Oestrogen and progesterone hormone receptors in Dupuytren''s disease

Dupuytren's disease is associated with alcoholism and chronic liver disease, conditions frequently associated with deranged steroid hormone metabolism. The possible influence of endogenous sex steroid hormones on the development of Dupuytren's disease has therefore been investigated. An analysis of diseased palmar fascia for oestrogen and progesterone receptors was undertaken in fifteen patients. Hormone specific receptors were not found in the palmar fascia of our patients with Dupuytren's disease, thus suggesting that other mechanisms or factors contribute to the pathogenesis of this fibrotic process.     

The collagen changes of Dupuytren's contracture

In Dupuytren's contracture there is an increase in the ratio of type III to type I collagen. The objective of this study was to determine if fibroblasts from patients with Dupuytren's contracture have an intrinsic aberration in collagen production or whether local factors govern the collagen changes in Dupuytren's contracture. Using a new collagen micro-method, we found that fibroblasts cultured from palmar fascia affected by Dupuytren's contracture produced similar collagen to fibroblasts derived from the palmar fascia of age- and sex-matched patients with carpal tunnel syndrome. Furthermore, the collagen changes of Dupuytren's contracture could be reproduced in all cell lines by increasing fibroblast density. At high fibroblast density, type I collagen production was inhibited: a finding that could account for the increased types III/I collagen ratio in Dupuytren's contracture. These results suggest that a genetic defect in collagen production is unlikely and that the important phenomenon is an increase in fibroblast density.     

Non-Dupuytren's disease of the palmar fascia

The typical Dupuytren's disease patient is of Northern European descent with bilateral progressive multiple digital contractures and is genetically predisposed, with a family history. Palmar fascial proliferations sometimes present as a different entity without the typical Dupuytren's disease characteristics. We identified 39 patients (20 women and 19 men) over a 4-year period with "Non-Dupuytren's palmar fascial disease", with unilateral involvement, without family history or ectopic manifestations. Twenty-three patients presented with unrelated complaints and were discovered, incidentally, to have the condition. In 28 patients, prior ipsilateral hand surgery or trauma precipitated the condition. Other related factors were diabetes mellitus and cardiovascular disease. Ten patients had skin tethering and subcutaneous thickening akin to Dupuytren's nodules and 29 had palmar fascial thickening into ill-defined pretendinous cords. The diseased tissue was in the line of the ring finger in 30 patients. The time from insult to onset of contracture averaged 3.6 months and from onset to follow-up averaged 5.3 years. The condition was non-progressive, or partially regressive, in 33 patients. Seven patients had operations for unrelated conditions and underwent simultaneous fasciectomy without recurrence. Environmental factors, especially trauma, surgery and diabetes, are important in the pathogenesis of Non-Dupuytren's palmar fascial disease, but these patients do not appear to be genetically predisposed for Dupuytren's disease. Typical Dupuytren's disease and Non-Dupuytren's palmar fascial disease are two clinical entities that run different courses and do not share a similar prognosis. This should be taken into account in future epidemiological and outcome studies.     

Gelatinase A activity in Dupuytren's disease

PURPOSE: Dupuytren's contracture is a fibroproliferative disorder of the hand characterized by an abnormal myofibroblast and fibroblast proliferation and extracellular matrix deposition leading to retraction and deformation of the palm. Recent studies have shown that molecules of extracellular matrix may coordinate morphogenesis, cell differentiation, and most importantly, fibrogenesis in tissue. Gelatinase A (MMP-2) is a member of the matrix metalloproteinase family of proteolytic enzymes that contribute to remodeling the extracellular matrix by degrading its components. The aim of this study was to determine the level of MMP-2 activation in the palmar fascia of patients with Dupuytren's contracture with reference to the clinical stages of disease progression and recurrence of the contracture after surgery. METHODS: The level of relative MMP-2 activation, expressed by the active to latent MMP-2 ratio, was investigated with use of zymography and computerized densitometry in 16 normal and 71 pathologic tissues characterizing different clinical stages of the disease progression. RESULTS: We found that the level of MMP-2 activation was significantly elevated in the palmar fascias with Dupuytren's contracture compared with normal tissues. We did not find statistically significant differences between groups with different stages of the disease progression. We also did not find a relation between a high level of MMP-2 activation and the recurrence in the area of surgically treated Dupuytren's contracture. CONCLUSIONS: The differences in MMP-2 activation between contractured and normal fascia suggest a participation of this enzyme in the promotion of Dupuytren's disease. We did not find a relationship, however, between the level of MMP-2 activation and the secondary contracture.     

