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Skeletal progenitors and the GNAS gene: fibrous dysplasia of bone read through stem cells.

ABSTRACT: Activating mutations of the GNAS gene, which causes fibrous dysplasia of bone (FD), lead to remarkable changes in the properties of skeletal progenitors, and it is these changes that mediate the pathological effect of this gene on bone. Mutated skeletal stem cells lose the ability to differentiate into adipocytes, and to maintain in situ, and transfer heterotopically, the hematopoietic microenvironment, leading to abnormal bone marrow histology in FD. They overexpress molecular effectors of osteoclastogenesis, thus promoting inappropriate bone resorption leading to fragility of FD bone. They express the phosphate-regulating hormone FGF-23 at normal levels, whose excess in the serum of FD patients correlates with the mass of osteogenic cells within FD lesions, leading to osteomalacia and deformity of the FD bone, and revealing that bone is an endocrine organ regulating renal handling of phosphate. Mechanisms of allelic selection and stem cell selection occur in mutated skeletal stem cells and contribute to the inherent diversity and evolution over time in FD. The definition of the etiological role of GNAS mutations marks the watershed between many decades of descriptive observation and the definition of cellular and molecular mechanisms that would explain and hopefully allow for a cure for the disease. Placing stem cells at center stage has permitted substantial advances in one decade, and promises more for the one to come.

SUBMITTER: Riminucci M

PROVIDER: S-EPMC3384548 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Skeletal progenitors and the GNAS gene: fibrous dysplasia of bone read through stem cells.

Riminucci Mara M Robey Pamela Gehron PG Saggio Isabella I Bianco Paolo P

Journal of molecular endocrinology 20100914 6

Activating mutations of the GNAS gene, which causes fibrous dysplasia of bone (FD), lead to remarkable changes in the properties of skeletal progenitors, and it is these changes that mediate the pathological effect of this gene on bone. Mutated skeletal stem cells lose the ability to differentiate into adipocytes, and to maintain in situ, and transfer heterotopically, the hematopoietic microenvironment, leading to abnormal bone marrow histology in FD. They overexpress molecular effectors of oste ...[more]

PMID: 20841428

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Project description:Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the α subunit of the G protein-coupled receptor complex (Gsα). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (GsαR201H or R201C), which leads to overproduction of cAMP. Several signaling pathways are implicated downstream of excess cAMP in the manifestation of disease. However, the pathogenesis of FD remains largely unknown. The overall FD phenotype can be attributed to alterations of skeletal stem/progenitor cells which normally develop into osteogenic or adipogenic cells (in cis), and are also known to provide support to angiogenesis, hematopoiesis, and osteoclastogenesis (in trans). In order to dissect the molecular pathways rooted in skeletal stem/progenitor cells by FD mutations, we engineered human skeletal stem/progenitor cells with the GsαR201C mutation and performed transcriptomic analysis. Our data suggest that this FD mutation profoundly alters the properties of skeletal stem/progenitor cells by pushing them towards formation of disorganized bone with a concomitant alteration of adipogenic differentiation. In addition, the mutation creates an altered in trans environment that induces neovascularization, cytokine/chemokine changes and osteoclastogenesis. In silico comparison of our data with the signature of FD craniofacial samples highlighted common traits, such as the upregulation of ADAM (A Disintegrin and Metalloprotease) proteins and other matrix-related factors, and of PDE7B (Phosphodiesterase 7B), which can be considered as a buffering process, activated to compensate for excess cAMP. We also observed high levels of CEBPs (CCAAT-Enhancer Binding Proteins) in both data sets, factors related to browning of white fat. This is the first analysis of the reaction of human skeletal stem/progenitor cells to the introduction of the FD mutation and we believe it provides a useful background for further studies on the molecular basis of the disease and for the identification of novel potential therapeutic targets.

Dataset Information

Skeletal progenitors and the GNAS gene: fibrous dysplasia of bone read through stem cells.

Publications

Skeletal progenitors and the GNAS gene: fibrous dysplasia of bone read through stem cells.

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