Hyperglycaemia is a causal risk factor for upper limb pathologies.

BACKGROUND: Diabetes (regardless of type) and obesity are associated with a range of musculoskeletal disorders. The causal mechanisms driving these associations are unknown for many upper limb pathologies. We used genetic techniques to test the causal link between glycemia, obesity and musculoskeletal conditions. METHODS: In the UK Biobank's unrelated European cohort (N = 379 708) we performed mendelian randomisation (MR) analyses to test for a causal effect of long-term high glycaemia and adiposity on four musculoskeletal pathologies: frozen shoulder, Dupuytren's disease, carpal tunnel syndrome and trigger finger. We also performed single-gene MR using rare variants in the GCK gene. RESULTS: Using MR, we found evidence that long-term high glycaemia has a causal role in the aetiology of upper limb conditions. A 10-mmol/mol increase in genetically predicted haemoglobin A1C (HbA1c) was associated with frozen shoulder: odds ratio (OR) = 1.50 [95% confidence interval (CI), 1.20-1.88], Dupuytren's disease: OR = 1.17 (95% CI, 1.01-1.35), trigger finger: OR = 1.30 (95% CI, 1.09-1.55) and carpal tunnel syndrome: OR = 1.20 (95% CI, 1.09-1.33). Carriers of GCK mutations have increased odds of frozen shoulder: OR = 7.16 (95% CI, 2.93-17.51) and carpal tunnel syndrome: OR = 2.86 (95% CI, 1.50-5.44) but not Dupuytren's disease or trigger finger. We found evidence that an increase in genetically predicted body mass index (BMI) of 5 kg/m2 was associated with carpal tunnel syndrome: OR = 1.13 (95% CI, 1.10-1.16) and associated negatively with Dupuytren's disease: OR = 0.94 (95% CI, 0.90-0.98), but no evidence of association with frozen shoulder or trigger finger. Trigger finger (OR 1.96 (95% CI, 1.42-2.69) P = 3.6e-05) and carpal tunnel syndrome [OR 1.63 (95% CI, 1.36-1.95) P = 8.5e-08] are associated with genetically predicted unfavourable adiposity increase of one standard deviation of body fat. CONCLUSIONS: Our study consistently demonstrates a causal role of long-term high glycaemia in the aetiology of upper limb musculoskeletal conditions. Clinicians treating diabetes patients should be aware of these complications in clinic, specifically those managing the care of GCK mutation carriers. Upper limb musculoskeletal conditions should be considered diabetes complications.

A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren's disease.

Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3-38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function.

Polygenic Risk Associations with Clinical Characteristics and Recurrence of Dupuytren Disease.

BACKGROUND: Dupuytren disease (DD) is a common complex trait, with varying severity and incompletely understood cause. Genome-wide association studies (GWAS) have identified risk loci. In this article, we examine whether genetic risk profiles of DD in patients are associated with clinical variation and disease severity and with patient genetic risk profiles of genetically correlated traits, including body mass index (BMI), triglycerides, high-density lipoproteins, type 2 diabetes mellitus, and endophenotypes fasting glucose and glycated hemoglobin. METHODS: The authors used a well-characterized cohort of 1461 DD patients with available phenotypic and genetic data. Phenotype data include age at onset, recurrence, and family history of disease. Polygenic risk scores (PRSs) of DD, BMI, triglycerides, high-density lipoprotein, type 2 diabetes, fasting glucose, and hemoglobin A1c using various significance thresholds were calculated with PRSice using the most recent GWAS summary statistics. Control data from LifeLines were used to determine P value cutoffs for PRS generation explaining most variance. RESULTS: The PRS for DD was significantly associated with a positive family history for DD, age at onset, disease onset before the age of 50, and recurrence. We also found a significant negative correlation between the PRSs for DD and BMI. CONCLUSIONS: Although GWAS studies of DD are designed to identify genetic risk factors distinguishing case/control status, we show that the genetic risk profile for DD also explains part of its clinical variation and disease severity. The PRS may therefore aid in accurate prognostication, choosing initial treatment and in personalized medicine in the future. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

C-X-C domain ligand 14-mediated stromal cell-macrophage interaction as a therapeutic target for hand dermal fibrosis.