Dupuytren's contracture: morphological and biochemical changes in palmar aponeurosis

The palmar aponeurosis removed from ten patients with Dupuytren's contracture was studied using morphological and biochemical approaches. The histological characteristic of Dupuytren's contracture is the presence of numerous nodules among the lamellar structures of the collagen fibres. In the nodules, there are many active fibroblasts which are surrounded by immature fibres and metachromatic substances demonstrated by toluidine blue staining. Ultrastructurally, the active fibroblasts have the characteristics of myofibroblasts, as previously reported by Dr. Gabbiani. We found that some fibroblasts have intracellular collagen fibrils in the cytoplasm. When assayed by Siegel and Martin's method, lysyl oxidase activity of the palmar aponeurosis was significantly higher in Dupuytren's contracture than in normal hands. Biochemical studies such as electrophoretic analysis of mucopolysaccharides, determination of uronic acid and collagen contents were undertaken to compare the aponeurosis of Dupuytren's contracture with normal cases. The uronic acid contents were higher in Dupuytren's contracture than in the controls. However, no difference between the two groups was found in the collagen contents and in the composition of the mucopolysaccharides. These characteristic features; existence of myofibroblasts and intracellular collagen fibrils and increase in the activity of lysyl oxidase probably play a significant role in the establishment of flexion contracture of the fingers in Dupuytren's contracture.     

Responsiveness of Dupuytren's disease fibroblasts to 5 alpha-dihydrotestosterone

PURPOSE: We recently showed that androgen receptors are expressed in Dupuytren's contracture. The aim of the present work was to test the responsiveness of Dupuytren's fibroblasts to 5 alpha-dihydrotestosterone (5 alpha-DHT), the active form of testosterone. RESULTS: Cultured palmar fascia cells from 10 patients with Dupuytren's contracture and 4 normal subjects were exposed to 5 alpha-DHT (10 or 100 ng/mL) for 1, 3, 7, and 15 days. Their phenotype was analyzed immunohistochemically for alpha-smooth muscle actin and androgen receptor expression and proliferation rates were studied. RESULTS: At 15 days the higher concentration of 5 alpha-DHT induced an increase in Dupuytren's fibroblast proliferation, whereas anti-alpha-smooth muscle actin exhibited the strongest expression. At the same time point androgen receptor expression decreased with the lower concentration and disappeared altogether with the higher dose of 5 alpha-DHT. CONCLUSIONS:The palmar fascia is a target tissue for androgen action via androgen receptors. Further studies are required to determine whether control of androgen receptor may control the evolution of Dupuytren's disease.     

Skin tension in the aetiology of Dupuytren's disease; a prospective trial

Tension in the palmar fascia has been proposed as a factor causing Dupuytren's disease. If tension does stimulate the growth of new Dupuytren's tissue, relieving longitudinal tension should reduce the recurrence rate following surgery. Thirty patients with palmar Dupuytren's contracture of a single ray that affected only the metacarpophalangeal joint were divided into two groups. Both groups had a fasciotomy: one group through a transverse incision that was closed directly and the other through a longitudinal incision with Z-plasty closure. Half the patients (seven of 14) who had direct closure had recurrence at 2 years as compared to two of the 13 in the Z-plasty group. The trial was stopped at the interim analysis stage due to the high recurrence rate in the first group. These results are consistent with the tension hypothesis for the aetiology of Dupuytren's disease.     

Dupuytren's contracture; increased cellularity--proliferation, is there equality?

BACKGROUND: Dupuytren's disease is a chronic inflammatory process which causes contractures of the fingers by shortening and thickening the palmar fascia. During the proliferative phase, fibroblasts transform into myofibroblasts apparently under the influence of several different factors. The disease usually develops slowly, but in some patients it tends to develop aggressively. The pathogenesis of Dupuytren's disease remains unsolved. In this study, we analyzed some histological characteristics that seem to predict rapid recurrence. MATERIAL AND METHODS: 21 patients were divided into two groups. In 11 patients the disease was classified as aggressive because it had recurred within two years after an operation. In 10 cases it was non-aggressive, as no recurrence had been seen. Five control samples were taken from healthy palmar aponeurosis. The differences in cellularity, collagen, Ki-67, MSA, alpha-SMA and tenascin between the specimens were analyzed using immunohistochemistry. RESULTS: Alpha-SMA and Ki-67 were present more often in the aggressive specimens. Immunohistochemical stainings for macrophages and lymphocytes were negative. CONCLUSION: There may be differences in the histology and/or immunohistochemical appearance of pathological palmar connective tissue cords in aggressive and normal Dupuytren's disease. Further studies are needed to elucidate the pathogenesis of this disease.     

