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?-Arrestin-1 mediates thyrotropin-enhanced osteoblast differentiation.


ABSTRACT: Thyrotropin (TSH) activation of the TSH receptor (TSHR), a 7-transmembrane-spanning receptor (7TMR), may have osteoprotective properties by direct effects on bone. TSHR activation by TSH phosphorylates protein kinases AKT1, p38?, and ERK1/2 in some cells. We found TSH-induced phosphorylation of these kinases in 2 cell lines engineered to express TSHRs, human embryonic kidney HEK-TSHR cells and human osteoblastic U2OS-TSHR cells. In U2OS-TSHR cells, TSH up-regulated pAKT1 (7.1±0.5-fold), p38? (2.9±0.4-fold), and pERK1/2 (3.1±0.2-fold), whereas small molecule TSHR agonist C2 had no or little effect on pAKT1 (1.8±0.08-fold), p38? (1.2±0.09-fold), and pERK1/2 (1.6±0.19-fold). Furthermore, TSH increased expression of osteoblast marker genes ALPL (8.2±4.6-fold), RANKL (21±5.9-fold), and osteopontin (OPN; 17±5.3-fold), whereas C2 had little effect (ALPL, 1.7±0.5-fold; RANKL, 1.3±0.6-fold; and OPN, 2.2±0.7-fold). ?-Arrestin-1 and -2 can mediate activatory signals by 7TMRs. TSH stimulated translocation of ?-arrestin-1 and -2 to TSHR, whereas C2 failed to translocate either ?-arrestin. Down-regulation of ?-arrestin-1 by siRNA inhibited TSH-stimulated phosphorylation of ERK1/2, p38?, and AKT1, whereas down-regulation of ?-arrestin-2 increased phosphorylation of AKT1 in both cell types and of ERK1/2 in HEK-TSHR cells. Knockdown of ?-arrestin-1 inhibited TSH-stimulated up-regulation of mRNAs for OPN by 87 ± 1.7% and RANKL by 73 ± 2.4%, and OPN secretion by 74 ± 10%. We conclude that TSH enhances osteoblast differentiation in U2OS cells that is, in part, caused by activatory signals mediated by ?-arrestin-1.

SUBMITTER: Boutin A 

PROVIDER: S-EPMC4101659 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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β-Arrestin-1 mediates thyrotropin-enhanced osteoblast differentiation.

Boutin Alisa A   Eliseeva Elena E   Gershengorn Marvin C MC   Neumann Susanne S  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20140410 8


Thyrotropin (TSH) activation of the TSH receptor (TSHR), a 7-transmembrane-spanning receptor (7TMR), may have osteoprotective properties by direct effects on bone. TSHR activation by TSH phosphorylates protein kinases AKT1, p38α, and ERK1/2 in some cells. We found TSH-induced phosphorylation of these kinases in 2 cell lines engineered to express TSHRs, human embryonic kidney HEK-TSHR cells and human osteoblastic U2OS-TSHR cells. In U2OS-TSHR cells, TSH up-regulated pAKT1 (7.1±0.5-fold), p38α (2.  ...[more]

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