Parental Origin of Gsα Inactivation Differentially Affects Bone Remodeling in a Mouse Model of Albright Hereditary Osteodystrophy

Abstract

Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivation of GNAS, a complex locus that encodes the alphastimulatory subunit of heterotrimeric G proteins (Gsα) in addition to NESP55 and XLαs 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 G protein-coupled receptors (GPCRs) requiring Gsα (eg, parathyroid hormone [PTH], thyroidstimulating hormone [TSH], growth hormone-releasing hormone [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 Gsα expression. Previous reports in mice have shown loss of Gsα causes osteopenia due to impaired osteoblast number and function and suggest that 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 laboratory's AHO mouse model to address whether Gsα heterozygous inactivation differentially affects bone remodeling based on the parental inheritance of the mutation. We identified fundamental distinctions in bone remodeling between mice with paternally-inherited (GnasE1+/Àp) versus maternally-inherited (GnasE1+/Àm) mutations, and these findings were observed predominantly in female mice. Specifically, GnasE1+/Àp mice exhibited reduced bone parameters due to impaired bone formation and enhanced bone resorption. GnasE1+/Àm mice, however, displayed enhanced bone parameters due to both increased osteoblast activity and normal bone resorption. These in vivo distinctions in bone remodeling between GnasE1+/Àp and GnasE1+/Àm mice could potentially be related to changes in the bone microenvironment driven by calcitonin-resistance within GnasE1+/Àm osteoclasts. Further studies are warranted to assess how Gsα influences osteoblast-osteoclast coupling.

GNAS locus: bone related diseases and mouse models

“…This increased osteoblast activity may be secondary to the partial resistance of osteoclast lineage cells to calcitonin. This provides the first direct evidence that Gsα affects osteoblast-osteoclast interactions and differential effects on bone remodeling based on different mutation inheritance patterns ( 126 ).…”

First Reported Case of Gabriele-de Vries Syndrome with Spinal Dysraphism

“…For this gene, many transcript variants have been discovered that encode various isoforms. Pseudohypoparathyroidism type 1a, type 1b, Albright hereditary osteodystrophy, pseudohypoparathyroidism, McCune-Albright syndrome, progressive osseus heteroplasia, polyostotic fibrous dysplasia of bone, and various types of pituitary tumors are all caused by mutations in this gene [ 10 ].…”

Hair follicle-resident progenitor cells are a major cellular contributor to heterotopic subcutaneous ossifications in a mouse model of Albright hereditary osteodystrophy

“…Bone mineral label visualization: WT and Gnas E1+/-mice were administered intraperitoneal injections of calcein [10mg/kg (Sigma C-0875)] or alizarin complexone (30mg/kg (Sigma A-3882)] 2-7 days prior to sacrifice. Dorsal skin sections were stained with calcein blue (Sigma M1255) for 10 minutes to visualize total mineral content, as previously described [30,83]. For multiplex staining, skin sections were decalcified using a sodium acetate and sodium tartrate dibasic dihydrate solution in water (pH 4.2) to remove bone mineral labels from the tissue section as described previously [83].…”

“…Patients with maternally inherited GNAS mutations develop pseudohypoparathyroidism type 1A (PHP1A) and exhibit extraskeletal manifestations that include obesity and resistance to multiple hormones requiring Gα s , such as PTH, TSH, GHRH, and LH/FSH, [18][19][20][21][22][23][24] whereas patients with paternally derived GNAS mutations develop pseudopseudohypoparathyroidism (PPHP), in which patients have AHO skeletal features without severe obesity [25] or hormonal resistance (for review [6][7][8][9][10][11]). Through studies of both humans and mouse models [6] these metabolic and hormonal distinctions were shown to be due to tissue-specific paternal imprinting of GNAS, typically within endocrine organs such as the pituitary [22,23,26], thyroid [18][19][20]27], gonads [20,27], renal cortex [27][28][29] and potentially osteoclasts [30].…”