The effect of steroids on Dupuytren's disease: role of programmed cell death

This study compared the rates of proliferation and apoptosis of cells within nodules of Dupuytren's disease and nodules from patients that had been injected preoperatively with steroid (Depo-Medrone). It also compared the effects of steroids in apoptosis in cultured Dupuytren's cells and control fibroblasts from palmar fascia and fascia lata. Steroids reduced the rate of fibroblast proliferation and increased the rate of apoptosis of both fibroblasts and inflammatory cells in Dupuytren's tissue. Steroids also produced apoptosis of cultured Dupuytren's cells but not of palmar fascia and fascia lata cells.     

Dupuytren's cord involving the septa of Legueu and Juvara: a case report

A patient with Dupuytren's disease with involvement of the palmar fascial complex and digital contracture is described. A vertical cord had developed in the transverse ligament of the palmar aponeurosis fibers and the underlying septa of Legueu and Juvara. The cord was composed of a pretendinous band, transverse ligament of the palmar aponeurosis, and septum of Legueu and Juvara. The cord was attached deeply in the soft tissue confluence of the sagittal band, palmar plate, and interpalmar plate ligament. Involvement of the transverse ligament of the palmar aponeurosis and septa of Legueu and Juvara in Dupuytren's disease is rare. Understanding of the normal and pathologic fascial anatomy explains their simultaneous involvement and is necessary for complete ablation of the diseased tissue.     

Plantar fibromatosis: an immunohistochemical and ultrastructural study

The analogies between plantar fibromatosis and Dupuytren's disease (palmar fibromatosis) are well known. The latter is clinically more frequent and has been the object of extensive immunohistochemical and ultrastructural studies, with a view to investigating its pathogenesis. By contrast, such data on plantar fibromatosis are quite scarce. A histochemical, immunohistochemical, and ultrastructural study was performed on nodule tissue from six patients who were subjected to total fasciectomy for plantar fibromatosis. The study of myofibroblasts revealed features suggestive of their fibroblastic origin and evidenced a cytoskeleton and an extracellular filamentous system that could enable myofibroblasts to generate and exert the intracellular forces that contribute to the contraction of the aponeurosis. These aspects are similar to those observed in Dupuytren's disease and seem to lend support to the theory that the two diseases are expressions of the same disorder.     

Cellular structure and biology of Dupuytren's disease

Numerous studies support the idea that the myofibroblast is a key cell responsible for the tissue contraction in Dupuytren's disease. In vitro models have been developed to study the underlying cellular basis of myofibroblast differentiation and contraction. Studies suggest that the growth factor TGF-beta 1 combined with mechanical stress can promote the differentiation of fibroblasts into myofibroblasts. Agonists, such as LPA and thrombin, can promote the contraction of myofibroblasts through specific intracellular signaling pathways that regulate levels of phosphorylated myosin light chain. Agents that can affect these intracellular signaling pathways hold promise as a means to decrease contraction of the myofibroblast and of the palmar fascia in Dupuytren's disease. Finally, the recent finding that IFN-gamma can suppress both the differentiation of the myofibroblast and the generation of contractile force, together with preliminary clinical results using IFN-gamma, suggest the potential use of IFN-gamma for nonsurgical therapy of Dupuytren's disease. Future studies into the cellular basis of tissue contraction should provide alternative methods to improve management of Dupuytren's contracture.     

掌腱膜桡侧挛缩的临床特点与治疗

目的探讨掌腱膜桡侧挛缩的病变特点和临床疗效。方法对8例因掌腱膜桡侧挛缩行手术治疗的病例进行回顾性研究。8例的病变均位于虎口和大鱼际区域，表现为皮肤纠集、结节和条索，很少影响拇指的活动范围。均手术切除局部的掌腱膜条索。7例患者获得随访，平均随访25．1个月；1例失访。结果掌腱膜桡侧挛缩多与尺侧挛缩并发，手术治疗总体疗效较好，仅有1例复发。术后病理证实切除的组织为挛缩的掌腱膜。结论掌腱膜桡侧挛缩的发病部位集中于第一掌指关节的掌侧、大鱼际尺侧、虎口部位和大鱼际桡侧，未见累及指问关节，手术治疗可取得良好效果。     

Pathogenesis of Dupuytren's contracture--a review]

Dupuytren's disease is a palmar fibromatosis bringing about irreversible finger contracture. Histopathologically, the disease is characterized by the presence of the two types of structures: nodules, containing of intensively proliferating cells, and fibrous cords, formed by thick bundles of collagen fibers. It seems that key role in the development of Dupuytren's contracture play alterations of palmar fibroblasts activity. These cells begin intensively proliferate and transform to myofibroblasts. The later ones sharing phenotypic features of fibroblasts and smooth muscle cells take part in remodelling of extracellular matrix and are a source of palmar contracture. The pivotal factors involved in changes of palmar fibroblasts functions seem to be growth factors (mainly TGF beta, PDGF and bFGF). However, the participation of reactive forms of oxygen in mentioned process is also considered.     

