title: RETRACTED: In vitro study of novel collagenase (XIAFLEX®) on Dupuytren's disease fibroblasts displays unique drug related properties.
abstract: Dupuytren's disease (DD) is a benign, fibroproliferative disease of the palmar fascia, with excessive extracellular matrix (ECM) deposition and over-production of cytokines and growth factors, resulting in digital fixed flexion contractures limiting hand function and patient quality of life. Surgical fasciectomy is the gold standard treatment but is invasive and has associated morbidity without limiting disease recurrence. Injectable Collagenase Clostridium histolyticum (CCH)--Xiaflex®--is a novel, nonsurgical option with clinically proven in vivo reduction of DD contractures but with limited in vitro data demonstrating its cellular and molecular effects. The aim of this study was to delineate the effects of CCH on primary fibroblasts isolated from DD and non-DD anatomical sites (using RTCA, LDH, WST-1, FACS, qRT-PCR, ELISA and In-Cell Quantitative Western Blotting) to compare the efficacy of varying concentrations of Xiaflex® against a reagent grade Collagenase, Collagenase A. Results demonstrated that DD nodule and cord fibroblasts had greater proliferation than those from fat and skin. Xiaflex® exposure resulted in dose- and time-dependent inhibition of cellular spreading, attachment and proliferation, with cellular recovery after enzyme removal. Unlike Collagenase A, Xiaflex® did not cause apoptosis. Collagen expression patterns were significantly (p<0.05) different in DD fibroblasts across anatomical sites - the highest levels of collagen I and III were detected in DD nodule, with DD cord and fat fibroblasts demonstrating a smaller increase in both collagen expression relative to DD skin. Xiaflex® significantly (p<0.05) down-regulated ECM components, cytokines and growth factors in a dose-dependent manner. An in vitro scratch wound assay model demonstrated that, at low concentrations, Xiaflex® enabled a faster fibroblast reparatory migration into the wound, whereas, at high concentrations, this process was significantly (p<0.05) inhibited. This is the first report elucidating potential mechanisms of action of Xiaflex® on Dupuytren fibroblasts, offering a greater insight and a better understanding of its effect in DD.
authors.affiliation: Plastic and Reconstructive Surgery Research, School of Translational Medicine, Manchester Interdisciplinary Biocentre, University of Manchester, Manchester, United Kingdom.
authors.forename: Farhatullah
authors.initials: F
authors.lastname: Syed
authors.forename: Alexis N
authors.initials: AN
authors.lastname: Thomas
authors.forename: Subir
authors.initials: S
authors.lastname: Singh
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Kolluru
authors.forename: Susan G
authors.initials: SG
authors.lastname: Emeigh Hart
authors.forename: Ardeshir
authors.initials: A
authors.lastname: Bayat
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004387:Dupuytren Contracture / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D003012:Microbial Collagenase / Q000378:metabolism* / Q000494:pharmacology*; D008875:Middle Aged; D009336:Necrosis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D003012:Microbial Collagenase