1360–1367CrossRefPubMedGoogle Scholar
  28. 28.
    Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, Keogh JM, Henning E, Reinemund J, Gevers E, Sarri M, Downes K, Offiah A, Albanese A, Halsall D, Schwabe JW, Bain M, Lindley K, Muntoni F, Khadem FV, Dattani M, Farooqi IS, Gurnell M, Chatterjee K (2012) A mutation in the thyroid hormone receptor alpha gene. N Engl J Med 366(3):243–249CrossRefPubMedGoogle Scholar
  29. 29.
    Moran C, Schoenmakers N, Agostini M, Schoenmakers E, Offiah A, Kydd A, Kahaly G, Mohr-Kahaly S, Rajanayagam O, Lyons G, Wareham N, Halsall D, Dattani M, Hughes S, Gurnell M, Park SM, Chatterjee K (2013) An adult female with resistance to thyroid hormone mediated by defective thyroid hormone receptor alpha. J Clin Endocrinol Metab 98(11):4254–4261CrossRefPubMedGoogle Scholar
  30. 30.
    van Mullem A, van Heerebeek R, Chrysis D, Visser E, Medici M, Andrikoula M, Tsatsoulis A, Peeters R, Visser TJ (2012) Clinical phenotype and mutant TRalpha1. N Engl J Med 366(15):1451–1453CrossRefPubMedGoogle Scholar
  31. 31.
    van Mullem AA, Chrysis D, Eythimiadou A, Chroni E, Tsatsoulis A, de Rijke YB, Visser WE, Visser TJ, Peeters RP (2013) Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRalpha1 receptor: consequences of LT4 treatment. J Clin Endocrinol Metab 98(7):3029–3038CrossRefPubMedGoogle Scholar
  32. 32.
    Tylki-Szymanska A, Acuna-Hidalgo R, Krajewska-Walasek M, Lecka-Ambroziak A, Steehouwer M, Gilissen C, Brunner HG, Jurecka A, Rozdzynska-Swiatkowska A, Hoischen A, Chrzanowska KH (2015) Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor alpha gene (THRA). J Med Genet 52(5):312–316CrossRefPubMedGoogle Scholar
  33. 33.
    Moran C, Agostini M, Visser WE, Schoenmakers E, Schoenmakers N, Offiah AC, Poole K, Rajanayagam O, Lyons G, Halsall D, Gurnell M, Chrysis D, Efthymiadou A, Buchanan C, Aylwin S, Chatterjee KK (2014) Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)alpha1 and TRalpha2: clinical, biochemical, and genetic analyses of three related patients. Lancet Diabetes Endocrinol 2(8):619–626CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Refetoff S, DeWind LT, DeGroot LJ (1967) Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J Clin Endocrinol Metab 27(2):279–294CrossRefPubMedGoogle Scholar
  35. 35.
    Sakurai A, Takeda K, Ain K, Ceccarelli P, Nakai A, Seino S, Bell GI, Refetoff S, DeGroot LJ (1989) Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta. Proc Natl Acad Sci U S A 86(22):8977–8981CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Weiss RE, Refetoff S (2000) Resistance to thyroid hormone. Rev Endocr Metab Disord 1(1–2):97–108CrossRefPubMedGoogle Scholar
  37. 37.
    Refetoff S, Dumitrescu AM (2007) Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab 21(2):277–305CrossRefPubMedGoogle Scholar
  38. 38.
    Weiss RE, Dumitrescu A, Refetoff S (2010) Approach to the patient with resistance to thyroid hormone and pregnancy. J Clin Endocrinol Metab 95(7):3094–3102CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Capelo LP, Beber EH, Fonseca TL, Gouveia CH (2009) The monocarboxylate transporter 8 and L-type amino acid transporters 1 and 2 are expressed in mouse skeletons and in osteoblastic MC3T3-E1 cells. Thyroid 19(2):171–180CrossRefPubMedGoogle Scholar
  40. 40.
    Williams AJ, Robson H, Kester MH, van Leeuwen JP, Shalet SM, Visser TJ, Williams GR (2008) Iodothyronine deiodinase enzyme activities in bone. Bone 43(1):126–134CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Abe S, Namba N, Abe M, Fujiwara M, Aikawa T, Kogo M, Ozono K (2012) Monocarboxylate transporter 10 functions as a thyroid hormone transporter in chondrocytes. Endocrinology 153(8):4049–4058CrossRefPubMedGoogle Scholar
  42. 42.
    Waung JA, Bassett JH, Williams GR (2012) Thyroid hormone metabolism in skeletal development and adult bone maintenance. Trends Endocrinol Metab 23(4):155–162CrossRefPubMedGoogle Scholar
  43. 43.
    Capelo LP, Beber EH, Huang SA, Zorn TM, Bianco AC, Gouveia CH (2008) Deiodinase-mediated thyroid hormone inactivation minimizes thyroid hormone signaling in the early development of fetal skeleton. Bone 43(5):921–930CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Gouveia CH, Christoffolete MA, Zaitune CR, Dora JM, Harney JW, Maia AL, Bianco AC (2005) Type 2 iodothyronine selenodeiodinase is expressed throughout the mouse skeleton and in the MC3T3-E1 mouse osteoblastic cell line during differentiation. Endocrinology 146(1):195–200CrossRefPubMedGoogle Scholar
  45. 45.
