Ricerc@Sapienza

Postnatal bone and bone marrow (BM) share a specialized vascular networks in which Skeletal Stem Cells (SSCs) reside as perivascular cells. These cells generate in vivo bone, cartilage, adipocytes and BM stroma. Although these lineages coincide with the assayable differentiation potential of SSCs, they emerge at different times during skeletal development. For example, both in mice and humans, BM adipocytes (BMAs) develop postnatally and fill completely specific skeletal sites at an early postnatal age.
Fibrous Dysplasia (FD) is a crippling and therapeutically orphan postnatal skeletal disease caused by postzygotic activating mutations of the Gsa gene. The defining features of FD pathology include BM fibrosis, osteomalacia, and osteolysis, that make the affected bone soft and prompt to fractures and deformities.
Key questions as to the natural history of the FD lesions, for example why and from which lineage they develop postnatally, have required modeling of the disease at organ/organism level and led to the development of specific transgenic models. In this context, mice with constitutive and ubiquitous (i.e. in all SSC-derived lineages) expression of GsaR201C, one of the mutations that cause FD in humans, replicate faithfully the human disease. However, if the same mutation is specifically targeted to osteoblasts, mice develop a high bone mass phenotype but not FD, indicating that cells other than osteoblasts are the key to the development of FD lesions.
Since, both in mice with constitutive expression of GsaR201C and humans, BMAs and FD lesions occur postnatally and earliest and most prevalent FD involved sites are those normally filled with adipocytes, we generated through a Cre-Lox approach two mouse lines in which the Cre expression was driven by Adipocyte Protein-2 or AdipoQ promoters, genes expressed in early and mature adipocytes respectively. The analysis of these mice will contribute to understand the pathogenetic role of BMAs in the development of FD.