The Nature of Expansion of Paget's Disease of Bone
Abstract
The purpose of this grant was to examine the mechanism by which Sequestosome 1 (SQSTM1) mutations initiate the sporadic form of Paget s Disease of Bone (PDB). We found that somatic SQSTM1 mutations in the osteoblasts of pagetic bone play a critical role in PDB formation. We isolated osteoblastic cells from pagetic lesions and analyzed their expression profiles using microarrays. From this, we developed a model in which mutant SQSTM1 protein interacts with the MyD88 gene product to activate NF- B via the Toll-like Receptor signaling pathway to activate chemokine signaling. We confirmed our results in an osteoblastic cell line that had a SQSTM1 mutation that was isolated from a PDB patient and again when we introduced a SQSTM1 mutation into a osteoblastic cell line wildtype for SQSTM1. This suggests that while regulation of osteoclastogenesis is a key process in PDB pathogenesis, osteoblastic cells containing SQSTM1 mutations play critical role in the initiation and progression of the disease. This is paradigm-shifting as it suggests a multi-cellular model of PDB where both osteoblastic and osteoclastic cells play a role in the initiation and progression of the disease. This research opens new avenues for treatment rather than the current bisphosphonate therapies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2013
- Accession Number
- ADA586286
Entities
People
- Marc Hansen
Organizations
- University of Connecticut Health Center