    Dentice M, Bandyopadhyay A, Gereben B, Callebaut I, Christoffolete MA, Kim BW, Nissim S, Mornon JP, Zavacki AM, Zeold A, Capelo LP, Curcio-Morelli C, Ribeiro R, Harney JW, Tabin CJ, Bianco AC (2005) The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate. Nat Cell Biol 7(7):698–705CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Bassett JH, Boyde A, Howell PG, Bassett RH, Galliford TM, Archanco M, Evans H, Lawson MA, Croucher P, St Germain DL, Galton VA, Williams GR (2010) Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts. Proc Natl Acad Sci U S A 107(16):7604–7609CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ (2006) Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126(4):789–799CrossRefPubMedGoogle Scholar
  48. 48.
    O’Shea PJ, Harvey CB, Suzuki H, Kaneshige M, Kaneshige K, Cheng SY, Williams GR (2003) A thyrotoxic skeletal phenotype of advanced bone formation in mice with resistance to thyroid hormone. Mol Endocrinol 17(7):1410–1424CrossRefPubMedGoogle Scholar
  49. 49.
    Bassett JH, Williams GR (2009) The skeletal phenotypes of TRalpha and TRbeta mutant mice. J Mol Endocrinol 42(4):269–282CrossRefPubMedGoogle Scholar
  50. 50.
    Chassande O, Fraichard A, Gauthier K, Flamant F, Legrand C, Savatier P, Laudet V, Samarut J (1997) Identification of transcripts initiated from an internal promoter in the c-erbA alpha locus that encode inhibitors of retinoic acid receptor-alpha and triiodothyronine receptor activities. Mol Endocrinol 11(9):1278–1290PubMedGoogle Scholar
  51. 51.
    Flamant F, Gauthier K (2012) Thyroid hormone receptors: the challenge of elucidating isotype-specific functions and cell-specific response. Biochim Biophys Acta 1830(7):3900–3907CrossRefPubMedGoogle Scholar
  52. 52.
    Flamant F, Samarut J (2003) Thyroid hormone receptors: lessons from knockout and knock-in mutant mice. Trends Endocrinol Metab 14(2):85–90CrossRefPubMedGoogle Scholar
  53. 53.
    O’Shea PJ, Williams GR (2002) Insight into the physiological actions of thyroid hormone receptors from genetically modified mice. J Endocrinol 175(3):553–570CrossRefPubMedGoogle Scholar
  54. 54.
    Salto C, Kindblom JM, Johansson C, Wang Z, Gullberg H, Nordstrom K, Mansen A, Ohlsson C, Thoren P, Forrest D, Vennstrom B (2001) Ablation of TRalpha2 and a concomitant overexpression of alpha1 yields a mixed hypo- and hyperthyroid phenotype in mice. Mol Endocrinol 15(12):2115–2128PubMedGoogle Scholar
  55. 55.
    Wikstrom L, Johansson C, Salto C, Barlow C, Campos Barros A, Baas F, Forrest D, Thoren P, Vennstrom B (1998) Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J 17(2):455–461CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Gothe S, Wang Z, Ng L, Kindblom JM, Barros AC, Ohlsson C, Vennstrom B, Forrest D (1999) Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation. Genes Dev 13(10):1329–1341CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Kindblom JM, Gevers EF, Skrtic SM, Lindberg MK, Gothe S, Tornell J, Vennstrom B, Ohlsson C (2005) Increased adipogenesis in bone marrow but decreased bone mineral density in mice devoid of thyroid hormone receptors. Bone 36(4):607–616CrossRefPubMedGoogle Scholar
  58. 58.
    Kindblom JM, Gothe S, Forrest D, Tornell J, Vennstrom B, Ohlsson C (2001) GH substitution reverses the growth phenotype but not the defective ossification in thyroid hormone receptor alpha 1−/−beta−/− mice. J Endocrinol 171(1):15–22CrossRefPubMedGoogle Scholar
  59. 59.
    Wallis K, Dudazy S, van Hogerlinden M, Nordstrom K, Mittag J, Vennstrom B (2010) The thyroid hormone receptor alpha1 protein is expressed in embryonic postmitotic neurons and persists in most adult neurons. Mol Endocrinol 24(10):1904–1916CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Fraichard A, Chassande O, Plateroti M, Roux JP, Trouillas J, Dehay C, Legrand C, Gauthier K, Kedinger M, Malaval L, Rousset B, Samarut J (1997) The T3R alpha gene encoding a thyroid hormone receptor is essential for post-natal development and thyroid hormone production. EMBO J 16(14):4412–4420CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Gauthier K, Chassande O, Plateroti M, Roux JP, Legrand C, Pain B, Rousset B, Weiss R, Trouillas J, Samarut J (1999) Different functions for the thyroid hormone receptors TRalpha and TRbeta in the control of thyroid hormone production and post-natal development. EMBO J 18(3):623–631CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Bassett JH, Nordstrom K, Boyde A, Howell PG, Kelly S, Vennstrom B, Williams GR (2007) Thyroid status during skeletal development determines adult bone structure and mineralization. Mol Endocrinol 21(8):1893–1904CrossRefPubMedGoogle Scholar
  63. 63.
