Systemic mesalazine treatment prevents spontaneous skin fibrosis in PLK2-deficient mice
Open Access
- 19 August 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie
- Vol. 394 (11), 2233-2244
- https://doi.org/10.1007/s00210-021-02135-w
Abstract
Skin fibrosis is a complex biological remodeling process occurring in disease like systemic sclerosis, morphea, or eosinophilic fasciitis. Since the knowledge about the underlying pathomechanisms is still incomplete, there is currently no therapy, which prevents or reverses skin fibrosis sufficiently. The present study investigates the role of polo-like kinase 2 (PLK2) and the pro-fibrotic cytokine osteopontin (OPN) in the pathogenesis of cutaneous fibrosis and demonstrates the antifibrotic effects of systemic mesalazine treatment in vivo. Isolated primary dermal fibroblasts of PLK2 wild-type (WT) and knockout (KO) mice were characterized in vitro. Skin thickness and histoarchitecture were studied in paraffin-embedded skin sections. The effects of mesalazine treatment were examined in isolated fibroblasts and PLK2 KO mice, which were fed 100 µg/g mesalazine for 6 months via the drinking water. Compared to WT, PLK2 KO fibroblasts displayed higher spontaneous myofibroblast differentiation, reduced proliferation rates, and overexpression of the fibrotic cytokine OPN. In vitro, 72 h of treatment with 10 mmol/L mesalazine induced phenotype conversion in PLK2 KO fibroblasts and attenuated OPN expression by inhibiting ERK1/2. In vivo, dermal myofibroblast differentiation, collagen accumulation, and skin thickening were prevented by mesalazine in PLK2 KO. Plasma creatinine levels indicated good tolerability of systemic long-term mesalazine treatment. The current study reveals a spontaneous fibrotic skin phenotype and ERK1/2-dependent OPN overexpression in PLK2 KO mice. We provide experimental evidence for the antifibrotic effectiveness of systemic mesalazine treatment to prevent fibrosis of the skin, suggesting further investigation in experimental and clinical settings.Funding Information
- Technische Universität Dresden
This publication has 56 references indexed in Scilit:
- Dermatological pharmacology: topical agentsMedicine, 2013
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- Osteopontin in Systemic Sclerosis and Its Role in Dermal FibrosisJournal of Investigative Dermatology, 2012
- Involvement of Polo-like Kinase 1 (Plk1) in Mitotic Arrest by Inhibition of Mitogen-activated Protein Kinase-Extracellular Signal-regulated Kinase-Ribosomal S6 Kinase 1 (MEK-ERK-RSK1) CascadeOnline Journal of Public Health Informatics, 2012
- Fibroblasts and Myofibroblasts: What Are We Talking About?Journal of Cardiovascular Pharmacology, 2011
- Requirement for Plk2 in Orchestrated Ras and Rap Signaling, Homeostatic Structural Plasticity, and MemoryNeuron, 2011
- Polo-like kinases mediate cell survival in mitochondrial dysfunctionProceedings of the National Academy of Sciences of the United States of America, 2009
- Up-Regulation and Profibrotic Role of Osteopontin in Human Idiopathic Pulmonary FibrosisPLoS Medicine, 2005
- Treatment of Orthognathic Problems Related to SclerodermaAnnals of Plastic Surgery, 1990
- Therapeutic Efficacy of Sulfasalazine and Its Metabolites in Patients with Ulcerative Colitis and Crohn's DiseaseThe New England Journal of Medicine, 1980