Dupuytren's Nodules Research Articles

The association between echogenicity and progression of Dupuytren’s disease (DD): Birth of an imaging biomarker?

The shift of focus towards disease-controlling treatments to prevent DD progression at an early stage underlines the need for objective and reliable measurements that can monitor and predict the course of disease. Ultrasound has been studied as a potential tool for this purpose. This study examined to what extent echogenicity of early DD nodules predicts clinical progression. Sonographic assessments of Dupuytren's nodules were performed by the same observer on 151 participants as part of an ongoing prospective cohort study on the course of DD. Echogenicity was assessed by determining the greyness of a nodule relative to the surrounding tissue, using ImageJ software. Progression of disease was defined as 1) an increase in total passive extension deficit (TPED) of ≥15 degrees and 2) surgical intervention of the examined ray, both occurring after the sonographic assessment. The associations between echogenicity and time to progression were estimated using Cox-regression models. The association between echogenicity and time to TPED progression showed that for every additional decrease of 1% in relative greyness (darker image) of a nodule, the risk of TPED progression during follow-up increases by 3.4% (hazard ratio [HR] = 0.966, 95% confidence interval [CI]: 0.935-0.966). Similarly, echogenicity was also associated with time to surgical intervention (HR = 0.967, 95% CI: 0.938-0.997), which indicates a higher risk for surgery during follow-up for darker nodules. These results suggest that echogenicity is predictive of the prognosis of the early stages of DD and might potentially be used as a prognostic imaging biomarker in the future.

What's New in Hand and Wrist Surgery.

What's New in Hand and Wrist Surgery.

A Simple Physical Exam Maneuver to Distinguish Trigger Digit, Dupuytren's Nodule, and Flexor Sheath Ganglion.

Trigger digit, Dupuytren's disease, and ganglion cysts are 3 common disorders treated by hand surgeons. Despite the varying nature of their pathology, these 3 entities can all present as a mass at the flexor crease in the distal palm. The regional similarity of these presentations can make diagnosis more difficult. In this paper, we describe a simple clinical exam method that can assist in distinguishing between trigger digit, Dupuytren's disease, and flexor sheath ganglion cysts.

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren's disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1 Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren's nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

Reliability and Interpretability of Sonographic Measurements of Palmar Dupuytren Nodules

In the future, it is expected that treatment of Dupuytren disease (DD) may shift toward control of early disease. Ultrasound might be an accurate method to measure the outcome of such treatment. The aim of this study was to assess the reliability of sonographic measurement of palmar nodules. Fifty patients with nodules characteristic for early disease were assessed with ultrasound by 2 observers. Four different aspects of DD nodules were measured in the transversal and sagittal planes, width, depth, circumference, and area. The intra- and interobserver reliabilities were calculated using the intraclass correlation coefficient (ICC). The standard error of measurement (SEM) and the smallest detectable change (SDC) were also calculated for each aspect. The intraobserver reliability was good (ICC, 0.724 [0.562-0.833] to 0.886 [0.808-0.934]), except for width in the sagittal direction (ICC, 0.671 [0.484-0.799]). The interobserver reliability was moderate (ICC, 0.385 [0.126-0.596] to 0.757 [0.538-0.869]). The intraobserver ICCs of area were highest (transverse, 0.847 [0.744-0.893]; sagittal, 0.886 [0.808-0.934]). The SEM and SDC of area were 6.1 and 16.9 mm2 in the transverse and 8.0 and 22.2 mm2 in the sagittal plane. The intraobserver reliability of sonographic assessment of DD nodules is good. The measurement of area is the most reliable and is, therefore, recommended for future studies. However, even single-observer measurements have a clear dispersion, and a change beyond 16.9 (61%) and 22.2 mm2 (79%) has to be observed in the transverse and sagittal planes, respectively, before it can be considered as regression or progression. Repeated ultrasonographic measurements in DD should ideally be done by a single observer, using area of the nodule in the sagittal plane. Change beyond 16.9 (transverse) and 22.2 (sagittal) mm2 can be considered as a real change in nodule size.

