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Pathological changes in extracellular matrix composition orchestrate the fibrotic feedback loop through macrophage activation in Dupuytren’s contracture

ABSTRACT: Dupuytren’s contracture belongs to a large group of fibrotic diseases that share similar mechanisms but lack effective treatment and prevention options. Unlike fibrotic diseases affecting internal organs such as the heart, lung or liver which are typically diagnosed at later stages when the functions of the organ are irreversibly impaired, DD tissue can be diagnosed early and is readily accessible for scientific research after surgical excision. This enables us to analyse the mechanism of active fibrotic process in the relatively early-stage nodular tissue ex vivo. Here we described the changes in ECM-associated proteome of DD tissue and identified the components that potentially activate or promote the fibrosis in DD. Furthermore, our results indicate that the pathological changes in diseased ECM composition orchestrate a feedback loop through macrophage activation which promotes myofibroblast activation and differentiation.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin

SUBMITTER: Mariliis Klaas

LAB HEAD: Mariliis Klaas

PROVIDER: PXD059943 | Pride | 2025-03-29

REPOSITORIES: Pride

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			Action	DRS
	220106_03_Orbi3_MS_SER_G120_T150_Klaas_TYMRI_DD_M49NK_2ug_100pgiRT.raw	Raw
	220106_05_Orbi3_MS_SER_G120_T150_Klaas_TYMRI_CTRL_F75MB_2ug_100pgiRT.raw	Raw
	220106_07_Orbi3_MS_SER_G120_T150_Klaas_TYMRI_CTRL_M61VH_2ug_100pgiRT.raw	Raw
	220106_09_Orbi3_MS_SER_G120_T150_Klaas_TYMRI_CTRL_M74OK1_2ug_100pgiRT.raw	Raw
	220106_11_Orbi3_MS_SER_G120_T150_Klaas_TYMRI_DD_M64AA_2ug_100pgiRT.raw	Raw

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Project description: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 the 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. Four exon arrays of DD primary fibroblasts derived from fibrotic tissue were compared to fibroblasts derived from skin punch biopsies from individuals who did not show DD symptoms.

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Pathological changes in extracellular matrix composition orchestrate the fibrotic feedback loop through macrophage activation in Dupuytren’s contracture

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