Thyrostimulin Regulates Osteoblastic Bone Formation During Early Skeletal Development

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.

Multigenic Delineation of Lower Jaw Deformity in Triploid Atlantic Salmon (Salmo salar L.)

“…In the present study, the expression of gphb5 in the skin cells is in accordance to that found in humans [42]. Furthermore, it has been recently shown that gphb5 plays a paracrine role in skeletal development and bone formation [41]. In light of the above, our results may suggest that gphb5 is expressed in the skin of the lower jaw and induce changes in cartilage or bone cells located at short distance.…”

“…Nevertheless, the primary role of the hormone is still unknown [41]. Gphb5 seems to have a paracrine rather than an endocrine function, implying that it can be expressed locally and induce changes in nearby cells [40, 41]. In the present study, the expression of gphb5 in the skin cells is in accordance to that found in humans [42].…”

“…Gphb5 is known to activate the thyroid-stimulating hormone (TSH) receptors in cells of thyroid and it was named thyrostimulin due to its ability to stimulate thyrotropin receptors [40]. Nevertheless, the primary role of the hormone is still unknown [41]. Gphb5 seems to have a paracrine rather than an endocrine function, implying that it can be expressed locally and induce changes in nearby cells [40, 41].…”

“…Furthermore, considering the aforementioned relation gphb5 -thyroid, gphb5 down-regulation and consequent lower expression in LJD-affected individuals may indicate an underactive thyroid. Underactive thyroid is generally linked with impairments in chondrocyte differentiation and linear growth as well as bone formation and mineralization [41]. Since, as suggested by our results, LJD could be the result of a cartilaginous impairment with resulting deleterious effects on bone development, the findings reported above support and reinforce our theory that gphb5 is likely involved in mechanisms underlying LJD and, although not expressed specifically in cartilage or bone in the present study (mostly in oral epithelium, teeth and skin), gphb5 may act through paracrine pathways.…”

The role of thyrostimulin and its potential clinical significance

“…Still, further research is needed into the mechanism of thyrostimulin in bone metabolism, as this is unclear. It does not induce a cAMP response in primary osteoblasts or osteoclasts, in addition to failing to activate noncanonical signaling pathways (Bassett et al 2015).…”