No gene copy number changes in Dupuytren's contracture by array comparative genomic hybridization
ABSTRACT Dupuytren's contracture (DC), a benign disease of unknown origin, is characterized by abnormal fibroblast proliferation and matrix deposition within the palmar and plantar faciae, causing contracture of the digits. Conventional cytogenetic studies of cultured fibroblast cells from DC nodules have revealed nonrecurrent, but usually normal, clonal (mainly +7, +8, and -Y, plus structural changes) and sporadic (nonclonal) numerical/structural rearrangements. No unique cytogenetic features of DC are known so far. We used 44K oligonucleotide-based array comparative genomic hybridization to obtain a wide pattern of chromosomal imbalances in 18 patients with DC. The genome-wide analysis revealed no changes of DNA copy number sequences. Accordingly, gene amplifications or deletions are apparently not involved in the progression of abnormal fibroblast proliferation and matrix deposition that lead to DC.
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ABSTRACT: Dupuytren's Disease (DD) is a common and heritable fibrosis of the palmar fascia that typically manifests as permanent finger contractures. The molecular interactions that induce the development of hyper-contractile fibroblasts, or myofibroblasts, in DD are poorly understood. We have identified IGF2 and IGFBP6, encoding insulin-like growth factor (IGF)-II and IGF binding protein (IGFBP)-6 respectively, as reciprocally dysregulated genes and proteins in primary cells derived from contracture tissues (DD cells). Recombinant IGFBP-6 inhibited the proliferation of DD cells, patient-matched controls (PF) cells and normal palmar fascia (CT) cells. Co-treatments with IGF-II, a high affinity IGFBP-6 ligand, were unable to rescue these effects. A non-IGF-II binding analog of IGFBP-6 also inhibited cellular proliferation, implicating IGF-II-independent roles for IGFBP-6 in this process. IGF-II enhanced the proliferation of CT cells, but not DD or PF cells, and significantly enhanced DD and PF cell contractility in stressed collagen lattices. While IGFBP-6 treatment did not affect cellular contractility, it abrogated the IGF-II-induced contractility of DD and PF cells in stressed collagen lattices. IGF-II also significantly increased the contraction of DD cells in relaxed lattices, however this effect was not evident in relaxed collagen lattices containing PF cells. The disparate effects of IGF-II on DD and PF cells in relaxed and stressed contraction models suggest that IGF-II can enhance lattice contractility through more than one mechanism. This is the first report to implicate IGFBP-6 as a suppressor of cellular proliferation and IGF-II as an inducer of cellular contractility in this connective tissue disease.Biochimica et Biophysica Acta 04/2013; DOI:10.1016/j.bbadis.2013.04.018 · 4.66 Impact Factor
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ABSTRACT: Dupuytren's disease (DD) is a common fibroproliferative disorder affecting the palmar fascia, which may lead to permanent contracture of the affected digit. Profiling studies investigating DD at whole-genomic, transcriptomic and proteomic levels have been carried out, from which large numbers of candidate genes potentially involved in DD have been reported. This review focuses on identifying genes reported by multiple studies or validated by multiple experimental techniques, as well as signalling pathways suggested to contribute to DD. Meta-analysis was also carried out on three microarray datasets. Twenty-one genes were found to be reported as dysregulated in multiple gene expression microarrays, seven of which have been further validated by other experimental methods. Sixty-four genes determined to be dsyregulated by meta-analysis correlate to those reported by published microarray studies. In addition, several pathways have been proposed to be involved in DD by whole-genome or global expression profiling. Further investigation in these genes and pathways, and correlating them to genotypes or environmental factors for DD, may aid in further elucidation of mechanisms involved in DD pathogenesis.Annals of the rheumatic diseases 07/2012; 71(9):1440-7. DOI:10.1136/annrheumdis-2012-201295 · 9.27 Impact Factor
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ABSTRACT: Dupuytren's disease is a common fibroproliferative disorder with an unknown etiology. Emerging evidence suggests a strong genetic component involved in the manifestation of the disease. This study aims to investigate the potential involvement of copy number variations in Dupuytren's disease pathogenesis. Array-based comparative genomic hybridization (NimbleGen Human CGH 2.1 M) was utilized to compare DNA from (1) nodules versus internal control (patient's blood; n = 4) and (2) nodules (n = 4) versus external control (commercial reference DNA pooled from 10 donors). Analysis was carried out using Nexus 5.1 (BioDiscovery, El Segundo, Calif.) with the inclusion of additional results from previously published array-based comparative genomic hybridization. Copy number variations were considered to be common in Dupuytren's disease if the overlap was statistically significant and they were present in the majority (75 to 87.5 percent when compared with controls) of Dupuytren's disease nodules. The copy number variations loci were also compared with recently published genome wide-association studies. Common copy number variations were further validated using quantitative polymerase chain reaction. DNA from 25 Dupuytren's disease cases and 30 external controls were used in the quantitative polymerase chain reaction validation. In addition, gene expression was compared between Dupuytren's disease nodules and internal controls (transverse palmar fascia; n = 7). Five common copy number variations, on chromosome 17q12, 1p31.1, 20p13, 7p14.1, and 14q11.2, were identified by array-based comparative genomic hybridization. Significantly higher copy numbers of copy number variations at chromosome 7p14.1 and 14q11.2 in Dupuytren's disease were confirmed in quantitative polymerase chain reaction validation. Matrix metalloproteinase-14 and secreted frizzled-related protein 4 (near a polymorphism recently associated with Dupuytren's disease) were significantly up-regulated in nodules. This study demonstrated an association between Dupuytren's disease and copy number variations at chromosomes 7p14.1 and 14q11.2.Plastic and Reconstructive Surgery 12/2011; 129(4):921-32. DOI:10.1097/PRS.0b013e3182442343 · 3.33 Impact Factor