SSAT1 inhibition slows synovial fibroblast invasion

Onuora, Sarah

doi:10.1038/nrrheum.2014.45

Cited by 2 publications

(2 citation statements)

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“…synoviocytes from patients with rheumatoid arthritis are particularly able to invade and destroy joints (28)(29)(30). Careful histological observations of the architecture of fibrosis also suggest an important contribution of fibroblast invasion to IPF pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

Ahluwalia

Grasberger

Mugo

et al. 2016

Am J Respir Cell Mol Biol

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Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-b, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.Keywords: idiopathic pulmonary fibrosis; pathogenesis; fibroblast; invasion; migration Idiopathic pulmonary fibrosis (IPF) is a disease of great unmet medical need. Aberrant or overexuberant wound healing responses to chronic lung injury are now thought to be responsible for the excessive fibroblast accumulation and extracellular matrix deposition that distort the lung's architecture and compromise its function in IPF (1, 2). Better characterization of these abnormal responses to lung injury should provide a rich set of therapeutic targets for novel IPF therapies.The abnormal accumulation of fibroblasts is a central hallmark of fibrotic tissues, including the lung in IPF. In addition to fibroblast proliferation, fibroblast accumulation in pulmonary fibrosis appears to fundamentally depend on: (1) the migration of these cells to sites of tissue injury; and (2) their ability to invade extracellular matrix. Although migration

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Section: Discussionmentioning

confidence: 99%

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

Ahluwalia

Grasberger

Mugo

et al. 2016

Am J Respir Cell Mol Biol

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“…More recently, it has been shown that diminazene aceturate (DA), an inhibitor of SSAT-1, can restore both the levels of DNA methylation and the expression of DNMT1, leading to reduced RASF invasive function [Neidhart et al 2014]. These results open up the possibility of using pharmacological therapy to restore the DNA methylation patterns in RASF, and subsequent efforts are being made to develop a more specific inhibitor of SSAT-1 [Onuora, 2014].…”

Section: Therapeutic Implications Of Altered Dna Methylation Patternsmentioning

confidence: 99%

Towards an understanding of the role of DNA methylation in rheumatoid arthritis: therapeutic and diagnostic implications

Cribbs

Feldmann²,

Oppermann

2015

Therapeutic Advances in Musculoskeletal

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The term 'epigenetics' loosely describes DNA-templated processes leading to heritable changes in gene activity and expression, which are independent of the underlying DNA sequence. Epigenetic mechanisms comprise of post-translational modifications of chromatin, methylation of DNA, nucleosome positioning as well as expression of noncoding RNAs. Major advances in understanding the role of DNA methylation in regulating chromatin functions have been made over the past decade, and point to a role of this epigenetic mechanism in human disease. Rheumatoid arthritis (RA) is an autoimmune disorder where altered DNA methylation patterns have been identified in a number of different disease-relevant cell types. However, the contribution of DNA methylation changes to RA disease pathogenesis is at present poorly understood and in need of further investigation. Here we review the current knowledge regarding the role of DNA methylation in rheumatoid arthritis and indicate its potential therapeutic implications.

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SSAT1 inhibition slows synovial fibroblast invasion

Cited by 2 publications

References 0 publications

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

Towards an understanding of the role of DNA methylation in rheumatoid arthritis: therapeutic and diagnostic implications

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