What is the pathophysiology of Dupuytren contracture?

Updated: Mar 02, 2020
  • Author: Eva Kovacs, MD; Chief Editor: Herbert S Diamond, MD  more...
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Although the underlying etiology for the development of Dupuytren disease is uncertain, the basic pathophysiology involves fibroblast proliferation, and collagen deposition leading to contractures of the palmar fascia. Investigators have proposed several hypotheses for the pathogenesis of Dupuytren disease. Al-Qattan hypothesizes that an individual with a genetic predisposition to develop Dupuytren disease experiences a second inciting event (ie, smoking, diabetes, trauma, alcoholism), resulting in microvascular ischemia. [9] The localized ischemia causes two events to take place in the palmar fascia: (1) the conversion of adenosine triphosphate to hypoxanthine and (2) the conversion of xanthine dehydrogenase to xanthine oxidase.

Xanthine oxidase acts as a catalyst for the oxidation of hypoxanthine to xanthine and uric acid; this conversion results in the production of free radicals. Free radicals result in fibroblast proliferation and the production of numerous cytokines. Interleukin 1 (IL-1) is the most abundant cytokine in Dupuytren disease and, via its receptor, upregulates the production of transforming growth factor beta (TGF-beta), fibroblast growth factor, epidermal-derived growth factor, and platelet-derived growth factor. [18, 19] This milieu of cytokines and growth factors results in the proliferation of fibroblasts and their differentiation into myofibroblasts (the primary cell type in Dupuytren disease). [20]

Increased levels of nerve growth factor are present, which induce fibroblast transformation to myofibroblasts, especially during stages II-III. The splicing of fibronectin affects collagen binding. Platelet activation produces lysophosphatidic acid (LPA). LPA is a signaling molecule for cell proliferation and myofibroblast contraction. After binding to its receptor on myofibroblasts, LPA leads to a decrease in cyclic adenosine monophosphate and an increase in intracellular calcium levels. These events mediate smooth muscle contraction of the myofibrils within the myofibroblast. Normal palmar fascia is primarily composed of type I collagen; Dupuytren disease is associated with an increase in type III collagen.

The ratio of type III collagen to type I collagen increases, the reverse of the normal pattern, in the palmar fascia. [13] Excess type III collagen production occurs from an increased density of fibroblasts secondary to enhanced stimulation and diminished apoptosis, as well as an imbalance between the collagenases and their endogenous inhibitors. Dupuytren fascia exhibits an increased ratio of tissue inhibitors of metalloproteinases (TIMP) to matrix metalloproteinases (MMP). [21, 22, 23]

The myofibroblasts are indirectly connected to collagen, and the contractile force is transmitted from the intracellular actin microfilaments to the collagen bundles. Ultimately, the end result is contracture from excess deposition of type III collagen and the formation of cross-links between myofibroblasts and collagen. Another hypothesis by Vi et al suggests an up regulation of the gene transcript POSTN mRNA that encodes the protein periostin. Periostin is secreted by diseased cord myofibroblasts into the extracellular matrix. It promotes the transition of palmar fascia fibroblasts into a myofibroblast phenotype, thereby enhancing disease progression. [24]

Additionally, periostin is prevalent during the early stages of bone fracture repair and vascular injury. Hueston advanced the extrinsic theory, suggesting that Dupuytren nodules arise de novo and progress to cords. [25] Vasomotor disturbance and neurovascular mediation by the skin are possible contributors to the development of Dupuytren disease.

In contrast, McFarlane postulated the intrinsic theory, that the cords of more advanced Dupuytren disease are derived from normal fascia. [16] A combination of these ideas forms the synthesis theory, which states that the nodules and pretendinous cords represent different forms of the disease. [26]

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