Scleroderma: nothing more true than “the root is skin-deep”

Sclerodermìa: la genetica individua altri fattori responsabili

A protein known to play a role in cancer may also be increasing fibrosis in scleroderma patients. Systemic sclerosis (Scleroderma, SSc) is a systemic chronic autoimmune disease comprised of blood vascular dysfunction, autoimmunity and excessive fibroblast activation that ultimately results in tissue damage and organ failure. Symptoms often include pain, stiffness, fatigue and breathing difficulties. The underlying cause of SSc appears to be multifactorial as various cell types and pathways have been implicated. Recent studies have provided strong support for the involvement of epigenetic mechanisms in SSc pathogenesis. Alterations of histone marks, DNA methylation, and noncoding RNAs were observed in immune cells, endothelial cells and fibroblasts isolated from patients with SSc, pointing to the importance of examining epigenetic regulation in this disease.  In a new study, published in Proceedings of the National Academy of Sciences, Dr. Amr Sawalha, MD, a professor in the Division of Rheumatology at the University of Michigan and his team, examined scleroderma at the molecular level to better understand the fibrosis process. “We examined the protein EZH2, which has been known to play a role in several types of cancer. This protein regulates gene expression, by affecting modifications that happen to DNA and other proteins attached to DNA”.

The team had previously identified a role for EZH2 in lupus, another autoimmune disease, flares.  EZH2 induces histone H3 methylation and is the catalytic component of the highly conserved polycomb-repressive complex 2 (PRC2) that represses transcription. However, in certain circumstances, EZH2 activates transcription, which is PRC2-independent. EZH2 is involved in gene expression, particularly by affecting genes associated with cell adhesion. EZH2 is overexpressed in lupus T cells, which makes these white blood cells active in lupus patients. We then expanded our studies to scleroderma and specifically looked at the role of EZH2 in fibroblasts and endothelial cells in this disease. The research team first isolated cells from scleroderma patients in collaboration with the Michigan Medicine Scleroderma Program. The program provides care for a large number of scleroderma patients at the University of Michigan. They then expanded their studies to animal models to further test findings identified in the human cells. Both increased fibrosis and abnormal blood vessel function, or defective angiogenesis, are major aspects of pathology in this autoimmune disease. After cellular analysis, researchers found that increased levels of EZH2 were contributing to this disease process in SSc patients.

After identifying the molecule, the research team examined what happened in the cells when EZH2 was inhibited. Because EZH2 is a protein known to play a role in cancers, says the ability to translate their laboratory work to patients may be easier. Therefore they employed one of the already known EZH2 inhibitor called DNZep, administering the drug to mice experimentally affected with a SSc model. Dr Sawalha explained the results and the hopes behind them: “When we suppressed EZH2, we found we could correct increased fibrosis and abnormal blood vessel function in scleroderma.  Inhibition of EZH2 reduces TGFβ-Smad signaling pathways and suppresses activation of the EGFR and PDGFR pathways. Both these growth factor receptors are involved in deregulated fibroblast growth, in other words in the onset of both skin and inner organs hardening. What is nice is that EZH2 inhibitors are already developed and in clinical trials in certain cancers. Therefore, our findings can be more readily translated to the bedside, by repurposing already existing inhibitors for EZH2 to treat scleroderma. As there are currently no effective treatment options for scleroderma, this type of research is important for future studies and trials”.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Tsou P et al. Proc Natl Acad Sci USA. 2019 Feb; 116(9):3695-3702.

Mariotti B et al., Bazzoni F. Front Immunol. 2019 Jan 31; 10:100. 

Ciechomska M et al. Eur J Clin Invest. 2017 Aug; 47(8):555-564.

Informazioni su Dott. Gianfrancesco Cormaci 1716 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it