CoChat
Sign Up
Cited by 691Bone Metabolism and DiseasesBone health and osteoporosis researchThyroid Disorders and Treatments

TSH Is a Negative Regulator of Skeletal Remodeling

Open access
Abe, Etsuko, Marians, Russell C, Yu, Wanqin, Wu, Xue-Bin, Ando, Takao, Li, Yanan, Iqbal, Jameel, Eldeiry, Leslie +4 more·2003·Cell
DOI 10.1016/s0092-8674(03)00771-2
Open this paper in CoChat — free accountOpen PDF

Abstract

The established function of thyroid stimulating hormone (TSH) is to promote thyroid follicle development and hormone secretion. The osteoporosis associated with hyperthyroidism is traditionally viewed as a secondary consequence of altered thyroid function. We provide evidence for direct effects of TSH on both components of skeletal remodeling, osteoblastic bone formation, and osteoclastic bone resorption, mediated via the TSH receptor (TSHR) found on osteoblast and osteoclast precursors. Even a 50% reduction in TSHR expression produces profound osteoporosis (bone loss) together with focal osteosclerosis (localized bone formation). TSH inhibits osteoclast formation and survival by attenuating JNK/c-jun and NFkappaB signaling triggered in response to RANK-L and TNFalpha. TSH also inhibits osteoblast differentiation and type 1 collagen expression in a Runx-2- and osterix-independent manner by downregulating Wnt (LRP-5) and VEGF (Flk) signaling. These studies define a role for TSH as a single molecular switch in the independent control of both bone formation and resorption.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/s0092-8674(03)00771-2

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • TSH and thyroid hormones are negative regulators of bone remodeling via TSH receptors on osteoclast and osteoblast precursors.

    “TSH and thyroid hormones are negative regulators of bone remodeling via TSH receptors on osteoclast and osteoblast precursors [35].”

    From Effects of levothyroxine therapy on bone and mineral metabolism in hypothyroidism: a systematic review and meta-analysis (2025) · cites this paper as [35]

    The Abstract and Introduction support that TSH negatively regulates bone remodeling through TSH receptors on osteoclast and osteoblast precursors. The Discussion instead distinguishes thyroid hormones from TSH, associating thyroid hormones with skeletal morphogenesis rather than showing that they negatively regulate remodeling via TSH receptors. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Part of this paper’s reference list could not be split into single entries.

