The same approach as used for FD contributed

decisively to identify and name Gnathodiaphyseal Dysplasia as a separate disease, distinct from both FD and Osteogenesis Imperfecta, and to predict from the cell-autonomous properties of stromal progenitors [32], its genetic nature, which was to be identified shortly thereafter [33]. Specific dysfunction in skeletal and dental progenitors was recognized in Cleidocranial Selleckchem Torin 1 Dysplasia [34], while heterotopic transplants of stromal progenitors from patients with Hurler’s disease, conversely, dispel an inherent disruption of stromal cell differentiation [35]. However, the use of novel types of heterotopic transplantation assays [6] reveals specific changes in cartilage metabolism in Hurler’s disease (Serafini et al., manuscript in preparation). Heterotopic transplantation of stromal progenitor cells serves also to demonstrate in vivo the functional impact of gene knockout or of transgenes [36] and [37]. The adoption of stem cells as a model of disease has been remarkably productive in the specific area in which it was Selleck MK2206 most intensively pursued,

Fibrous Dysplasia. Use of cultures of FD-derived bone marrow stromal cells resulted in the development of simple diagnostic tests for the identification of the causative GNAS mutations [28] and [38], and for the quantification of the mutational load in a somatic mosaic disease [39]. Correlation of quantitative estimates of mutational load with patient age and clinical and pathological assessment of organ lesions led to the recognition that GNAS-mutated and wild-type stromal progenitors have different

lifespans and self-renewal kinetics, explaining the natural occurrence of a spontaneous sterilization over time of the bone marrow progenitor compartment from the disease gene in some patients [40]. Using clonal populations of GNAS-mutated stromal progenitors, it was also selleck chemicals possible to determine the imprinting profile of GNAS transcripts in skeletal progenitors. This revealed that while alternative transcripts of GNAS are expressed in osteoprogenitors and imprinted, Gsα is asymmetrically expressed in different clones in a random fashion, independent on imprinting, but potentially contributing to disease heterogeneity [41]. Finally, recognition of FGF23 as a product of the osteogenic lineage, and consequently of the role of bone as an endocrine organ regulating phosphate metabolism in the kidney, came from the use of stromal osteoprogenitors as an in vitro and in vivo model of FD. Overproduction of FGF23 in FD can account for the occurrence of hypophosphatemic rickets/osteomalacia in patients with severe panostotic forms of the disease [42].