Abstract
The ancestral glycoprotein hormone thyrostimulin is a heterodimer of unique glycoprotein hormone subunit alpha (GPA)2 and glycoprotein hormone subunit beta (GPB)5 subunits with high affinity for the TSH receptor. Transgenic overexpression of GPB5 in mice results in cranial abnormalities, but the role of thyrostimulin in bone remains unknown. We hypothesized that thyrostimulin exerts paracrine actions in bone and determined: 1) GPA2 and GPB5 expression in osteoblasts and osteoclasts, 2) the skeletal consequences of thyrostimulin deficiency in GPB5 knockout (KO) mice, and 3) osteoblast and osteoclast responses to thyrostimulin treatment. Gpa2 and Gpb5 expression was identified in the newborn skeleton but declined rapidly thereafter. GPA2 and GPB5 mRNAs were also expressed in primary osteoblasts and osteoclasts at varying concentrations. Juvenile thyrostimulin-deficient mice had increased bone volume and mineralization as a result of increased osteoblastic bone formation. However, thyrostimulin failed to induce a canonical cAMP response or activate the noncanonical Akt, ERK, or mitogen-activated protein kinase (P38) signaling pathways in primary calvarial or bone marrow stromal cell-derived osteoblasts. Furthermore, thyrostimulin did not directly inhibit osteoblast proliferation, differentiation or mineralization in vitro. These studies identify thyrostimulin as a negative but indirect regulator of osteoblastic bone formation during skeletal development.
Highlights
The ancestral glycoprotein hormone thyrostimulin is a heterodimer of unique glycoprotein hormone subunit alpha (GPA)2 and glycoprotein hormone subunit beta (GPB)5 subunits with high affinity for the TSH receptor
The GPA2 mRNAs expressed in human osteoblasts and osteoclasts consisted of the full-length correctly spliced GPA2 mRNA (283 bp) and an unspliced transcript (581 bp), in which introns 2 and 3 are retained (Supplemental Figure 1A)
MRNAs were variable in cultured osteoblasts and osteoclasts, whilst currently available antibodies were not sufficiently sensitive or specific to determine expression of GPA2 and GPB5 proteins
Summary
The ancestral glycoprotein hormone thyrostimulin is a heterodimer of unique glycoprotein hormone subunit alpha (GPA) and glycoprotein hormone subunit beta (GPB) subunits with high affinity for the TSH receptor. Thyrostimulin did not directly inhibit osteoblast proliferation, differentiation or mineralization in vitro. These studies identify thyrostimulin as a negative but indirect regulator of osteoblastic bone formation during skeletal development. Human thyrostimulin is 4-fold more potent than human TSH at inducing a TSHR-mediated cAMP response [1, 4], whereas glycosylation of both GPA2 and GPB5 subunits are essential for secretion and activity of thyrostimulin [5, 6]. GPA2 and GPB5 are, present in both vertebrates and invertebrates and thought to have given rise to the vertebrate common ␣-subunit (glycoprotein hormone ␣) and unique -subunits (TSH, LH, and FSH) by gene duplication [10, 11]
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