Flagged first, then by citations

Research works printed but not linked: 37

  1. [1]1. Abe, E ∙ Yamamoto, M ∙ Taguchi, Y ... Essential requirement of BMPs-2/4 for both osteoblast and osteoclast formation in murine bone marrow cultures from adult miceantagonism by noggin J. Bone Miner. Res. 2000; 4:663-673 Google Scholar
  2. [2]2. Ando, T ∙ Lauf, R ∙ Moran, T ... A monoclonal thyroid-stimulating antibody J. Clin. Invest. 2002; 110:1667-1674 Crossref Scopus (112) PubMed Google Scholar
  3. [3]3. Bagriacik, E.U ∙ Klein, J.R The thyrotropin (thyroid-stimulating hormone) receptor is expressed on murine dendritic cells and on a subset of CD45RB high lymph node T cellsfunctional role for thyroid-stimulating hormone during immune activation J. Immunol. 2000; 164:6158-6165 PubMed Google Scholar
  4. [4]4. Blair, H.C ∙ Zaidi, M ∙ Schlesinger, P.H Mechanisms balancing skeletal matrix synthesis and degradation Biochem. J. 2002; 364:329-341 Crossref Scopus (138) PubMed Google Scholar
  5. [5]5. Bordier, P ∙ Miravet, L ∙ Matrajt, H ... Bone changes in adult patients with abnormal thyroid function (with special reference to 45Ca kinetics and quantitative histology) Proc. R. Soc. Med. 1967; 60:1132-1134 PubMed Google Scholar
  6. [6]6. Britto, J.M ∙ Fenton, A.J ∙ Holloway, W.R ... Osteoblasts mediate thyroid hormone stimulation of osteoclastic bone resorption Endocrinology. 1994; 134:169-176 Crossref Scopus (185) PubMed Google Scholar
  7. [7]7. Davies, T.F ∙ Marians, R ∙ Latif, R The TSH receptor reveals itself J. Clin. Invest. 2002; 110:161-164 Crossref Scopus (204) PubMed Google Scholar
  8. [8]8. Endo, T ∙ Ohta, K ∙ Haraguchi, K ... Cloning and functional expression of a thyrotropin receptor cDNA from rat fat cells J. Biol. Chem. 1995; 270:10833-10837 Crossref Scopus (118) PubMed Google Scholar
  9. [9]9. Gong, Y ∙ Slee, R.B ∙ Fukai, N ... LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development Cell. 2001; 107:513-523 Full Text Full Text (PDF) Scopus (1925) PubMed Google Scholar
  10. [10]10. Gothe, S ∙ Wang, Z ∙ Ng, L ... Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation Genes Dev. 1999; 13:1329-1341 Crossref Scopus (380) PubMed Google Scholar
  11. [11]11. Greenspan, S.L ∙ Greenspan, F.S The effect of thyroid hormone on skeletal integrity Ann. Intern. Med. 1999; 130:750-758 Crossref Scopus (207) PubMed Google Scholar
  12. [12]12. Hofbauer, L.C ∙ Kluger, S ∙ Kuhne, C.A ... Detection and characterization of RANK ligand and osteoprotegerin in the thyroid gland J. Cell. Biochem. 2002; 86:642-650 Crossref Scopus (39) PubMed Google Scholar
  13. [13]13. Inoue, M ∙ Tawata, M ∙ Yokomori, N ... Expression of thyrotropin receptor on clonal osteoblast-like rat osteosarcoma cells Thyroid. 1998; 8:1059-1064 Crossref Scopus (44) PubMed Google Scholar
  14. [14]14. Iotsova, V ∙ Caamano, J ∙ Loy, J ... Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2 Nat. Med. 1997; 3:1285-1289 Crossref Scopus (904) PubMed Google Scholar
  15. [15]15. Karsenty, G ∙ Wagner, E.F Reaching a genetic and molecular understanding of skeletal development Dev. Cell. 2002; 2:389-406 Full Text Full Text (PDF) Scopus (1252) PubMed Google Scholar
  16. [17]17. Kawaida, R ∙ Ohtsuka, T ∙ Jokutsu, J ... Jun dimerization protein 2 (JDP2), a member of the AP-1 family of transcription factor, mediates osteoclast differentiation induced by RANKL J. Exp. Med. 2003; 197:1029-1035 Crossref Scopus (78) PubMed Google Scholar
  17. [18]18. Khosla, S Minireviewthe OPG/RANKL/RANK system Endocrinology. 2001; 142:5050-5055 Crossref Scopus (923) PubMed Google Scholar
  18. [19]19. Kohn, L.D ∙ Shimura, H ∙ Shimura, Y ... The thyrotropin receptor Vitam. Horm. 1995; 50:287-384 Crossref Scopus (137) PubMed Google Scholar
  19. [21]21. Lecka-Czernik, B ∙ Gubrij, I ∙ Moerman, E.J ... Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPARgamma2 J. Cell. Biochem. 1999; 74:357-371 Crossref Scopus (455) PubMed Google Scholar
  20. [22]22. Manolagas, S.C ∙ Jilka, R.L Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis N. Engl. J. Med. 1995; 332:305-311 Crossref Scopus (1606) PubMed Google Scholar
  21. [23]23. Marians, R.C ∙ Ng, L ∙ Blair, H.C ... Defining TSH-dependent and TSH-independent steps of thyroid hormone synthesis using thyrotropin receptor-null mice Proc. Natl. Acad. Sci. USA. 2002; 99:15776-15781 Crossref Scopus (184) PubMed Google Scholar
  22. [24]24. Parfitt, A.M ∙ Drezner, M.K ∙ Glorieux, F.H ... Bone histomorphometrystandardization of nomenclature, symbols, and units J. Bone Miner. Res. 1987; 2:595-610 Crossref Scopus (4992) PubMed Google Scholar
  23. [25]25. Peng, H ∙ Wright, V ∙ Usas, A ... Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4 J. Clin. Invest. 2002; 110:751-759 Crossref Scopus (684) PubMed Google Scholar
  24. [26]26. Prummel, M.F ∙ Brokken, L.J ∙ Meduri, G ... Expression of the thyroid-stimulating hormone receptor in the folliculo-stellate cells of the human anterior pituitary J. Clin. Endocrinol. Metab. 2000; 85:4347-4353 Crossref Scopus (62) PubMed Google Scholar
  25. [28]28. Sato, K ∙ Han, D.C ∙ Fujii, Y ... Thyroid hormone stimulates alkaline phosphatase activity in cultured rat osteoblastic cells (ROS 17/2.8) through 3,5,3′-triiodo-L-thyronine nuclear receptors Endocrinology. 1987; 120:1873-1881 Crossref Scopus (97) PubMed Google Scholar
  26. [29]29. Shevde, N.K ∙ Bendixen, A.C ∙ Dienger, K.M ... Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression Proc. Natl. Acad. Sci. USA. 2000; 97:7829-7834 Crossref Scopus (431) PubMed Google Scholar
  27. [30]30. Sims, N.A ∙ Clement-Lacroix, P ∙ Minet, D ... A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice J. Clin. Invest. 2003; 111:1319-1327 Crossref Scopus (183) PubMed Google Scholar
  28. [31]31. Sun, L ∙ Iqbal, J ∙ Dolgilevich, S ... Disordered osteoclast formation and function in a CD38 (ADP-ribosyl cyclase)-deficient mouse establishes an essential role for CD38 in bone resorption FASEB J. 2003; 17:369-375 Crossref Scopus (63) PubMed Google Scholar
  29. [32]32. Srivastava, S ∙ Toraldo, G ∙ Weitzmann, M.N ... Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kappa B ligand (RANKL)-induced JNK activation J. Biol. Chem. 2001; 276:8836-8840 Crossref Scopus (317) PubMed Google Scholar
  30. [33]33. Takahashi, N ∙ Udagawa, N ∙ Tanaka, S ... Generating murine osteoclasts from bone marrow Methods Mol. Med. 2003; 80:129-144 PubMed Google Scholar
  31. [34]34. Teitelbaum, S.L ∙ Ross, F.P Genetic regulation of osteoclast development and function Nat. Rev. Genet. 2003; 4:638-649 Crossref Scopus (1397) PubMed Google Scholar
  32. [35]35. Valyasevi, R.W ∙ Erickson, D.Z ∙ Harteneck, D.A ... Differentiation of human orbital preadipocyte fibroblasts induces expression of functional thyrotropin receptor J. Clin. Endocrinol. Metab. 1999; 84:2557-2562 Crossref Scopus (184) PubMed Google Scholar
  33. [37]37. Wang, H.-C ∙ Dragoo, J ∙ Zhou, Q ... An intrinsic thyrotropin-mediated pathway of TNF−α production by bone marrow cells Blood. 2003; 101:119-123 Crossref Scopus (67) PubMed Google Scholar
  34. [38]38. Wang, J ∙ Klein, J.R Hormonal regulation of extrathymic gut T cell developmentinvolvement of thyroid stimulating hormone Cell. Immunol. 1995; 161:299-302 Crossref Scopus (33) PubMed Google Scholar
  35. [39]39. Webber, D.M ∙ Braidman, I.P ∙ Robertson, W.R ... A quantitative cytochemical assay for osteoclast acid phosphatase activity in foetal rat calvaria Histochem. J. 1988; 20:269-275 Crossref Scopus (25) PubMed Google Scholar
  36. [40]40. Wei, S ∙ Teitelbaum, S.L ∙ Wang, M.W ... Receptor activator of nuclear factor-kappa B ligand activated nuclear factor-kappa B in osteoclasts Endocrinology. 2001; 142:1290-1295 Crossref Scopus (95) PubMed Google Scholar
  37. [41]41. Zaidi, M ∙ Blair, H.C ∙ Abe, E ... Osteoclastogenesis, bone resorption and osteoclast-based therapeutics J. Bone Miner. Res. 2003; 18:599-609 Crossref Scopus (160) PubMed Google Scholar

