Collagen metabolism and mechanical loading in Dupuytren's disease

Dupuytren's Disease results in disabling contracture of the fingers, which often requires corrective surgery, and amputation in the most severe cases. It is a common disease affecting up to 40% of the population over 70 years old. It is caused by a contracture of the palmar fascia, which is an intricate three- dimensional network of connective tissue lying between the tendons and skin in the palm and fingers. The affected tissue is under significant tension, and it is this tension which contracts the fingers into the palm. This tension is thought to originate from fibroblasts within the palmar fascia. The excess fibrotic tissue which accumulates in the disease is composed mainly of collagen. This thesis investigates the relationship between fibroblasts, collagen metabolism and tension in Dupuytren's Disease. In vitro studies were performed to examine the effect of loading on normal palmar fascia fibroblasts (controls), and fibroblasts affected with Dupuytren's Disease. Fibroblasts were cultured from operative specimens and seeded into collagen gels to mimic the in vivo environment. The gels were then either left to float freely in media, or were mechanically loaded in a tensioning culture force monitor. The gels and media were then processed to quantitate collagen, non- collagenous protein, collagenase, and TIMP-1 levels. Results show that fibroblasts cultured from Dupuytren's Disease have a statistically higher production of both collagen and non-collagenous protein in response to mechanical load. This is an original observation, and helps to explain various concepts in the understanding of the disease, in particular a historic theory (work hypertrophy) from 1959 suggested by Luck. This understanding opens avenues for further research towards therapeutic targets