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bioRxiv · 10.1101/2021.07.27.453811

Parental origin of Gsα inactivation differentially affects bone remodeling in a mouse model of Albright hereditary osteodystrophy

McMullan, P.·Yang, Q.·Maye, P.·Rowe, D.·Germain-Lee, E.
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Abstract

Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivation of GNAS, a complex locus that encodes the alpha-stimulatory subunit of GPCRs (Gs) in addition to NESP55 and XLs due to alternative first exons. AHO skeletal manifestations include brachydactyly, brachymetacarpia, compromised adult stature, and subcutaneous ossifications. AHO patients with maternally-inherited GNAS mutations develop pseudohypoparathyroidism type 1A (PHP1A) with resistance to multiple hormones that mediate their actions through GPCRs requiring Gs (eg., PTH, TSH, GHRH, calcitonin) and severe obesity. Paternally-inherited GNAS mutations cause pseudopseudohypoparathyroidism (PPHP), in which patients have AHO skeletal features but do not develop hormonal resistance or marked obesity. These differences between PHP1A and PPHP are caused by tissue-specific reduction of paternal Gs expression. Previous reports in mice have shown loss of Gs causes osteopenia due to impaired osteoblast number and function and suggest AHO patients could display evidence of reduced bone mineral density (BMD). However, we previously demonstrated PHP1A patients display normal-increased BMD measurements without any correlation to body mass index or serum PTH. Due to these observed differences between PHP1A and PPHP, we utilized our laboratorys AHO mouse model to address whether Gs heterozygous inactivation by the targeted disruption of exon 1 of Gnas differentially affects bone remodeling based on the parental inheritance of the mutation. Mice with paternally-inherited (GnasE1+/-p) and maternally-inherited (GnasE1+/-m) mutations displayed reductions in osteoblasts along the bone surface compared to wildtype. GnasE1+/-p mice displayed reduced cortical and trabecular bone parameters due to impaired bone formation and excessive bone resorption. GnasE1+/-m mice however displayed enhanced bone parameters due to increased osteoblast activity and normal bone resorption. These distinctions in bone remodeling between GnasE1+/-p and GnasE1+/-m mice appear to be secondary to changes in the bone microenvironment driven by calcitonin-resistance within GnasE1+/-m osteoclasts and therefore warrant further studies into understanding how Gs influences osteoblast-osteoclast coupling interactions.

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McMullan, P., Yang, Q., Maye, P., Rowe, D., Germain-Lee, E.. 2021-07-27. Parental origin of Gsα inactivation differentially affects bone remodeling in a mouse model of Albright hereditary osteodystrophy. https://doi.org/10.1101/2021.07.27.453811

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