Dupuytren's disease (DD) is a nodular palmar fibromatosis that causes irreversible permanent contracture of fingers and results in the loss of hand function. Surgery still remains the only available solution for DD patients but cannot permanently cure the disease nor reduce high recurrence rates. With this rationale, we designed a study aimed at an improved understanding of the molecular mechanisms underlying DD. Our major focus was an analysis of the global gene expression profile and signalling pathways in DD cells with the aim of identifying novel biomarkers and/or therapeutic targets. Primary cells were cultured from surgically removed diseased and healthy tissue. Microarray expression analysis (HG-U133A array, Affymetrix) and qPCR was performed with total RNA isolated from primary DD cells. Mechanistic studies involving inhibition of p38 phosphorylation were performed on normal human fibroblasts' and primary DD cells' in vitro models. Expression of stem cell markers in primary fibroblasts/myofibroblasts was assessed as well. We identified 3 p38MAPK signalling pathway regulatory genes, THBS1, GADD45α and NUAK1, all involved in cellular proliferation and production of the extracellular matrix proteins. Inhibition of the p38MAPK signalling pathway induced down-regulation of myofibroblast markers, α-smooth muscle actin and palladin. A stem-cell like subpopulation positive for CD90 marker was identified among primary DD cells. The study reveals involvement of the p38 MAPK pathway as a possible signalling cascade in the pathogenesis of Dupuytren's disease. Moreover, a particular stem cell-like CD90(+) subpopulation was identified that might contribute to DD development.

This report describes a variable microsatellite repeat sequence located in the 5′ untranslated exon of NSPAS2, a gene encoding a clock transcription factor. Significantly, this study is the first to show that a variant copy number GGC repeat sequence in the NPAS2 clock gene associates with melanoma risk and which may be useful in the assessment of melanoma predisposition.

Psoriasis is a benign, chronic skin disease characterized by keratinocyte hyperproliferation and abnormal differentiation. Telomerase is an enzyme-reverse transcriptase that protects chromosomes from degradation by stabilizing telomere length. Recent studies suggest that telomerase activity (TA) may be responsible in part for some of nonmalignant proliferative skin diseases. There is evidence that telomerase has an active anti-apoptotic role. TA in general is associated with cellular proliferation. We hypothesize a relationship between TA, keratinocyte proliferation and apoptosis in psoriatic skin lesions. The TA in telomere elongation makes keratinocyte hyperproliferation possible and is at the same time, one of its limiting factors. This hyperproliferation in psoriasis occurs as a result of significant keratinocyte damage caused by self-reactive T-cells through induction of various apoptotic pathways. On the other hand, TA in telomere elongation, together with other factors, has an active anti-apoptotic role, preserving the necessary amount of equilibrium between these two processes (apoptosis and proliferation) therefore being the main reason why conversion of a psoriatic plaque to squamous cell carcinoma is rare. As there is little data on TA in psoriatic lesions, in evaluation of our hypothesis we suggest thorough parallel studies of TA, telomere length, apoptosis and proliferation in psoriatic lesional skin on multiple checkpoints and targets, using more samples so the reliability of the results would be higher. This is important since a better understanding of these factors might provide new possible therapeutic targets.

Although functional genomics methods offer new viewpoint on molecular processes involved in particular pathological state, these methods, in particular proteomics, are still under-represented in Dupuytren's contracture research. However, several recent papers based on functional genomics technologies represent a breakthrough in studying Dupuytren's contracture as they revealed new molecular players that had been impossible to detect by traditional molecular biology methods. Using computational tools to provide biological context for such broad arrays of data accelerates the process of homing in on the potential molecular markers and drug targets. Interactomes, maps of protein-protein interactions characteristic for the disease and as such putative models of its molecular pathology, are especially useful for this purpose, facilitating the transition from global screening methods to specific experiments aimed at therapy development. The combination of these approaches in Dupuytren's contracture research might therefore facilitate the discovery of novel therapeutic targets and diagnostic markers indicative of disease progression.