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Importance of p38 MAPK pathway in development of Dupuytren's disease


Bujak, Maro; Ratkaj, Ivana; Baus Lončar, Mirela; Jurišić, Davor; Pavelić, Krešimir; Kraljević Pavelić, Sandra
Importance of p38 MAPK pathway in development of Dupuytren's disease // FEBS3+ Meeting From molecules to life and back / Dumić J, Kovarik Z, Varljen J (ur.).
Rijeka: Croatian Society of Biochemistry and Molecular Biology, 2012. str. 218-218 (poster, međunarodna recenzija, sažetak, znanstveni)


Naslov
Importance of p38 MAPK pathway in development of Dupuytren's disease

Autori
Bujak, Maro ; Ratkaj, Ivana ; Baus Lončar, Mirela ; Jurišić, Davor ; Pavelić, Krešimir ; Kraljević Pavelić, Sandra

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
FEBS3+ Meeting From molecules to life and back / Dumić J, Kovarik Z, Varljen J - Rijeka : Croatian Society of Biochemistry and Molecular Biology, 2012, 218-218

ISBN
978-953-95551-4-4

Skup
FEBS3+ Meeting From molecules to life and back

Mjesto i datum
Opatija, Hrvatska, 13-16.06.2012

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Dupuytren disease; p38; TGF-β

Sažetak
Dupuytren's disease (DD) is a fibroproliferative disorder of the palmar fascia described as irreversible permanent contracture of fingers resulting with the permanent loss of hand function. Similar to other fibrosis, the hallmarks of DD are intensive fibroblasts/myofibroblasts proliferation, excessive collagen and extra-cellular matrix deposition and myofibroblasts driven contraction.. Myofibroblasts are thus central to DD pathogenesis and may even be considered an active part of the innate immune system that displays many functions and receptors in common with macrophages. Due to such features, myofibroblasts can recruit immunomodulatory molecules and stimulate the immune response thus amplifying fibrotic processes. Among known fibrogenic cytokines, TGF-β has been implicated as a key stimulator of myofibroblasts activity and fascial contraction in Dupuytren's disease. TGF-β exerts its activities through the Smad proteins or alternatively through Ras, Erk, Rho GTPase, JNK or p38 MAP kinases. The inhibiton of the p38 MAPK pathway has indeed, been reported to reduce some fibroses such as pulmonary and renal fibroses in animal models. We have therefore, developed a primary cell culture model to assess the role of p38 MAPK pathway in Dupyutren’s disease. For that purpose, the cells were grown from unaffected Dupuytren’s disease patients fascia obtained from the edge of primary incision. Cells were treated with TGF-β alone and together with the p38 phosphorylation inhibitor. Upon treatment of cells, we assessed the (1) activation status of a kinase phosphorylated solely by p38, namely the MK2 kinase by Western blotting (2) measured the expression levels of fibrotic-related genes and genes involved in human autoimmune and inflammatory immune responses by quantitative real-time PCR and (3) the effect on fibroblast/myofibroblast contractility by use of three-dimensional collagen gel contraction assay. Obtained results reveal that treatment of cells by TGF-β successfully induced activation of various fibrotic genes, i.e. α-SMA, fibronectin, palladin, collagen 1 α1, ARHGDIA, IGFR-1, THBS-1, PAI-1, TIMP-1, CCL11 and IL-6. Moreover, inhibition of p38 phosphorylation inhibited phosphorilation of MK2 kinase that led to decreased expression of fibrotic genes THBS-1, collagen 1α1, fibronectin, PAI-1 and CCL11. In line with these results, we managed to measure increased fibroblast contractility upon TGF-β treatment and decreased contractility of cells upon inhibition of p38 phosphorylation. In conclusion, inhibition of p38MAPK signalling pathway may provide a novel therapeutic avenue for the treatment of Dupuytren’s disease.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Biotehnologija



POVEZANOST RADA


Ustanove
Institut "Ruđer Bošković", Zagreb,
Klinički bolnički centar Rijeka,
Sveučilište u Rijeci - Odjel za biotehnologiju