Aberrant Recapitulation of Developmental Program: Novel Target in Scleroderma
Abstract
Fibrosis in scleroderma is associated with altered Wnt/Beta-catenin signaling. This project seeks to define how Wnts activate fibrotic responses, to determine whether blocking Wnt/Beta -catenin signaling can prevent or attenuate fibrosis in scleroderma, and to ascertain whether markers of Wnt/Beta-catenin signaling can be used as biomarkers of disease activity, progression and severity, as well as tools to identify patient subsets that will respond to catenin-targeted therapy in a personalized or precision medicine strategy. We have previously shown that in scleroderma, fibrosis is consistently accompanied by subdermal fat loss and is associated with the down-regulation of PPAR-(peroxisome proliferator activated receptor), a master regulator of adipogenesis that signals through the adipokine adiponectin (APN). Circulating and tissue levels of adiponectin are significantly reduced in scleroderma. Here were port that APN causes a time-dependent down-regulation of both Wnt3a-induced canonical signaling and fibrotic responses at the mRNA and protein levels. Mechanistically, these effects involve suppression of both the expression and activation of the Wnt co-receptor low density lipoprotein receptor-related protein-6 (LRP6). These results demonstrate that adiponectin inhibits short-term-catenin signaling as well as the Wnt3a-mediated fibrotic response, identifying adiponectin as a natural anti-fibrotic agent with tremendous therapeutic potential.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2015
- Accession Number
- AD1014040
Entities
People
- Robert Lafyatis
Organizations
- Boston University Medical Campus