Echogenicity of Palmar Dupuytren’s Nodules Is Not a Predictor of Disease Progression in Terms of Increase in Nodule Size

Ultrasound might enable us to measure Dupuytren's disease activity and predict disease progression. The aim of this study was to analyze whether echogenicity of Dupuytren's nodules can be used to predict progression in terms of increase in nodule size. Ultrasonographic assessment of a Dupuytren's nodule was performed in 91 patients participating in an existing longitudinal cohort study. Images were scored for echogenicity by two observers. Echogenicity of 89 nodules was matched to growth 1 year later using linear regression analysis. Sensitivity analysis was performed using data obtained 1 year before ultrasound. The interobserver and intraobserver reliability was calculated using the intraclass correlation coefficient. Hypoechogenicity was not a predictor of growth 1 year later (beta = -0.019, p = 0.748). Sensitivity analysis looking at the year before ultrasonographic measurement showed that hypoechogenic nodules were more likely to have grown in the past year (beta = 0.173, p = 0.011). However, these data were influenced by nodules that developed in the year before ultrasound. The intraobserver reliability of echogenicity of Dupuytren's nodules was excellent (intraclass correlation coefficient, 0.996; 95 percent CI, 0.993 to 0.998) and the interobserver reliability was fairly good but imprecise (intraclass correlation coefficient, 0.688; 95 percent CI, 0.329 to 0.977). Hypoechogenicity is not a predictor of progression in terms of increase in nodule size measured by physical examination 1 year later. When using ultrasound to assess echogenicity of Dupuytren's nodules, the use of a single observer leads to more consistent results. Risk III.

Mechanical and migratory properties of normal, scar, and Dupuytren's fibroblasts.

Mechanical properties of myofibroblasts play a key role in Dupuytren's disease. Here, we used atomic force microscopy to measure the viscoelastic properties of 3 different types of human primary fibroblasts derived from a same patient: normal and scar dermal fibroblasts and palmar fascial fibroblasts from Dupuytren's nodules. Different stiffness hydrogels (soft ~1kPa and stiff ~ 50kPa) were used as cell culture matrix to mimic the mechanical properties of the natural tissues, and atomic force microscopy step response force curves were used to discriminate between elastic and viscous properties of cells. Since transforming growth factor-β1 (TGF-β1) is known to induce expression of α-smooth muscle actin positive stress fibers in myofibroblasts, we investigated the behavior of these fibroblasts before and after applying TGF-β1. Finally, we performed an in vitro cell motility test, the wound healing or scratch assay, to evaluate the migratory properties of these fibroblasts. We found that (1) Dupuytren's fibroblasts are stiffer than normal and scar fibroblasts, the elastic modulus E ranging from 4.4, 2.1, to 1.8kPa, for Dupuytren's, normal and scar fibroblasts, respectively; (2) TGF-β1 enhances the level of α-smooth muscle actin expression and thus cell stiffness in Dupuytren's fibroblasts (E, ~6.2kPa); (3) matrix stiffness influences cell mechanical properties most prominently in Dupuytren's fibroblasts; and (4) Dupuytren's fibroblasts migrate slower than the other fibroblasts by a factor of 3. Taking together, our results showed that mechanical and migratory properties of fibroblasts might help to discriminate between different pathological conditions, helping to identify and recognize specific cell phenotypes.

Increased expression of αv integrin as a regulator of fibrosis in Dupuytren's nodules.

IV.

