Showing papers by "Fernando Gianfrancesco published in 2014"

Paget's disease of bone: Epidemiology, pathogenesis and pharmacotherapy

Abstract: Introduction: Paget’s disease of bone (PDB) is a chronic disorder of bone turnover, characterized by increased osteoclast-mediated bone resorption and subsequent compensatory increase in new bone formation, resulting in a disorganized mosaic of woven and lamellar bone at the affected skeletal sites. As a result, bone pain, osteoarthritis, noticeable deformities, nerve compression syndromes, fractures and, less frequently, neoplastic degeneration can occur. Areas covered: The published literature has been critically appraised, focusing on three main areas: epidemiology, pathogenesis (particularly regarding SQSTM1 mutations and other genetic aspects) and treatment of PDB. Expert opinion: Over the last two decades, there have been major advances in our understanding of pathogenesis and management of PDB. Mutations in SQSTM1 gene (encoding p62) have been identified in a consistent proportion of familial cases and treatment opportunities have been recently improved with the use of intravenous aminobisphosphona...

Exclusion of TNFRSF11B as Candidate Gene for Otosclerosis in Campania Population.

Abstract: The etiology of otosclerosis is unknown. The etiopathogenesis of otosclerosis seems similar to that occurring in Paget’s disease of bone, for which mutations or polymorphisms in several genes have been identified. Among these, TNFRSF11B gene encoding the osteoprotegerin is produced at high levels in the normal inner ear and at low level in active otosclerotic stapes footplates. The aim of this work was to verify the presence of a correlation between the rs2073618 (N3K) polymorphism in the TNFRSF11B gene and otosclerosis. Mutational screening in the TNFRSF11B gene was performed by direct sequencing. SNPs analysis was performed by PCR and by specific restriction enzyme assay with HpaI. The significance of the association was analyzed by statistical specific software. No causative mutation has been identified but the data suggested a strong correlation between the rs2073618 (N3K) polymorphism and otosclerosis. This correlation, however, has been excluded in a case–control study. This study excluded the association between the N3K polymorphism and otosclerosis in Campania region population.

Mesenchymal Stromal Cells: from Bone Marrow to Neoplastic Disorders

Abstract: Mesenchymal stromal cells (MSCs) represent a small and heterogeneous subpopulation of mesenchymal stem cells that possesses multilineage differentiation potential. These cells are mainly present in bone marrow, but also in other tissues, and represent a valuable resource for their ability to differentiate into different cell lines and for many therapeutic approaches. MSCs are able to differentiate into cells of mesodermal origin such as adipocytes, chondrocytes, osteoblasts or fibroblasts and in vitro also into cells of non-mesodermal lineages. In bone marrow, they establish the microenvironment for the growth and differentiation of the hematopoietic stem cells (HSCs) resulting crucial for HSC maintenance and haematopoiesis. Nevertheless, the proliferation and/or the survival rate of MSCs may contribute to the onset of different types of bone sarcomas, such as Osteosarcoma, Chondrosarcoma and Giant Cell Tumor of Bone that represent the result of neoplastic degeneration of their corresponding committed mesenchymal precursors, probably as a consequence of the alteration of different or common biochemical pathways.

Molecular Genetics of Paget's Disease of Bone

Abstract: Paget's disease of bone (PDB) is a chronic disorder of bone metabolism, which typically results in enlarged and deformed bones in one or more regions of the skeleton. The aetiology of PDB has remained unknown for several decades, but either environmental or genetic factors have been implicated. The former mainly concern the presence of a slow-acting viral infection, a condition that may be present for many years before symptoms appear. However, there are also several data supporting a hereditary hypothesis, since in up to 40% of patients the disease may appear in more than one family member. The genetic architecture of PDB is incompletely understood, but recent evidence suggests that the disease may be caused by a combination of rare variants in genes such as SQSTM1 (detected in up to 50% of familial cases of PDB) and more common variants (i.e. polymorphisms) in genes such as CSF1, TNFRSF11A, OPTN and TM7SF4. Key Concepts: Paget's disease of bone (PDB) is a focal disorder of bone metabolism characterised by enlarged and deformed bones in one (monostotic form) or more regions (polyostotic form) of the skeleton. Over the last two decades there have been major advances in our understanding of the genetic basis of the disorder. Mutations in 3 genes have been detected in rare syndromes related to PDB and mutations in SQSTM1 gene have been associated with the classical form of PDB in up to 50% of familial cases. SQSTM1 gene encodes for the p62/sequestosome 1 protein, which acts as a scaffold protein in the NFκB pathway as well as an intermediate protein in the proteosomal degradation of polyubiquitinated proteins. To date the exact molecular mechanisms leading to the development of pagetic lesions in SQSTM1 mutation carriers remain to be defined. Indeed, recent experimental evidence suggests that additional contribution from environmental factors (i.e. a viral infection with paramyxovirus) or other genetic factors (i.e. polymorphisms) may be required to induce the full pagetic phenotype in the presence of SQSTM1 mutation. The genetic cause of PDB in familial cases negative for SQSTM1 mutations remains to be determined in more detail. Keywords: Paget's disease of bone; p62/sequestosome; bone metabolism; genetics; NFκB signalling