    Gauthier K, Plateroti M, Harvey CB, Williams GR, Weiss RE, Refetoff S, Willott JF, Sundin V, Roux JP, Malaval L, Hara M, Samarut J, Chassande O (2001) Genetic analysis reveals different functions for the products of the thyroid hormone receptor alpha locus. Mol Cell Biol 21(14):4748–4760CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Parrilla R, Mixson AJ, McPherson JA, McClaskey JH, Weintraub BD (1991) Characterization of seven novel mutations of the c-erbA beta gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two "hot spot" regions of the ligand binding domain. J Clin Invest 88(6):2123–2130CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Kaneshige M, Suzuki H, Kaneshige K, Cheng J, Wimbrow H, Barlow C, Willingham MC, Cheng S (2001) A targeted dominant negative mutation of the thyroid hormone alpha 1 receptor causes increased mortality, infertility, and dwarfism in mice. Proc Natl Acad Sci U S A 98(26):15095–15100CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    O’Shea PJ, Bassett JH, Cheng SY, Williams GR (2006) Characterization of skeletal phenotypes of TRalpha1 and TRbeta mutant mice: implications for tissue thyroid status and T3 target gene expression. Nucl Recept Signal 4:e011PubMedPubMedCentralGoogle Scholar
  67. 67.
    O’Shea PJ, Bassett JH, Sriskantharajah S, Ying H, Cheng SY, Williams GR (2005) Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor alpha1 or beta. Mol Endocrinol 19(12):3045–3059CrossRefPubMedGoogle Scholar
  68. 68.
    Bassett JH, Boyde A, Zikmund T, Evans H, Croucher PI, Zhu X, Park JW, Cheng SY, Williams GR (2014) Thyroid hormone receptor alpha mutation causes a severe and thyroxine-resistant skeletal dysplasia in female mice. Endocrinology 155(9):3699–3712CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Quignodon L, Vincent S, Winter H, Samarut J, Flamant F (2007) A point mutation in the activation function 2 domain of thyroid hormone receptor alpha1 expressed after CRE-mediated recombination partially recapitulates hypothyroidism. Mol Endocrinol 21(10):2350–2360CrossRefPubMedGoogle Scholar
  70. 70.
    Desjardin C, Charles C, Benoist-Lasselin C, Riviere J, Gilles M, Chassande O, Morgenthaler C, Laloe D, Lecardonnel J, Flamant F, Legeai-Mallet L, Schibler L (2014) Chondrocytes play a major role in the stimulation of bone growth by thyroid hormone. Endocrinology 155(8):3123–3135CrossRefPubMedGoogle Scholar
  71. 71.
    Bassett JH, O’Shea PJ, Sriskantharajah S, Rabier B, Boyde A, Howell PG, Weiss RE, Roux JP, Malaval L, Clement-Lacroix P, Samarut J, Chassande O, Williams GR (2007) Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism. Mol Endocrinol 21(5):1095–1107CrossRefPubMedGoogle Scholar
  72. 72.
    Forrest D, Hanebuth E, Smeyne RJ, Everds N, Stewart CL, Wehner JM, Curran T (1996) Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue-specific modulation of receptor function. EMBO J 15(12):3006–3015PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Bassett JH, Williams GR (2008) Critical role of the hypothalamic-pituitary-thyroid axis in bone. Bone 43(3):418–426CrossRefPubMedGoogle Scholar
  74. 74.
    Kaneshige M, Kaneshige K, Zhu X, Dace A, Garrett L, Carter TA, Kazlauskaite R, Pankratz DG, Wynshaw-Boris A, Refetoff S, Weintraub B, Willingham MC, Barlow C, Cheng S (2000) Mice with a targeted mutation in the thyroid hormone beta receptor gene exhibit impaired growth and resistance to thyroid hormone. Proc Natl Acad Sci U S A 97(24):13209–13214CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Abel ED, Ahima RS, Boers ME, Elmquist JK, Wondisford FE (2001) Critical role for thyroid hormone receptor beta2 in the regulation of paraventricular thyrotropin-releasing hormone neurons. J Clin Invest 107(8):1017–1023CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Demidenko E (1994) Kolmogorov-Smirnov Test for image comparison. In: Laganá A, Gavrilova ML, Kumar V, Mun Y, CJK T, Gervasi O (eds) Computational science and its applications – ICCSA 2004. Lecture notes in computer science, vol 3046. Springer, Berlin, pp 933–939CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Medicine, Molecular Endocrinology LaboratoryImperial College LondonLondonUK

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