Paget's disease of bone: molecular genetic investigation of the NFkB signaling regulating genes CBL, CBLB, and NR4A1 and functional validation in vitro and in Danio rerio.

Bone may look static, but it is a highly dynamic organ in which the tissue is continuously broken down and formed anew by osteoclasts and osteoblasts, respectively. A disturbance between the activities of these cells leads to bone diseases. Paget's disease of bone (PDB) is the second most prevalent bone disorder, affecting 2-5% of Caucasian individuals >55 years of age. PDB is caused by defects in the bone-resorbing osteoclasts which become hyperactive, leading to focal skeletal lesions. For a minority of cases, a clear genetic cause has been identified. Mutations in the sequestosome 1 (SQSTM1) gene can be found in 20% of patients and account for 50% of familial cases. Recent genetic studies led to the association of 7 loci with PDB. Several genes found at these loci are involved in NF-kB signaling. We looked for variation in the genes that encode different components of the pathway in PDB patients, and identified interesting variants in the CBL, CBLB and NR4A1 genes. These genes act as a break on osteoclast formation and activity. During this project, we will study the effect of variants on signaling intensity and the formation and activity of osteoclasts. Ultimately, we will study the variant's effect on the skeletal system in zebrafishes. This will demonstrate the role that genes play in the disease mechanism in vivo, hereby giving us a deeper understanding of the human disease process and could offer opportunities for the development of new therapeutics.

Keywords:PAGET DISEASE

Disciplines:Systems biology

Project type:Collaboration project