Elucidating the mechanisms underlying aberrant bone regulation due to Gnas heterozygous inactivation using a mouse model of Albright hereditary osteodystrophy

Albright Hereditary Osteodystrophy (AHO) is a disorder characterized by the heterozygous
inactivation of GNAS, which encodes for the alpha-stimulatory subunit (Gαs) for G-Protein
Coupled Receptors, and causes a constellation of skeletal symptoms including shortened stature,
brachydactyly and the formation of subcutaneous ossifications (SCOs). AHO patients with
maternally inherited GNAS mutations develop pseudohypoparathyroidism type 1A (PHP1A) and
exhibit severe obesity as well as resistance to multiple hormones requiring Gαs-signaling.
Alternatively, AHO patients with paternally inherited GNAS mutations develop
pseudopseudohypoparathyroidism (PPHP) and exhibit AHO skeletal features without obesity or
hormonal resistance. These metabolic and hormonal distinctions between PHP1A and PPHP have
been shown to be due to tissue-specific paternal imprinting of GNAS, typically within endocrine
organs.
The purpose of this study was to evaluate the impact of Gnas heterozygous inactivation on
both skeletal remodeling and the development of SCOs by utilizing an AHO mouse model
generated in our laboratory by the targeted disruption of Gnas exon 1. We first utilized this AHO
model to understand the extent by which Gnas heterozygous inactivation influences bone
remodeling, and whether the remodeling is differentially regulated by parental inheritance of the
acquired mutation. We demonstrate cortical and trabecular bone formation is significantly
enhanced within mice with maternally inherited Gnas mutations, whereas mice with paternally-inherited Gnas mutations display a reduced cortical and trabecular bone formation. These
distinctions appear to stem from impaired Gαs-mediated calcitonin receptor signaling within mice
with maternally-inherited Gnas mutations, and suggest evidence of partial Gnas imprinting within
the osteoclast lineage.
This study also utilized our AHO mouse model to understand the etiologies surrounding
the formation of subcutaneous ossifications within the skin and subcutaneous tissue. Our studies
demonstrate that these lesions consistently form directly adjacent to or surrounding hair
follicles. Through the use of genetic fate mapping studies, we have demonstrated that this
localization to the hair follicle microenvironment is driven by hair follicle resident mesenchymal
progenitor populations inappropriately expanding and Sonic Hedgehog and TGF-β1 as essential
signaling pathways involved in aberrant osteogenesis and potential therapeutic targets for the
prevention and treatment of heterotopic bone.