β-Arrestin 1 in Thyrotropin Receptor Signaling in Bone: Studies in Osteoblast-Like Cells.

Alisa Boutin,Marvin C Gershengorn,Susanne Neumann

doi:10.3389/fendo.2020.00312

Alisa Boutin, Marvin C Gershengorn + Show 1 more

Open Access

https://doi.org/10.3389/fendo.2020.00312

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Abstract

A direct action of thyrotropin (TSH, thyroid-stimulating hormone) on bone precursors in humans is controversial. Studies in rodent models have provided conflicting findings. We used cells derived from a moderately differentiated osteosarcoma stably overexpressing human TSH receptors (TSHRs) as a model of osteoblast precursors (U2OS-TSHR cells) to investigate TSHR-mediated effects in bone differentiation in human cells. We review our findings that (1) TSHR couples to several different G proteins to induce upregulation of genes associated with osteoblast activity—interleukin 11 (IL-11), osteopontin (OPN), and alkaline phosphatase (ALPL) and that the kinetics of the induction and the G protein-mediated signaling pathways involved were different for these genes; (2) TSH can stimulate β-arrestin-mediated signal transduction and that β-arrestin 1 in part mediates TSH-induced pre-osteoblast differentiation; and (3) TSHR/insulin-like growth factor 1 (IGF1) receptor (IGF1R) synergistically increased OPN secretion by TSH and IGF1 and that this crosstalk was mediated by physical association of these receptors in a signaling complex that uses β-arrestin 1 as a scaffold. These findings were complemented using a novel β-arrestin 1-biased agonist of TSHR. We conclude that TSHR can signal via several transduction pathways leading to differentiation of this model system of human pre-osteoblast cells and, therefore, that TSH can directly regulate these bone cells.

Highlights

Thyroid-stimulating hormone (TSH), known as thyrotropin, is a hormone that activates TSH receptors (TSHRs) to stimulate development of the thyroid in utero and on thyroid cells to stimulate production of thyroid hormones thyroxine (T4) and triiodothyronine (T3) in the adult
We demonstrated that TSHR couples to several different G proteins to induce upregulation of genes associated with osteoblast activity in U2OS-TSHR cells: interleukin 11 (IL-11) [28, 29], osteopontin (OPN) [30], and alkaline phosphatase (ALPL) [31]
We summarized our findings showing that the role of β-arrestins in TSHR signal transduction in osteoblast-like cells is more prominent than previously understood

Summary

INTRODUCTION

Thyroid-stimulating hormone (TSH), known as thyrotropin, is a hormone that activates TSH receptors (TSHRs) to stimulate development of the thyroid in utero and on thyroid cells to stimulate production of thyroid hormones thyroxine (T4) and triiodothyronine (T3) in the adult. In vitro studies in bone cells were initially hampered by the assumption that TSH-induced cAMP production is the primary TSHR-mediated signaling pathway. Recent studies have shown that other G protein- and β-arrestin-mediated signaling pathways can be activated via TSHR and the quest for the role of TSH in bone metabolism gained traction again. Our group has demonstrated that TSH mediates activatory TSHR signaling through β-arrestin 1, and that this pathway plays an important role in stimulating upregulation of osteoblast markers driving the precursors toward an osteoblast phenotype [21]. This review will focus on TSH signaling in human osteoblast precursor cells and summarize the roles of G protein- and βarrestin-mediated signaling pathways with a special emphasis on the role of β-arrestin 1 in bone physiology

G PROTEIN-MEDIATED TSHR SIGNALING IN U2OS-TSHR CELLS

Findings

CONCLUSION