A Randomized Phase 2A, Double-blind, Placebo-controlled, Dose-ranging Study to Evaluate the Safety and Effectiveness of Collagenase Clostridium Histolyticum in the Treatment of Dupuytren Disease Nodules: Level 1 Evidence

Salary: Auxilium Pharmaceuticals Inc. (Kaufmann, James, Cohen), Ferring Pharmaceuticals (Kaufmann), US WorldMeds (James), Endo Pharmaceuticals Inc. (Cohen)Consulting Fee: Endo, BME, Biomet, Smith and Nephew (Gaston)▴This presentation will discuss Collagenase clostridium histolyticum. The objectives of this dose-ranging study were to assess the safety and effectiveness of CCH in treating palmar Dupuytren disease nodules. Nodules can cause significant pain and interference with patients’ activities of daily living (ADLs) involving gripping. Presently, there are no approved medical treatments for Dupuytren disease nodules. Subjects (n = 76) with Dupuytren disease and at least 1 palpable palmar nodule were randomized to receive a single injection of either CCH (0.60mg, 0.40mg, or 0.25mg) or placebo on Day 1. Nodules were massaged twice daily from Days 8 - 29. Nodule (size, consistency, hardness, pain, ultrasound measurements, and patient satisfaction) and safety assessments were conducted at specific time points throughout the study. Safety was monitored continuously. Surface area and volume of nodules assessed by calipers were significantly reduced (P = 0.0001) in CCH 0.6mg and 0.4mg groups compared to placebo group at Day 57. Significant improvements from baseline at endpoint were observed in consistency (0.6mg, P < 0.0001; 0.4mg, P = 0.0002; and 0.25mg, P = 0.0139) and hardness in CCH groups (0.6mg, P = 0.0075; 0.4mg, P < 0.0001; and 0.25mg, P = 0.0031) compared with the placebo group. 83.3% (15/18) and 88.9% (16/18) of subjects in CCH 0.60-mg group and CCH 0.40-mg group, respectively, were very satisfied or quite satisfied with treatment. Significantly higher percentage of composite responders (subject with an improved investigator assessment and a satisfied subject assessment) at Day 57 was observed in CCH 0.6mg group (77.8%; P = 0.0349) and 0.4mg group (88.9%; P = 0.0033) compared to placebo group (37.5%). Ultrasound findings were not statistically different between the CCH groups and placebo. Common adverse events in CCH subjects ( = 25.0%) were local swelling, injection bruising, axillary pain, contusion, pain in extremity; most were mild/moderate and resolved in 14 days (median). •CCH-treatment groups (0.60mg and 0.40mg) showed significant reduction in surface area and volume and softening of the treated nodule.•Subjective measures of investigator assessment of improvement and subject satisfaction with treatment were statistically significant.•Safety profile of single injection of CCH into a Dupuytren nodule was similar to that observed after single injection of CCH in treatment of adults with Dupuytren contracture with a palpable cord.

Wnt pathway in Dupuytren disease: connecting profibrotic signals.

A role of Wnt signaling in Dupuytren disease, a fibroproliferative disease of the hand and fingers, has not been fully elucidated. We examined a large set of Wnt pathway components and signaling targets and found significant dysregulation of 41 Wnt-related genes in tissue from the Dupuytren nodules compared with patient-matched control tissue. A large proportion of genes coding for Wnt proteins themselves was downregulated. However, both canonical Wnt targets and components of the noncanonical signaling pathway were upregulated. Immunohistochemical analysis revealed that protein expression of Wnt1-inducible secreted protein 1 (WISP1), a known Wnt target, was increased in nodules compared with control tissue, but knockdown of WISP1 using small interfering RNA (siRNA) in the Dupuytren myofibroblasts did not confirm a functional role. The protein expression of noncanonical pathway components Wnt5A and VANGL2 as well as noncanonical coreceptors Ror2 and Ryk was increased in nodules. On the contrary, the strongest downregulated genes in this study were 4 antagonists of Wnt signaling (DKK1, FRZB, SFRP1, and WIF1). Downregulation of these genes in the Dupuytren tissue was mimicked in vitro by treating normal fibroblasts with transforming growth factor β1 (TGF-β1), suggesting cross talk between different profibrotic pathways. Furthermore, siRNA-mediated knockdown of these antagonists in normal fibroblasts led to increased nuclear translocation of Wnt target β-catenin in response to TGF-β1 treatment. In conclusion, we have shown extensive dysregulation of Wnt signaling in affected tissue from Dupuytren disease patients. Components of both the canonical and the noncanonical pathways are upregulated, whereas endogenous antagonists are downregulated, possibly via interaction with other profibrotic pathways.