Dupuytren's contracture, a superficial dermal fibrosis, causes flexion contracture of the affected finger, impairing hand function. Specific single-nucleotide polymorphisms within genes in the Wnt signalling pathway are associated with the disease. However, the precise role of Wnt signalling dysregulation in the onset and progression of Dupuytren's contracture remains unclear. Here, using a fibrosis mouse model and clinical samples of human Dupuytren's contractures, we demonstrate that the activation of Wnt/ß-catenin signalling in Tppp3-positive cells in the dermis of the paw is associated with the development of fibrosis. Fibrosis development and progression via Wnt/ß-catenin signalling are closely related to stromal cell-macrophage interactions, and Wnt/ß-catenin signalling activation in Tppp3-positive stromal cells causes M2 macrophage infiltration via chemokine Cxcl14, resulting in the formation of a TGF-ß-expressing fibrotic niche. Inhibition of Cxcl14 mitigates fibrosis by decreasing macrophage infiltration. These findings suggest that Cxcl14-mediated stromal cell-macrophage interaction is a promising therapeutic target for Wnt/ß-catenin-induced fibrosis.

Dupuytren's Disease Is Mediated by Insufficient TGF-ß1 Release and Degradation.

Dupuytren's disease (DD) is a fibroproliferative disorder affecting the palmar fascia, causing functional restrictions of the hand and thereby limiting patients' daily lives. The disturbed and excessive myofibroblastogenesis, causing DD, is mainly induced by transforming growth factor (TGF)-ß1. But, the extent to which impaired TGF-ß1 release or TGF-ß signal degradation is involved in pathologically altered myofibroblastogenesis in DD has been barely examined. Therefore, the complex in which TGF-ß1 is secreted in the extracellular matrix to elicit its biological activity, and proteins such as plasmin, integrins, and matrix metalloproteinases (MMPs), which are involved in the TGF-ß1 activation, were herein analyzed in DD-fibroblasts (DD-FBs). Additionally, TGF-ß signal degradation via caveolin-1 was examined with 5-fluoruracil (5-FU) in detail. Gene expression analysis was performed via Western blot, PCR, and immunofluorescence analyses. As a surrogate parameter for disturbed myofibroblastogenesis, 𝛼-smooth-muscle-actin (𝛼-SMA) expression was evaluated. It was demonstrated that latency-associated peptide (LAP)-TGF-ß and latent TGF-ß-binding protein (LTBP)-1 involved in TGF-ß-complex building were significantly upregulated in DD. Plasmin a serinprotease responsible for the TGF-ß release was significantly downregulated. The application of exogenous plasmin was able to inhibit disturbed myofibroblastogenesis, as measured via 𝛼-SMA expression. Furthermore, a reduced TGF-ß1 degradation was also involved in the pathological phenotype of DD, because caveolin-1 expression was significantly downregulated, and if rescued, myofibroblastogenesis was also inhibited. Therefore, our study demonstrates that a deficient release and degradation of TGF-ß1 are important players in the pathological phenotype of DD and should be addressed in future research studies to improve DD therapy or other related fibrotic conditions.

Exploring the potential relationship between frozen shoulder and Dupuytren's disease through bioinformatics analysis and machine learning.

