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Targeting CD109 In Dupuytren's Disease
Yasser Almadani1, Ana Maria  Pena Diaz2, Kenneth Finnson1, David O'Gorman2, Anie Philip1.
1McGill University, Montreal, QC, Canada, 2Western University, London, ON, Canada.

Background and Rationale: Persistent accumulation of extracellular matrix (ECM) proteins, represents the clinical hallmark of several fibrotic disorders including Dupuytren’s disease. Aberrant activation of TGF-β signaling has been strongly implicated in Dupuytren’s disease fibrosis (DD). We have previously identified CD109, a membrane-anchored protein, as a potent inhibitor of TGF-β signaling and fibrotic responses in vitro and in vivo. Our objectives were to determine whether CD109 regulates the fibrotic process in DD and to understand the underlying mechanisms involved.

Methods and Results: We examined CD109 expression and function in primary human DD fibroblasts (DDF) as compared to phenotypically normal fibroblasts from adjacent palmar fascia (DPF), or anatomically-matched normal fibroblasts (control) from carpal tunnel syndrome patients (CTF), using immunofluorescent staining, Western blot, qPCR or siRNA mediated deletion. Our results show that CD109 protein levels are decreased in DDF and adjacent normal DPF when compared to control CTF, while CD109 mRNA expression levels are similar in DD, PF and CT fibroblasts. Our results also suggest that CD109 protein released from the cell surface are similar in all three types of fibroblasts implying that CD109 degradation is likely enhanced in DDF. In addition, the diminished CD109 protein levels in DDF and DPF are associated with increased alpha-smooth muscle expression in those cells, which is consistent with the known function of CD109 to decrease fibrotic responses in several cell types. Furthermore, manipulation of CD109 protein levels leads to a differential regulation of ALK5/Smad2/3 signaling versus ALK1/Smad1/5 signaling with increased CD109 levels promoting the anti-fibrotic ALK1/Smad1/5 signaling.

Conclusion: Our finding that CD109 protein levels are decreased in DD fibroblasts and adjacent PF fibroblasts as compared to normal CT fibroblasts, provides a mechanistic explanation for the increased fibrotic response in DD. This together with our finding that CD109 promotes the anti-fibrotic Smad1/5 pathway over the pro-fibrotic Smad2/3 pathway in these cells, suggests that CD109 plays an important role in DD fibrosis and thus may represent a molecular target for therapeutic intervention in DD.

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