Abstract
Albright hereditary osteodystrophy (AHO) is characterized by short stature, brachydactyly, and often heterotopic ossifications that are typically subcutaneous. Subcutaneous ossifications (SCO) cause considerable morbidity in AHO with no effective treatment. AHO is caused by heterozygous inactivating mutations in those GNAS exons encoding the α-subunit of the stimulatory G protein (Gαs). When inherited maternally, these mutations are associated with obesity, cognitive impairment, and resistance to certain hormones that mediate their actions through G protein-coupled receptors, a condition termed pseudohypoparathyroidism type 1a (PHP1a). When inherited paternally, GNAS mutations cause only AHO but not hormonal resistance, termed pseudopseudohypoparathyroidism (PPHP). Mice with targeted disruption of exon 1 of Gnas (Gnas E1−/+) replicate human PHP1a or PPHP phenotypically and hormonally. However, SCO have not yet been reported in Gnas E1+/− mice, at least not those that had been analyzed by us up to 3 months of age. Here we now show that Gnas E1−/+ animals develop SCO over time. The ossified lesions increase in number and size and are uniformly detected in adult mice by one year of age. They are located in both the dermis, often in perifollicular areas, and the subcutis. These lesions are particularly prominent in skin prone to injury or pressure. The SCO comprise mature bone with evidence of mineral deposition and bone marrow elements. Superficial localization was confirmed by radiographic and computerized tomographic imaging. In situ hybridization of SCO lesions were positive for both osteonectin and osteopontin. Notably, the ossifications were much more extensive in males than females. Because Gnas E1−/+ mice develop SCO features that are similar to those observed in AHO patients, these animals provide a model system suitable for investigating pathogenic mechanisms involved in SCO formation and for developing novel therapeutics for heterotopic bone formation. Moreover, these mice provide a model with which to investigate the regulatory mechanisms of bone formation.
Highlights
Mutations in GNAS exons that encode the alpha-subunit of the stimulatory G protein (Gas) lead to Albright Hereditary Osteodystrophy (AHO), which is characterized by brachydactyly, brachymetacarpia, short stature, and frequently subcutaneous ossifications (SCO), i.e. heterotopic bone formation [1,2,3,4]
When GNAS mutations are inherited maternally, AHO is associated with the development of pseudohypoparathyroidism type 1a (PHP1a), i.e. PTH-resistance leading to hypocalcemia and hyperphosphatemia, resistance to several other peptide hormones that mediate their actions through G protein-coupled receptors, as well as obesity and various degrees of cognitive impairment
Our findings demonstrate that the Gnas exon 1-disrupted mouse model faithfully recapitulates the development of subcutaneous ossifications observed in PHP1a and PPHP patients
Summary
Mutations in GNAS exons that encode the alpha-subunit of the stimulatory G protein (Gas) lead to Albright Hereditary Osteodystrophy (AHO), which is characterized by brachydactyly, brachymetacarpia, short stature, and frequently subcutaneous ossifications (SCO), i.e. heterotopic bone formation [1,2,3,4]. Ossifications are limited to the dermis and subcutaneous tissue whereas in others the ossifications are deeply invasive [2,4] It is the only monogenic condition in which de novo ossifications form subcutaneously and remain limited to the skin, but both the etiology of the ossifications and their extent of invasiveness are as yet a mystery. Even though loss of G protein-signaling from one parental allele seems to be required for the formation of ossified areas, the underlying mechanisms are incompletely understood
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