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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Bone Remodeling / drug effects
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Bone Remodeling / physiology*
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Bone Resorption / genetics
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Bone Resorption / physiopathology
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Bone and Bones / cytology
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Cell Differentiation
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Cells, Cultured
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Collagen Type I / metabolism
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Down-Regulation
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Gene Expression Regulation
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Glycoproteins / metabolism
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LDL-Receptor Related Proteins
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Low Density Lipoprotein Receptor-Related Protein-5
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Mice
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Mice, Knockout
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Osteoblasts / cytology
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Osteoblasts / drug effects
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Osteoblasts / physiology
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Osteoclasts / cytology
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Osteoclasts / drug effects
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Osteoclasts / physiology
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Osteoprotegerin
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Proto-Oncogene Proteins / metabolism
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, LDL / metabolism
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Receptors, Thyrotropin / metabolism
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Receptors, Tumor Necrosis Factor
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Signal Transduction
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Stem Cells / physiology
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Thyrotropin / genetics
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Thyrotropin / metabolism
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Thyrotropin / pharmacology
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Thyrotropin / physiology*
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Tumor Necrosis Factor-alpha / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Wnt Proteins
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Zebrafish Proteins*
Substances
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Collagen Type I
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Glycoproteins
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LDL-Receptor Related Proteins
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Low Density Lipoprotein Receptor-Related Protein-5
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Lrp5 protein, mouse
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Osteoprotegerin
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Proto-Oncogene Proteins
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Receptors, Cytoplasmic and Nuclear
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Receptors, LDL
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Receptors, Thyrotropin
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Receptors, Tumor Necrosis Factor
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Tnfrsf11b protein, mouse
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Tumor Necrosis Factor-alpha
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Wnt Proteins
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Zebrafish Proteins
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Thyrotropin
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Vascular Endothelial Growth Factor Receptor-2