The myofibroblast in Dupuytren's contracture.

Dupuytren's contracture nodules, but not cords, contain myofibroblasts. These cells, which combine many electron microscopic, physiologic, and immunohistochemical characteristics of fibroblasts and smooth muscle cells, are probably the active force of contraction. Prominent myofibroblasts and intracellular microtubules correlate with increased likelihood of clinical recurrence after surgery. Tissue culture of cells derived from Dupuytren's contracture myofibroblasts show consistently slower cell replication than from fibroblasts and show persistence of electron microscopic characteristics in early passages. Research in Dupuytren's contracture myofibroblasts has been done on human tissue and so has clinical correlation. Myofibroblast presence may help to predict recurrence of disease and suggests that palmar skin should be excised when adherent to disease nodules. The theory of myofibroblasts helps explain why the open technique often succeeds, and why full thickness skin grafts inhibit recurrent contracture.     

Palmar fascial complex anatomy and pathology in Dupuytren's disease

Familiarity with the normal palmar fascial anatomy of the hand is necessary for understanding the convoluted pathologic changes that take place in Dupuytren's disease. This article includes a literature review and the findings of a study by the author of the fascial anatomy and pathology as related to Dupuytren's disease. Gross and microdissection of the palmar fascial structures were carried out with the aid of the operative microscope and an arthroscope, which allowed examination of the fine and undisturbed retinacular anatomy. The palmar fascial complex of the hand has five components: the radial aponeurosis, ulnar aponeurosis, central (palmar) aponeurosis, palmo-digital fascia, and digital fascia. The subtle constituents of each component are outlined and the transformation from normal to pathologic anatomy is clarified.     

Gene expression analysis of Dupuytren's disease: the role of TGF-beta2

Dupuytren's disease is characterised by nodular fibroblastic proliferation of the palmar fascia leading to contracture of the hand. Transforming growth factor beta (TGF-beta) is thought to play a role in its pathogenesis. We performed a cDNA microarray analysis of Dupuytren's diseased cord tissue with an emphasis on TGF-beta isoforms. Normal-appearing transverse ligament of the palmar fascia from adjacent to the diseased cord and palmar fascia from patients undergoing carpal tunnel release were used as controls. TGF-beta gene expression was confirmed by quantitative real-time polymerase chain reaction. Over 20 unique genes were found to be significantly up-regulated, including several previously reported genes. A dominant increase in TGF-beta2 expression was seen in the cord tissue, whereas TGF-beta1 and TGF-beta3 were found not to be significantly up-regulated. Quantitative real-time polymerase chain reaction confirmed these findings. This gene expression profile allows for further experiments that may eventually lead to gene therapy to block the development and progression of Dupuytren's disease clinically.     

Prostaglandins influence myofibroblast contractility in Dupuytren''s disease

This study investigated if the vasoactive prostaglandins, PGE2, and PGF2 alpha, were identifiable in association with nodular myofibroblasts of patients with Dupuytren's disease. Immunocytochemic studies, using antibodies specific for these prostaglandins, have confirmed their association with myofibroblasts. Radioimmunoassay was used to quantitate the prostaglandins. Our results indicate a significant increase of both prostaglandins, especially PGF2 alpha, in Dupuytren's palmar fascia when compared with control fascia. These endogenous prostaglandins may influence the contractile behavior of myofibroblasts in Dupuytren's disease to contribute to the pathobiology of this disorder.     

An investigation into the role of inflammatory cells in Dupuytren's disease

An immunohistochemical study was performed on nodules excised from the palmar fascia of patients with Dupuytren's contracture. In cellular nodules, antibodies to actin (used as a marker for myofibroblasts), desmin, vimentin, Mac 387 (a macrophage marker) and leucocyte common antigen were used. A correlation was demonstrated between the numbers of macrophages and the presence of myofibroblasts. The presence of myofibroblasts is generally considered to indicate the active stage of the disease. Inflammatory cells other than macrophages were largely absent from the nodules, although lymphocytes were frequent in the tissue around the nodules. Microvascular changes were prominent in the nodules and pericyte proliferation was observed around occluded capillaries. Release of growth factors from macrophages may be important in Dupuytren's contracture, as is the case in other fibrotic diseases. The possible role of macrophages in the aetiology of Dupuytren's disease is discussed.