Background: Frozen shoulder (FS) and Dupuytren's disease (DD) are two closely related diseases, but the mechanism of their interaction is unknown. Our study sought to elucidate the molecular mechanism of these two diseases through shared gene and protein interactions. Methods: GSE75152 and GSE140731 data were downloaded from the Gene Expression Omnibus (GEO) database, and shared genes between FS and DD were selected by using R packages. Then, we used Cytoscape software and the STRING database to produce a protein-protein interaction (PPI) network. Important interaction networks and hub genes were selected through MCODE and cytoHubba algorithms. To explore the potential mechanisms of the development of the two diseases, the hub genes were further enriched by GO and KEGG analyses. We predicted the transcription factors (TFs) of hub genes with Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRRUST). Moreover, we identified candidate genes for FS with DD with cytoHubba and machine learning algorithms. Finally, we analyzed the role of immunocyte infiltration in FS and constructed the relationship between candidate genes and immunocytes in FS. Results: We identified a total of 321 shared genes. The results of GO and KEGG enrichment of shared genes showed that extracellular matrix and collagen fibril tissue play a certain role in the occurrence and development of disease. According to the importance of genes, we constructed the key PPI network of shared genes and the top 15 hub genes for FS with DD. Then, we predicted that five TFs are related to the hub genes and are highly expressed in the FS group. Machine learning results show that the candidate genes POSTN and COL11A1 may be key for FS with DD. Finally, immune cell infiltration revealed the disorder of immunocytes in FS patients, and expression of candidate genes can affect immunocyte infiltration. Conclusion: We identified a PPI network, 15 hub genes, and two immune-related candidate genes (POSTN and COL11A1) using bioinformatics analysis and machine learning algorithms. These genes have the potential to serve as diagnostic genes for FS in DD patients. Furthermore, our study reveals disorder of immunocytes in FS.

Smoking, alcohol consumption and risk of Dupuytren's disease: a Mendelian randomization study.

BACKGROUND: The correlation between smoking and alcohol consumption and the development of Dupuytren's disease (DD) has been acknowledged. However, the definitive causal relationship between these two factors and DD remains elusive. In order to establish a causal connection, we employed the two-sample Mendelian randomization method to evaluate the relationship between smoking and alcohol consumption and DD. METHODS: Based on publicly available genome-wide association studies (GWAS), two-sample univariate MR analyses were performed to assess the causal effects of drinks per week, cigarettes per day, smoking initiation, age of initiation, and smoking cessation on DD. We used inverse variance weighted (IVW) to generate the primary results for the MR analysis. Furthermore, we performed sensitivity MR analyses based on various methods to assess the robustness of estimations. Bidirectional MR analyses were used to study the interaction between smoking and alcohol consumption. Multivariate MR analyses were used to obtain independent causal effects of smoking or drinking on DD. RESULTS: Our two-sample MR, which was predominately based on IVW, revealed a causal relationship between drinks per week and DD (OR = 2.948, 95%CI: 1.746-4.975, P = 5.16E-05). In addition, there is no causal association between cigarettes per day, smoking initiation, age of initiation, smoking cessation and DD. Similar conclusions were reached by other MR methods. The results of the bidirectional MR analyses showed that the causal relationships between age of initiation and drinks per week were robust and significant. Multivariate MR results indicated that the causal effect of alcohol consumption on DD was independent of smoking. CONCLUSION: Our Mendelian Randomization study indicated that there is a causality between drinking alcohol and DD, but no such causality was found between smoking and DD. This is the first study to prove that drinking alcohol could cause DD. This could help people who are trying to prevent DD from happening in the first place.

Major Genetic Risk Factors for Dupuytren's Disease Are Inherited From Neandertals.

Dupuytren's disease is characterized by fingers becoming permanently bent in a flexed position. Whereas people of African ancestry are rarely afflicted by Dupuytren's disease, up to ∼30% of men over 60 years suffer from this condition in northern Europe. Here, we meta-analyze 3 biobanks comprising 7,871 cases and 645,880 controls and find 61 genome-wide significant variants associated with Dupuytren's disease. We show that 3 of the 61 loci harbor alleles of Neandertal origin, including the second and third most strongly associated ones (P = 6.4 × 10-132 and P = 9.2 × 10-69, respectively). For the most strongly associated Neandertal variant, we identify EPDR1 as the causal gene. Dupuytren's disease is an example of how admixture with Neandertals has shaped regional differences in disease prevalence.

Dupuytren's contracture-associated SNPs increase SFRP4 expression in non-immune cells including fibroblasts to enhance inflammation development.

Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two single nucleotide polymorphisms (SNPs) associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and ßTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC.

Dupuytren's disease: a localised and accessible human fibrotic disorder.

