Genome-Wide Analysis Using Exon Arrays Demonstrates an Important Role for Expression of Extra-Cellular Matrix, Fibrotic Control and Tissue Remodelling Genes in Dupuytren's Disease

Abstract

Dupuytren's disease (DD) is a classic example of pathological fibrosis which results in a debilitating disorder affecting a large sector of the human population. It is characterized by excessive local proliferation of fibroblasts and over-production of collagen and other components of extracellular matrix (ECM) in the palmar fascia. The fibrosis progressively results in contracture of elements between the palmar fascia and skin causing flexion deformity or clawing of the fingers and a severe reduction in hand function. While much is known about the pathogenesis and surgical treatment of DD, little is known about the factors that cause its onset and progression, despite many years of research. Gene expression patterns in DD patients now offers the potential to identify genes that direct the pathogenesis of DD. In this study we used primary cultures of fibroblasts derived from excisional biopsies of fibrotic tissue from DD patients to compare the gene expression profiles on a genome-wide basis with normal control fibroblasts. Our investigations have identified genes that may be involved with DD pathogenesis including some which are directly relevant to fibrosis. In particular, these include significantly reduced expression levels of three matrix metallopeptidases (MMP1, MMP3, MMP16), follistatin, and STAT1, and significantly increased expression levels of fibroblast growth factors (FGF9, FGF11), a number of collagen genes and other ECM genes in DD patient samples. Many of these gene products are known to be involved in fibrosis, tumour formation and in the normal processes of tissue remodelling. In addition, alternative splicing was identified in some DD associated genes. These highly sensitive genomic investigations provide new insight into the molecular mechanisms that may underpin the development and progression of DD.

Distinct Expression Profiles of lncRNAs Between Regressive and Mature Scars

“…Type I collagenolysis is mediated by secreted, as well as membrane-anchored members of the matrix metalloproteinase (MMP) gene family during fibroblast-mediated matrix remodeling [22]. MMP16 is part of the matrix metalloproteinase (MMP) gene family that is directly relevant to fibrosis [23]. Previous reports demonstrated that severe hypoxia existed in regressive scars, and oxygen levels return to normal in mature scars, findings that are consistent with dynamic changes in microvessel density [5].…”

Non-Coding RNAs: The New Insight on Hypertrophic Scar

“…Type I collagenolysis is mediated by secreted, as well as membrane‐anchored members of the matrix metalloproteinase (MMP) gene family during fibroblast‐mediated matrix remodeling [Sabeh et al, ]. MMP16 is part of the matrix metalloproteinase (MMP) gene family that is directly relevant to fibrosis [Forrester et al, ].…”

Dupuytren’s contracture: the status and impact of collagenase Clostridium histolyticum treatment in Austria

“…Further proteins are platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF) and interleukin-1 (IL-1), as well as the cell matrix proteins Tenascin and Periostin that also affect differentiation, growth and contractility of myofibroblasts. However, the exact pathogenesis and pathology have yet to be decrypted [1,[9][10][11][12].…”