On the Nature of Expansion of Paget's Disease of Bone
Abstract
This proposal addressed the FY10 PRMRP topic of Paget s disease of bone (PDB). This proposal addressed the genetic events that place in the affected bone of PDB patients who do not have the familial form of the disease. Laser capture microdissection of osteoblasts within the affected bone revealed somatic SQSTM1 mutations had taken place in some patients. Curiously, it appeared that the SQSTM1 mutation was not present in all of the osteoblasts in the pagetic bone, but rather in a subset of cells. This discovery suggests that this subset of cells must be the origin of the pagetic lesion and the mutations must have taken place in the cells at the site of the pagetic bone. This proposal is intended to characterize the frequency and nature of this critical subset of cells and how they give rise to pagetic bone formation. Our hypothesis for this application is that sporadic PDB arises as the result of a combination of somatic mutations and environmental events that give rise to the pagetic lesion and that in sporadic PDB there is a small population of cells that are critical to the formation of the pagetic bone. These mutant-containing cells recruit normal bone to the affected site and drive the abnormal bone formation phenotype. Moreover, this subset of mutation-containing cells affects gene expression throughout the overall pagetic lesion. To test this hypothesis, we proposed to use a combination of in vitro experiments to complete the following specific aims: 1) to demonstrate the presence and nature of this subset of critical cells within the pagetic bone. 2) to determine whether a subset of cells containing the critical mutation can affect the overall nature of a culture containing cells with and without the mutations.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2012
- Accession Number
- ADA573353
Entities
People
- Marc Hansen
Organizations
- University of Connecticut Health Center