Abstract
ABSTRACTThe physiological role and the regulation of ADGRG7 are not yet elucidated. The functional involvement of this receptor was linked with different physiological process such as reduced body weight, gastrointestinal function and recently, a gene variant in ADGRG7 was observed in patients with adolescent idiopathic scoliosis. Here, we identify the ADGRG7 as an estrogen-responsive gene under the regulation of estrogen receptor ERα in scoliotic osteoblasts and other cells lines. We found that ADGRG7 expression was upregulated in response to estrogen (E2) in adolescent idiopathic scoliosis (AIS) cells. ADGRG7 promoter studies indicate the presence of an ERα response half site in close vicinity of a specificity protein 1 (SP1) binding site. Mutation of the SP1 site completely abrogated the response to E2, indicating its essential requirement. ChIP confirmed the binding of SP1 and ERα to the ADGRG7 promoter. Our results identify the ADGRG7 gene as an estrogen-responsive gene under the control of ERα and SP1 tethered actions, suggesting a possible role of estrogens in the regulation of ADGRG7. This article has an associated First Person interview with the first author of the paper.
Highlights
Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional deformity of the spine that mostly occurs during late childhood or puberty (Konieczny et al, 2013)
ADGRG7 and specificity protein 1 (SP1) were expressed in the bone; this suggests a wider function than expected and an undetermined role of ADGRG7 in bone
The recruitment of ERα and SP1 proteins with the proximal region of the ADGRG7 promoter (−448 to −435) was investigated and the results indicated that both ERα and SP1 antibodies immunoprecipitate this region of ADGRG7 promoter as determined by qPCR (Fig. 5C)
Summary
Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional deformity of the spine that mostly occurs during late childhood or puberty (Konieczny et al, 2013). Severe forms of AIS are more common in girls compared to boys (Cheng et al, 2015). Estrogens (including estradiol) (E2) and estrogen receptors (ERs), including the ERα and ERβ isoforms, are suspected of influencing AIS severity and delayed puberty which has been directly associated with a higher prevalence of AIS in girls than in boys with an incidence ratio of 7.1:1 (Konieczny et al, 2013). E2 participation in puberty, spinal growth and bone metabolism is an important factor to consider in AIS. Until now, it was not clear how E2 could affect the initiation or progression of AIS. Estrogens interact with many physiopathological factors (including neuroendocrine, neurological, muscular, biochemical and structural) relevant to the etiology of scoliosis, and there is interdependence between the concentration of E2 and development of scoliosis (Leboeuf et al, 2009)
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