We review the biology of Dupuytren's disease (DD), a common localised fibrotic disorder of the hand. The disease develops through a complex interplay of genetic and environmental factors, and epigenetic signalling. The early-stage disease nodules comprise a complex milieu of stromal and immune cells which interact to promote disease development. Recently, inhibition of tumour necrosis factor (TNF) locally resulted in softening and a decrease in nodule size, potentially controlling disease progression. Unlike fibrotic disorders of the visceral organs, the easy access to tissue in DD patients enables dissection of the cellular landscape and molecular signalling pathways. In addition, the study of DD may have wider benefits in enhancing our understanding of less-accessible fibrotic tissues.

Effect of nanoparticle-mediated delivery of SFRP4 siRNA for treating Dupuytren disease.

Dupuytren disease (DD) is a progressive fibrous proliferative disease. It invades the palmar aponeurosis and extends to the finger fascia, eventually leading to flexion contracture of the metacarpophalangeal or interphalangeal joint. At present, surgical resection and the local injection of collagenase are the main methods for the treatment of DD, but postoperative complications and high recurrence rates often occur. Bioinformatics analysis showed that the increased expression of SFRP4 protein was closely related to the incidence of DD. Persistent and effective inhibition of SFRP4 expression may be a promising treatment for DD. We prepared SFRP4 siRNA/nanoparticle complexes (si-SFRP4) and negative siRNA/nanoparticle complexes (NC) and applied them in vitro and in vivo. Flow cytometry analysis showed that si-SFRP4 could be successfully transfected into DD cells. MTT and EdU staining assays showed that the OD values and percentage of EdU-positive cells in the si-SFRP4 group were significantly lower than those in the NC group. Scratch tests showed that the wound healing rate of the si-SFRP4 group was lower than that of the NC group, and the difference was statistically significant. The expression of SFRP4 and α-SMA protein in the si-SFRP4 group significantly decreased in both DD cells and xenografts. Compared with the NC group, the xenograft quality of the si-SFRP4 group was significantly reduced. Masson's trichrome staining showed that the collagen and fibrous cells in the si-SFRP4 group were more uniform, slender, parallel and regular. The above experimental results suggest that the proliferation and metabolism of palmar aponeurosis cells and the quality of metacarpal fascia xenografts were both significantly decreased. We speculated that nanoparticle-mediated SFRP4 siRNA can be used as a potential new method for the treatment of DD.

A shared genetic architecture between adhesive capsulitis and Dupuytren disease.

BACKGROUND: The etiology of adhesive capsulitis involves inflammation, thickening, and fibrosis of the shoulder capsule. The underlying genetic factors are poorly understood. The purpose of this study was to identify genetic variants associated with adhesive capsulitis using the UK Biobank (UKB) cohort and compare them with variants associated with Dupuytren disease investigating a common etiology between the 2 fibrotic disorders. METHODS: A genome-wide association study (GWAS) was performed using data from UKB with 10,773 cases of adhesive capsulitis, and a second GWAS was performed with 8891 cases of Dupuytren disease. Next, a comparison of association statistics was performed between adhesive capsulitis and Dupuytren disease using the data from both GWAS. Finally, single-nucleotide polymorphisms (SNPs) previously reported from candidate gene studies for adhesive capsulitis and Dupuytren disease were tested for association with adhesive capsulitis and Dupuytren disease using the summary statistics from their respective GWAS. RESULTS: The UKB GWAS for adhesive capsulitis identified 6 loci that reached genome-wide statistical significance: a cluster of 11 closely linked SNPs on chromosome 1; a single SNP on chromosome 2; a single SNP on chromosome 14; 2 closely linked SNPs on chromosome 21; 33 closely linked SNPs on chromosome 22; and 3 closely linked SNPs on the X chromosome. These SNPs were associated with 8 different genes including TSPAN2/NGF, SATB2, MRPL52/MMP14, ERG, WNT7B, and FGF13. A GWAS for Dupuytren disease was performed and a comparison to the adhesive capsulitis GWAS showed 13 loci significantly associated with both phenotypes. A validation attempt of 6 previously reported SNPs associated with adhesive capsulitis using UKB summary statistics was unable to confirm any of the previously reported SNPs (all P > .19). All 23 previously reported SNPs associated with Dupuytren disease were confirmed using the UKB summary statistics (P < 2.1 × 10-3) CONCLUSION: This GWAS investigating adhesive capsulitis has identified 6 novel loci involving 8 different genes to be associated with adhesive capsulitis. A GWAS investigating Dupuytren disease was performed and compared to the adhesive capsulitis GWAS, and 13 common loci were identified between the 2 disorders with genes involved in pathologic fibrosis. We were unable to validate the SNPs in candidate genes previously reported to be associated with adhesive capsulitis although we were able to confirm all previously reported SNPs associated with Dupuytren disease. The strong genetic overlap between the adhesive capsulitis and Dupuytren disease loci suggests a similar etiology between the 2 diseases.

