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Heterotopic ossifications in a mouse model of albright hereditary osteodystrophy.
PLoS One 2011; 6(6):e21755Plos

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 (Gα(s)). 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.

Authors+Show Affiliations

Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21747923

Citation

Huso, David L., et al. "Heterotopic Ossifications in a Mouse Model of Albright Hereditary Osteodystrophy." PloS One, vol. 6, no. 6, 2011, pp. e21755.
Huso DL, Edie S, Levine MA, et al. Heterotopic ossifications in a mouse model of albright hereditary osteodystrophy. PLoS ONE. 2011;6(6):e21755.
Huso, D. L., Edie, S., Levine, M. A., Schwindinger, W., Wang, Y., Jüppner, H., & Germain-Lee, E. L. (2011). Heterotopic ossifications in a mouse model of albright hereditary osteodystrophy. PloS One, 6(6), pp. e21755. doi:10.1371/journal.pone.0021755.
Huso DL, et al. Heterotopic Ossifications in a Mouse Model of Albright Hereditary Osteodystrophy. PLoS ONE. 2011;6(6):e21755. PubMed PMID: 21747923.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Heterotopic ossifications in a mouse model of albright hereditary osteodystrophy. AU - Huso,David L, AU - Edie,Sarah, AU - Levine,Michael A, AU - Schwindinger,William, AU - Wang,Yingli, AU - Jüppner,Harald, AU - Germain-Lee,Emily L, Y1 - 2011/06/29/ PY - 2011/04/26/received PY - 2011/06/06/accepted PY - 2011/7/13/entrez PY - 2011/7/13/pubmed PY - 2011/11/5/medline SP - e21755 EP - e21755 JF - PloS one JO - PLoS ONE VL - 6 IS - 6 N2 - 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 (Gα(s)). 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/21747923/Heterotopic_ossifications_in_a_mouse_model_of_albright_hereditary_osteodystrophy_ L2 - http://dx.plos.org/10.1371/journal.pone.0021755 DB - PRIME DP - Unbound Medicine ER -