Involvement of pro-inflammatory cytokines and growth factors in the pathogenesis of Dupuytren's contracture: a novel target for a possible future therapeutic strategy?

Dupuytren's contracture (DC) is a benign fibro-proliferative disease of the hand causing fibrotic nodules and fascial cords which determine debilitating contracture and deformities of fingers and hands. The present study was designed to characterize pro-inflammatory cytokines and growth factors involved in the pathogenesis, progression and recurrence of this disease, in order to find novel targets for alternative therapies and strategies in controlling DC. The expression of pro-inflammatory cytokines and of growth factors was detected by immunohistochemistry in fibrotic nodules and normal palmar fascia resected respectively from patients affected by DC and carpal tunnel syndrome (CTS; as negative controls). Reverse transcription (RT)-PCR analysis and immunofluorescence were performed to quantify the expression of transforming growth factor (TGF)-β1, interleukin (IL)-1β and vascular endothelial growth factor (VEGF) by primary cultures of myofibroblasts and fibroblasts isolated from Dupuytren's nodules. Histological analysis showed high cellularity and high proliferation rate in Dupuytren's tissue, together with the presence of myofibroblastic isotypes; immunohistochemical staining for macrophages was completely negative. In addition, a strong expression of TGF-β1, IL-1β and VEGF was evident in the extracellular matrix and in the cytoplasm of fibroblasts and myofibroblasts in Dupuytren's nodular tissues, as compared with control tissues. These results were confirmed by RT-PCR and by immunofluorescence in pathological and normal primary cell cultures. These preliminary observations suggest that TGF-β1, IL-1β and VEGF may be considered potential therapeutic targets in the treatment of Dupuytren's disease (DD).

Down‐regulation of collagen synthesis and matrix metalloproteinase expression in myofibroblasts from dupuytren nodule using adenovirus‐mediated relaxin gene therapy

Dupuytren's disease is a fibroproliferative connective tissue disorder characterized by contracture of the palmer fascia of the hand. Relaxin (RLN) is a multifunctional factor which contributes to the remodeling of the pelvic ligament by inhibiting fibrosis and inflammatory activities. The aim of this study was to investigate the effect of the RLN gene on the inhibition of fibrosis in myofibroblastic cells. Myofibroblast cells with adenovirus LacZ (Ad-LacZ) as a marker gene or adenovirus relaxin (Ad-RLN) as therapeutic gene showed transgene expressions in beta-galactosidase assay and Western blot analysis. Myofibroblastic cells with Ad-RLN demonstrated a 22% and 48% reduction in collagen I and III mRNA expressions respectively, a 50% decrease in MMP-1, 70% decrease in MMP-2, 80% decrease in MMP-9, and a 15% reduction in MMP-13 protein expression compared with cultures with viral control and saline control. In addition, myofibroblastic cells with Ad-RLN showed a 40% decrease in TIMP 1 and a 15% increase in TIMP 3 protein expression at 48 h compared to cultures with viral control and saline control. Also, myofibroblastic cell with Ad-RLN demonstrated a 74% inhibition of fibronectin and a 52% decrease in total collagen synthesis at 48 h compared with cultures with viral control and saline control. In conclusion, the RLN gene render antifibrogenic effect on myofibroblastic cells from Dupuytren's nodule via direct inhibition of collagen synthesis not through collagenolytic pathway such as MMP-1, -13, TIMP 1, and 3. Therefore relaxin can be an alternative therapeutic strategy in initial stage of Dupuytren's disease by its antifibrogenic effect.