Cited by

Sorted by citations

Authors
Abe, E., Marians, R. C., Yu, W., Wu, X.-B., Ando, T., Li, Y., Iqbal, J., Eldeiry, L., Rajendren, G., Blair, H. C., Davies, T. F., & Zaidi, M.
Affiliations
  • Veterans Health Administration (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • University of Pittsburgh (US)
Corresponding author
Zaidi, Mone
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2003-10
Volume
115
Issue
2
Pages
151-162
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/s0092-8674(03)00771-2
OpenAlex
W2108897036
Cited by
691
References
3
Citations by year
2026: 19 · 2025: 32 · 2024: 24 · 2023: 22 · 2022: 33 · 2021: 37 · 2020: 37 · 2019: 17 · 2018: 37 · 2017: 36 · 2016: 35 · 2015: 37 · 2014: 35 · 2013: 37 · 2012: 23
FWCI
6.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01dk045011-08)
  • U.S. Public Health Service (A124671)
  • National Institute on Aging (AG-14917-8, R01AG014917, R01AG023176, AG23176-01)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-07646, DK 52464, DK-45011, R01DK052464, T32DK007646)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
Keywords
thyroid-stimulating hormone, TSH receptor, skeletal remodeling, osteoporosis, hyperthyroidism, osteoclastogenesis, osteogenic differentiation, bone resorption, bone formation, JNK/c-Jun signaling, NF-κB signaling, RANKL, TNF-α, Wnt signaling, VEGF signaling, FLK, type I collagen, Runx2, Osterix, osteosclerosis
MeSH terms
Animals, Bone and Bones, Bone Resorption, Cell Differentiation, Cells, Cultured, Gene Expression Regulation, Glycoproteins, Osteoblasts, Osteoclasts, Proto-Oncogene Proteins, Receptors, LDL, Receptors, Thyrotropin, Stem Cells, Thyrotropin, Tumor Necrosis Factor-alpha, Signal Transduction, Down-Regulation, Bone Remodeling, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Collagen Type I, LDL-Receptor Related Proteins, Zebrafish Proteins, Vascular Endothelial Growth Factor Receptor-2, Wnt Proteins, Mice, Osteoprotegerin, Low Density Lipoprotein Receptor-Related Protein-5

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review