Active synthesis of type I collagen homotrimer in Dupuytren’s fibrosis is unaffected by anti–TNF-α treatment

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Abstract

Dupuytren’s disease is a common fibroproliferative disease of the palmar fascia of the hand, with advanced cases treated surgically. Anti-TNF injection has undergone phase 2 trials and may be effective in slowing early-stage disease progression. Here we sought to determine how new synthesis of type I collagen in Dupuytren’s differs from normal palmar fascia samples and to analyze the role of TNF in aberrant collagen synthesis. Model nonfibrotic but fibrous connective tissues were used to analyze active type I collagen protein synthesis in development, aging, and degenerative disease, where it was restricted to early development and ruptured tissue. Dupuytren’s tissue was shown to actively synthesize type I collagen, including abnormal type I collagen homotrimer. TNF-α reduced COL1A2 gene expression only in the presence of serum in 2D cell culture and had opposing effects on collagen protein production in the presence or absence of serum. TNF-α had only limited effects in 3D tendon–like constructs. Anti-TNF did not reduce type I collagen synthesis in 3D tendon–like constructs or prevent type I collagen homotrimer synthesis in Dupuytren’s tissue. Hence, modulation of the TNF-α pathway in Dupuytren’s disease is unlikely to prevent the pathological collagen accumulation that is characteristic of fibrosis.

Authors

Kate Williamson, Katie J. Lee, Emma L. Beamish, Alan Carter, Jade A. Gumbs, Gabriella Cooper, Niamh S. O’Heneghan-Yates, Lisa A. Menezes, Graham Cheung, Daniel Brown, Rob Pettitt, Brendan Geraghty, Lucy A. Bosworth, Eithne J. Comerford, Peter D. Clegg, Elizabeth G. Canty-Laird