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Comparative Evaluation of Agents on Dupuytren’s Contracture and Keloid Fibrosis
Yvonne Pierpont, MD1, M. Georgina Uberti, MD2, Martin C. Robson, MD1, Wyatt G. Payne, MD2.
1University of South Florida, Tampa, FL, USA, 2Institute for Tissue Regeneration, Repair, & Rehabilitation, Bay Pines V.A. Healthcare System, Bay Pines, FL, USA.
Purpose: Neoplasms are the result of abnormal proliferation of cells. Dupuytren’s contracture and keloid scar, similarly, is characterized by fibroblast hyperproliferation and collagen deposition. This common trait of over proliferation of cells has lead to investigation of antiproliferative/antimetabolite agents normally used in the treatment of neoplasms to be used to control/alleviate Dupuytren’s contracture and Keloid scar. While individual drug treatments show some decrease in contraction, there has not been reported investigation comparing antiproliferative/antimetabolite substances and their proposed mechanism of action. The purpose of this experimental series is to comparatively evaluate respective levels of TGFβ1 and 2 , and the rate and extent of contraction of fibroblasts derived from Keloid scar and Dupuytren’s contracture compared with control and when treated with antiproliferative/antimetabolite agents.
Methods: Fibroblasts obtained from human fibroblasts isolated from explants of Dupuytren’s contracture and palmar fascia (control) as well as Keloid scar and normal scar were embedded in collagen lattices. These fibroblast populated collagen lattices (FPCL) were exposed to 72 hr exposure on non-cytotoxic doses of 5-Fluorouracil, Methotrexate, Paclitaxel, Tamoxifen, Mitomycin-C, and Bleomycin. Standardized photography with digital planimetry and Sigma Scan software was utilized to evaluate FPCL contraction. Supernatant of FPCL was then analyzed using TGFβ1 and 2 immunoassays.
Results: When comparing untreated controls with abnormal scar sources, Dupuytren’s affected palmar fascia and keloid scar showed a greater degree of contraction when compared with respective controls. All FPCLs, regardless of the condition, showed a decrease in area one day after treatment. Dupuytren’s and keloid fibroblasts FPCLs showed greater sensitivity after exposure to 5 fluorouracil, mitomycin-c, tamoxifen, methotrexate, bleomycin, or paclitaxel; causing a significant decrease of contraction (p<0.05). While there was no statistical significant difference between drugs with Dupuyten's contracture fibroblasts, there was statistical significant difference found with contraction of Keloid derived FPCLs in which inhibition of contraction was significantly greater in the FPCLs that were treated with paclitaxel, tamoxifen and methotrexate (p=0.005). Expression of TGF-β2 from the supernatant of untreated FPCLs was significantly increased (p<0.05) in those which were populated with fibroblasts from Keloid scar and Dupuytren's affected fascia than that of their respective controls. Treatment of fibroblasts with all drugs tested resulted in significant down -regulation of TGF-β2 expression compared to untreated fibroblasts from these abnormal scar types.TGF-β1 secretion did not result in a significant difference between Keloid scar and Dupuytren's affected fascia when compared to their respective controls. Treatment with 5 fluorouracil, paclitaxel, tamoxifen and methotrexate on the Keloid scar group, and 5 fluorouracil, mitomycin-c, or methotrexate on the Dupuytren’s affected fascia group decreased the expression of TGF-β1 compared to the untreated controls.
Conclusion: Non-cytotoxic doses of antiproliferative/antimetabolite agents used in this study decrease FPCL contraction significantly when compared with untreated FPCL. These agents also cause a significant decrease in both TGFβ1 and 2, a likely cause to decreased contraction. Improved function, range of motion, and cosmesis are possible positive clinical effects of less scarring. Data from these investigations has potential to for treatment of the fibrosing conditions of Dupuytren’s contracture and keloids. Further investigation is warranted.
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