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American Association for Hand Surgery
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Theme: Inclusion and Collaboration Theme: Inclusion and Collaboration

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Actions of Pirfenidone on TGFbeta1- stimulated Non-Smad Signaling Pathways in Dupuytren's-derived fibroblasts
Chaoming Zhou, MD1; Yael Zeldin, BS1; Mark E. Baratz, MD2; Sandeep Kathju, MD, PhD1; Latha Satish, MSc, PhD3,4; (1)University of Pittsburgh, Pittsburgh, PA, (2)Hand and Upper Extremity Surgery, Orthopaedic Specialists at University of Pittsburgh Medical Center, Washington, PA, (3)Shriners Hospitals for Children, Cincinnati, OH, (4)Plastic Surgery, University of Pittsburgh, Pittsburgh, PA

Background: Dupuytren's disease (DD) is a complex fibro-proliferative disorder of the hand that is often progressive and eventually can cause contractures of the affected fingers. The increase in transforming growth factor (TGF-?1) expression has been implicated as a key stimulator of myofibroblast activity and palmar fascial contraction in DD. Pirfenidone (PFD), is an active small molecule with potential to inhibit TGF?1-mediated action in fibrotic disorders. Our recent published findings show that PFD reduced TGF-?1- mediated cellular functions leading to Dupuytren's through Smad signaling pathway. In the present study, the effect of PFD on TGF-?1-mediated non-Smad signaling pathway was determined in both CT- and DD-derived fibroblasts.

Materials and Methods: Fibroblasts harvested from Dupuytren's disease (DD) and carpal tunnel (CT)-derived fibroblasts were treated with or without TGF-?1 (10 ng/ml) and/or PFD (800 ?g/ml) and were subjected to Western blots analyses to determine the phosphorylation levels of phosphatidylinositol-3 kinase (PI3K/AKT), extracellular regulated kinases (ERK1/2), p38 and Rho family related myosin light chain (MLC).

Results: Our results show that the basal phosphorylation levels of ERK1/2, Akt and MLC and p38 were increased by stimulating by TGF-?1 in DD-and CT-derived fibroblasts. Treatment with PFD led to the inhibition of both basal and TGF-?1-induced phosphorylation of the above proteins in both CT-and DD-derived fibroblasts. PFD inhibits not only expression and activation of downstream p-Smad 2/3 effectors but also non-Smad signaling targets.

Discussion: We have previously shown that pirfenidone can effectively downregulate TGF- ?1 induced phosphorylation of Smad2/Smad3, a key factor in the TGF-?1 signaling pathways. Our present study indicates for the first time that PFD has potential to inhibit TGF-?1 induced non-Smad signaling molecules. Taken together, these in vitro results suggest PFD as a promising candidate to inhibit both Smad and non-Smad signaling molecules stimulated by TGF-?1 that lead to fibrosis. Further, in vivo studies are required to determine the therapeutic efficacy of PFD in preventing DD contractures.


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