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Developing an Animal Model of Dupuytren's Disease by Orthotopic Transplantation of Human Fibroblasts into Athymic Rat
Latha Satish, MSc, MPhil, PhD1; Bradley A. Palmer, MD2; Fang Liu, BS1; Loukia Papatheodorou, MD4; Lora Rigatti, VMD, DACVP3; Mark E. Baratz, MD4; Sandeep Kathju, MD, PhD1
1Plastic Surgery, University of Pittsburgh, Pittsburgh; 2Orthopaedic Surgery, Allegheny General Hospital, Pittsburgh, PA; 3University of Pittsburgh, Pittsburgh, PA; 4Hand and Upper Extremity Surgery, Orthopaedic Specialists at University of Pittsburgh Medical Center, Washington, PA

Background: Dupuytren’s disease (DD) is a slow, progressive fibroproliferative disorder affecting the palms of the hands. The disease is characterized by the formation of collagen rich- cords which gradually shorten by the action of myofibroblasts resulting in finger contractures. It is a disease that is confined to humans, and a major limiting factor in investigating this disorder has been the lack of a faithful animal model that can recapitulate its distinct biology. The aim of this study was to develop such a model by determining if Dupuytren’s disease (DD)- and control carpal tunnel (CT)-derived fibroblasts could survive in the forepaw of the nude rats and continue to exhibit the distinct characteristics they display in in vitro cultures.

Methods: 1x107 fluorescently labeled DD - and CT-derived fibroblasts were transplanted into the left and right forepaws of nude rats respectively. Cells transplanted to the forepaws were tracked at regular intervals for a period of two months by quantifying emitted fluorescent signal using an IVIS imaging system. After a period of 62 days rat forepaw connective tissues were harvested for histology and total RNA was isolated. Human-specific probes were used to perform real time RT-PCR assays to examine the expression patterns of gene products associated with fibrosis in DD. Rat forepaw skin was also harvested to serve as an internal control.

Results: Both CT- and DD-derived fibroblasts survived for a period of 62 days, but DD-derived cells showed a significantly greater level of persistent fluorescent signal at the end of this time than did CT-derived cells. mRNA expression levels of ?-smooth muscle actin (?-SMA), type I- and type III- collagens were all significantly elevated in the forepaw receiving DD cord-derived fibroblasts in comparison to CT-derived fibroblasts. Masson trichrome stain confirmed increased collagen deposition in the forepaw that was injected with DD cord-derived fibroblasts.

Conclusion: In conclusion, for the first time we describe an animal model for Dupuytren’s disease at the orthotopic anatomical location. We further show that gene expression differences between control (CT) and diseased (DD) derived fibroblasts persist when these cells are transplanted to the forepaw of the nude rat. These preliminary findings indicate that, with further refinements, this animal model holds promise as a baseline for investigating novel therapeutic regimens to determine an effective strategy in treating DD.


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