The mechanical environment in dupuytren's contracture determines cell contractility and associated MMP‐mediated matrix remodeling

Matrix metalloproteinases (MMPs) are expressed in Dupuytren's contracture and play a role in matrix remodeling. We tested the role of tension on contractility and MMP expression in Dupuytren's nodule and cord cells. Cells were subjected to pre-determined loading patterns of known repeatable magnitudes (static load, unloading, and overloading) and tested for MMP gene expression (MMP-1, -2, -9, -13, and TIMP-1, -2) and force generation using a tension-culture force monitor. Matrix remodeling was assessed by addition of cytochalasin D and residual matrix tension was quantified. Nodule compared to cord and control cells demonstrate greater force generation and remodeling (p < 0.05). Nodule cells subjected to a reduced load and overloading led to threefold increase of MMP-1, -2, and -9 compared to static load, whilst cord and control cells only showed a twofold increase of MMP-9. Nodule cells subjected to overloading showed a twofold increase in TIMP-2 expression, whilst cord and control cells showed a twofold increase in TIMP-1 expression. Nodule cells differ from cord cells by increased force generation in response to changes in the mechanical environment and related MMP/TIMP-mediated matrix remodeling. In turn this may lead to permanent matrix shortening and digital contracture. Interventional therapies should be aimed at nodule cells to prevent contraction and subsequent permanent matrix remodeling.

Calcium-Dependent Signaling in Dupuytren's Disease

Previous studies suggest that Dupuytren's disease is caused by fibroblast and myofibroblast contractility. Cell contractility in smooth muscle cells is caused by calcium-dependent and calcium-independent signaling mechanisms. In the calcium-dependent pathway, calcium/calmodulin activates myosin light chain kinase (MLCK). In this study, the effects of calcium/calmodulin inhibition with the FDA-approved drug fluphenazine on Dupuytren's fibroblast contractility and MLCK expression were tested. Fibroblast lines from the palmar fascia of patients with Dupuytren's disease were explanted and used for in vitro study. The effect of fluphenazine on Dupuytren's fibroblast migration was determined using a scratch migration assay, and contractility was determined using fibroblast-populated collagen lattice (FPCL) assays. Immunohistochemical staining of MLCK in different samples of Dupuytren's tissue and normal fascia were compared. Fluphenazine demonstrated a dose-dependent inhibition of Dupuytren's fibroblast migration, with the maximum inhibition of migration observed at 20μM (69.8 ± 1.9%). Fluphenazine also inhibited FPCL contraction in a dose-dependent manner. Maximal inhibition was observed at a fluphenazine concentration of 20μM (52.5 ± 6.1%). Immunohistological staining illustrated that MLCK was predominantly expressed throughout the cytoplasm of select fibroblasts within Dupuytren's nodules, yet was absent in the fibroblasts of Dupuytren's cords and normal palmar fascia. Fluphenazine inhibits Dupuytren's fibroblast contractility and migration through inhibition of MLCK in vitro. However, the inconsistent expression of MLCK throughout Dupuytren's tissue suggests that calcium-dependent signaling may not be a primary mode of contracture formation. Fluphenazine inhibition of MLCK is not likely to be a target for the treatment of Dupuytren's disease.

Dupuytren's Fibroblast Contractility by Sphingosine-1-Phosphate Is Mediated Through Non-Muscle Myosin II

