Osteoclast Inhibitory Peptide-1 Therapy for Paget's Disease
Annual rept. 1 Aug 2009-31 Jul 2010
SOUTH CAROLINA STATE DEPT OF EDUCATION CHARLESTON SC
Pagination or Media Count:
Both viral and genetic factors have been implicated in the pathogenesis of Pagets disease PD. Mutations P392L in the ubiquitin-associated UBA domain of sequestosome 1 SQSTM1p62gene have been identified in patients with PD. PD is characterized by markedly increased osteoclast OCL formation characterized by presence of paramyxoviral nuclear inclusions. MVNP gene transduction to normal human OCL precursors results in formation of OCLs with pagetic phenotype. Retroviral expression of MVNP in osteoclast OCL progenitor cells from osteoclast inhibitory peptide OIP-1 transgenic mouse showed a significant decrease 43 in OCL formation and inhibition 38 of bone resorption area compared to wild-type mice. We hypothesize that over-expression of osteoclast inhibitory peptide-1 OIP-1 in cells of osteoclast OCL lineage in vivo inhibits measles virus nucleocapsid protein MVNP and p62P392L mutant induced pagetic osteoclast developmentbone resorption. We established microarray profiling of differential gene expression in p62 wild-type, non- UBA domain mutation in exon-7 A381V and UBA domain mutation in exon-8 P392L and MVNP transduced human bone marrow derived preosteoclast cells. We identified CYLD protein lacks interaction with p62 UBA mutant specifically and thus induces increased OCL development. These findings implicate functional role for MVNP and p62 UBA mutant in the pathogenesis of pagetic osteoclasts.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research