Osteoclast Inhibitory Peptide-1 Therapy for Paget's Disease
Abstract
Both viral and genetic factors have been implicated in the pathogenesis of Paget's disease (PD). Mutations (P392L) in the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1/p62)gene 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 p62(P392L) mutant induced pagetic osteoclast development/bone 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2010
- Accession Number
- ADA539193
Entities
People
- Sakamuri Reddy