Previous studies suggest that Dupuytren's disease is caused by fibroblast and myofibroblast contractility within Dupuytren's nodules; however, the stimulus for cell contractility is unknown. Sphingosine-1-phosphate (S1P) is a serum-derived lysophospholipid mediator that enhances cell contractility by activating the S1P receptor, S1P(2). It is hypothesized that S1P stimulates Dupuytren's fibroblast contractility through S1P(2) activation of non-muscle myosin II (NMMII). This investigation examined the role of S1P and NMMII activation in Dupuytren's disease progression and suggests potential targets for treatment. We enmeshed Dupuytren's fibroblasts into fibroblast-populated collagen lattices (FPCLs) and assayed S1P-stimulated FPCL contraction in the presence of the S1P(2) receptor inhibitor JTE-013, the Rho kinase inhibitor Y-27632, the myosin light chain kinase inhibitor ML-7, and the NMMII inhibitor blebbistatin. Tissues from Dupuytren's fascia (n = 10) and normal palmar fascia (n = 10) were immunostained for NMMIIA and NMMIIB. Sphingosine-1-phosphate stimulated FPCL contraction in a dose-dependent manner. Inhibition of S1P(2) and NMMII prevented S1P-stimulated FPCL contraction. Rho kinase and myosin light chain kinase inhibited both S1P and control FPCL contraction. Dupuytren's nodule fibroblasts robustly expressed NMMIIA and NMMIIB, compared with quiescent-appearing cords and normal palmar fascia. Sphingosine-1-phosphate promotes Dupuytren's fibroblast contractility through S1P(2), which stimulates activation of NMMII. NMMII isoforms are ubiquitously expressed throughout Dupuytren's nodules, which suggests that nodule fibroblasts are primed to respond to S1P stimulation to cause contracture formation. S1P-promoted activation of NMMII may be a target for disease treatment.

Dorsal Pads Versus Nodules in Normal Population and Dupuytren's Disease Patients

There is ambiguity about using the term "knuckle pads" in Dupuytren's disease (DD). Clear definitions of dorsal knuckle pads and nodules are lacking and the prevalence of these 2 entities has not been determined. We sought to define these terms and investigate the distribution and frequency of dorsal knuckle pads and dorsal nodules in the normal volunteers and in DD patients. We assessed 50 consecutive study patients with DD and a convenience sample group of 50 control patients without DD for dorsal cutaneous pads (DCP) (ie, thickening, sclerosis, and loss of skin elasticity) and dorsal Dupuytren's nodules (DDN) (ie, solid tumor-like masses over the digital joints). Demographic information was collected for both groups, including the extent of the disease in DD patients. We examined both groups for the presence of dorsal lesions and their characteristics, and the DD patients for other local and ectopic Dupuytren's lesions and for the level of diathesis. None of the control patients had DDN, whereas 9 DD patients had DDN (p = .002). Nine control patients had DCP, whereas 11 DD patients had DCP (p = .803) Among the 9 control patients with DCP, pads were predominantly over the proximal interphalangeal joints and tended to occur in men with physically demanding occupations, and in the dominant hand. The index and long fingers were most frequently affected. Six patients had only DCP, 4 had only DDN, and 5 had both DDN and DCP. In the control and study groups, the DCP characteristics and patients' demographic data were comparable. Patients with DDN were white men with physically undemanding occupations and had lesions over the proximal interphalangeal joints, most frequently in the index finger, with an average size of 6 mm. Neither DCP nor DDN were encountered in the thumb. Future studies should clearly distinguish between DCP and DDN. Although DDN are pathognomonic of DD, DCP demonstrates similar prevalence in normal and DD populations.

Post‐transcriptional regulation of α‐smooth muscle actin determines the contractile phenotype of Dupuytren's nodular cells

The objective was to study Dupuytren's myofibroblast cells in constrained collagen matrices in order to more closely emulate their in vivo environment and, to correlate their contractility with alpha-smooth muscle actin (alpha-SMA) expression and determine if dermal fibroblasts regulate Dupuytren's myofibroblast phenotype. Isotonic and isometric force contraction by cells isolated from Dupuytren's nodules, palmar and non-palmar skin fibroblasts was measured in collagen matrices. The effect of co-culturing nodule cells with dermal fibroblasts on isometric contraction was examined. Isometric contraction was correlated with levels of alpha-SMA mRNA by pcr and protein by Western blotting, and alpha-SMA distribution assessed by immunofluorescence. Dupuytren's nodule cells exhibited similar levels of isotonic contraction to both palmar and non-palmar dermal fibroblasts. However, nodule cells generated high levels of isometric force (mean: 3.5 dynes/h), which continued to increase over 24 h to a maximum of 173 dynes. In contrast, dermal fibroblasts initially exhibited low levels of contraction (mean: 0.5 dynes/h) and reached tensional homeostasis on average after 15 h (range: 4-20 h), with a maximum force of 52 dynes. Although all three cell types had similar alpha-SMA mRNA levels, increased levels of alpha-SMA protein were observed in nodule cells compared to dermal fibroblasts. alpha-SMA localised to stress fibres in 35% (range: 26-50%) of nodule cells compared to only 3% (range:0-6%) of dermal fibroblasts. Co-cultures of Dupuytren's cells and dermal fibroblasts showed no contractile differences. The contractile phenotype of Dupuytren's myofibroblasts is determined by increased alpha-SMA protein distributed in stress fibres, not by cellular mRNA levels. Dupuytren's cell contractility is not influenced by dermal fibroblasts.

