| The influence of thyroid-stimulating hormone and thyroid-stimulating hormone receptor antibodies on osteoclastogenesis. | |
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MedLine Citation:
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PMID: 21745106 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: We have shown that thyroid-stimulating hormone (TSH) has a direct inhibitory effect on osteoclastic bone resorption and that TSH receptor (TSHR) null mice display osteoporosis. To determine the stage of osteoclast development at which TSH may exert its effect, we examined the influence of TSH and agonist TSHR antibodies (TSHR-Ab) on osteoclast differentiation from murine embryonic stem (ES) cells to gain insight into bone remodeling in hyperthyroid Graves' disease. METHODS: Osteoclast differentiation was initiated in murine ES cell cultures through exposure to macrophage colony stimulation factor, receptor activator of nuclear factor кB ligand, vitamin D, and dexamethasone. RESULTS: Tartrate resistant acid phosphatase (TRAP)-positive osteoclasts formed in ~12 days. This coincided with the expected downregulation of known markers of self renewal and pluripotency (including Oct4, Sox2, and REX1). Both TSH and TSHR-Abs inhibited osteoclastogenesis as evidenced by decreased development of TRAP-positive cells (~40%-50% reduction, p = 0.0047), and by decreased expression, in a concentration-dependent manner, of osteoclast differentiation markers (including the calcitonin receptor, TRAP, cathepsin K, matrix metallo-proteinase-9, and carbonic anhydrase II). Similar data were obtained using serum immunoglobulin-Gs (IgGs) from patients with hyperthyroid Graves' disease and known TSHR-Abs. TSHR stimulators inhibited tumor necrosis factor-alpha mRNA and protein expression, but increased the expression of osteoprotegerin (OPG), an antiosteoclastogenic human soluble receptor activator of nuclear factor кB ligand receptor. Neutralizing antibody to OPG reversed the inhibitory effect of TSH on osteoclast differentiation evidencing that the TSH effect was at least in part mediated by increased OPG. CONCLUSION: These data establish ES-derived osteoclastogenesis as an effective model system to study the regulation of osteoclast differentiation in early development. The results support the observations that TSH has a bone protective action by negatively regulating osteoclastogenesis. Further, our results implicate TSHR-Abs in offering skeletal protection in hyperthyroid Graves' disease, even in the face of high thyroid hormone and low TSH levels. |
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Authors:
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Risheng Ma; Syed Morshed; Rauf Latif; Mone Zaidi; Terry F Davies |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2011-07-11 |
Journal Detail:
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Title: Thyroid : official journal of the American Thyroid Association Volume: 21 ISSN: 1557-9077 ISO Abbreviation: Thyroid Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-08-03 Completed Date: 2012-01-09 Revised Date: 2012-09-25 |
Medline Journal Info:
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Nlm Unique ID: 9104317 Medline TA: Thyroid Country: United States |
Other Details:
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Languages: eng Pagination: 897-906 Citation Subset: IM |
Affiliation:
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Thyroid Research Unit, Mount Sinai School of Medicine and James J Peters Veterans Affairs Medical Center, New York, New York 10468, USA. risheng.ma@mssm.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Differentiation Dexamethasone / pharmacology Embryonic Stem Cells / cytology Homozygote Humans Macrophage Colony-Stimulating Factor / metabolism Mice Mice, Transgenic Osteoclasts / cytology* RANK Ligand / metabolism Receptors, Thyrotropin / blood*, immunology Thyrotropin / blood*, immunology Tumor Necrosis Factor-alpha / biosynthesis Vitamin D / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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DK052464/DK/NIDDK NIH HHS; DK069713/DK/NIDDK NIH HHS; DK080459/DK/NIDDK NIH HHS; R01 AG023176/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/RANK Ligand; 0/Receptors, Thyrotropin; 0/Tnfsf11 protein, mouse; 0/Tumor Necrosis Factor-alpha; 1406-16-2/Vitamin D; 50-02-2/Dexamethasone; 81627-83-0/Macrophage Colony-Stimulating Factor; 9002-71-5/Thyrotropin |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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