Suppression ofαSmooth Muscle Actin Expression by IFN-γin Established Myofibroblast Cell Lines

The purpose of this study is to investigate the effect of interferon-gamma (IFN-gamma) on myofibroblast generation using four myofibroblast cell lines that we established from Dupuytren's nodules. Cells were cultured in Earl's medium with 15% fetal bovine serum (FBS) and plated on a microplate at a density of 10(4) cells/well. These cells were treated with various concentrations of IFN-gamma (0-1000 U/mL) for 3 days. By cell-capture enzyme immunoassay (CC-EIA), immunofluorescence staining, and reverse transcriptase polymerase chain reaction (RT-PCR) analysis, we evaluated the effect of IFN-gamma on the expression of alpha smooth muscle actin (alphaSMA) in these cells. CC-EIA and RT-PCR analysis showed that IFN-gamma suppressed alphaSMA expression, and immunofluorescence microscopy demonstrated that IFN-gamma markedly decreased the number of alphaSMA-positive cells. These results showed that IFN-gamma strongly inhibits myofibroblast generation in established myofibroblast cell lines and suggest the possibility of using IFN-gamma therapy for contractile disease.

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.

A Retrospective Review of the Management of Dupuytren’s Nodules

To evaluate the progression of Depuytren's nodules with more than 6 years of follow-up study. Fifty-nine patients who presented initially with Dupuytren's nodules returned for physical examination at an average follow-up period of 8.7 years (range, 6-15 y). Patients were questioned regarding family history of Dupuytren's disease, family ethnicity, alcohol consumption, smoking, liver disease, seizures, diabetes, and signs of systemic disease such as knuckle pads and plantar nodules. Physical examination evaluated disease state, loss of extension of the finger joints, and disease location. Thirty of the 59 patients with previously diagnosed isolated nodules developed a cord. Twenty-two percent of patients presented with bilateral disease and another 26% developed bilateral disease. Of those patients whose disease progressed 43% had European heritage, 37% had disease onset before the age of 50 years, 30% had bilateral disease, 23% had a family history of Dupuytren's disease, and 13% had plantar nodules. Five patients lost extension averaging 60 degrees at the metacarpophalangeal joint and 40 degrees at the proximal interphalangeal joint. Three of these 5 had surgical excision because they had a flexion contracture of the metacarpophalangeal or proximal interphalangeal joints averaging 60 degrees and 43 degrees , respectively. Another 7 patients did not meet standard criteria but had surgery for persistent pain associated with grasping objects (without contracture). All surgically treated patients had at least 1 risk factor and 7 patients had more than 1 risk factor. In 7 patients the Dupuytren's nodule had resolved at the time of follow-up evaluation. The progression of the nodular form of Dupuytren's disease to cord-like disease is common but not inevitable. This evaluation of Dupuytren's nodules has shown that at an average of 8.7 years after diagnosis 5 patients met standard surgical criteria of metacarpophalangeal contracture of greater than 30 degrees or any proximal interphalangeal contracture. Age of onset (before 50 years) is correlated most closely with disease progression, and the disease regressed in 7 patients (12%).