The Role of Functional Polymorphisms in the Extracellular Matrix Modulation-Related Genes on Dupuytren's Contracture.

(1) Background: genetic variations, localized in the functional regions of the extracellular matrix (ECM) modulation-related genes, may alter the transcription process and impact the Dupuytren's contracture (DC). The present study investigated the association of single nucleotide polymorphisms (SNPs), localized in the functional regions of the MMP8, MMP14, and CHST6 genes, with DC risk. (2) Methods: we enrolled 219 genomic DNA samples, which were extracted from 116 patients with DC and 103 healthy controls. Genotyping of selected SNPs was performed using TaqMan single nucleotide polymorphisms genotyping assay. Three polymorphisms (MMP8 rs11225395, MMP14 rs1042704, and CHST6 rs977987) were analyzed. All studied SNPs were in Hardy-Weinberg equilibrium. (3) Results: significant associations of the studied SNPs with the previous onset of the disease were observed between the CHST6 rs977987 minor T allele (p = 0.036) and the MMP14 rs1042704 mutant AA genotype (p = 0.024). Significant associations with the previous onset of the disease were also observed with a positive family history of the DC (p = 0.035). Moreover, risk factor analysis revealed that a combination of major disease risk factors (smoking and manual labor) and the MMP14 minor A allele increases the risk of DC development by fourteen times (p = 0.010). (4) Conclusions: our findings suggest that CHST6 rs977987, MMP14 rs1042704, and positive family history are associated with the previous onset of Dupuytren's contracture. In addition, the combination of the MMP14 minor A allele and additional risk factors increase the likelihood of the manifestation of the DC.

Study on the Action Mechanism of Dkk-1, TGF-ß1 and TNF-α Expression Levels in Dupuytren's Contracture.

BACKGROUND: The biological mechanism of Dupuytren's contracture needs to be further studied in order to minimize postoperative recurrence and provide a pathological basis for the development of new therapeutic targets. METHODS: HE staining, immunohistochemistry, PCR and western blotting were performed in pathological palmar aponeurosis specimens and normal palmar aponeurosis tissues for comparative study. RESULTS: (1) TNF-α expression was up-regulated: TNF-α mRNA was more highly expressed in the pathological tissues of DD patients than in the CT group, P < 0.05, and the difference between the two groups was statistically significant; (2) Dkk-1 expression was down-regulated: Dkk-1 mRNA was lower expressed in the pathological tissues of DD patients than in the CT group, P < 0.05, and the difference between the two groups was statistically significant; (3) TGF-ß1 expression was up-regulated: TGF-ß1 mRNA was higher expressed in the pathological tissues of DD patients than in the CT group, P < 0.05, and the difference between the two groups was statistically significant; (4) Pearson correlation analysis suggested that TNF-α expression was positively correlated with TGF-ß1 expression, TNF-α expression was negatively correlated with DKK-1 expression, and TGF-ß1 expression was negatively correlated with DKK-1 expression. CONCLUSION: TNF-α, DKK-1 and TGF-ß1 may play a role in the pathogenesis of palmar aponeurosis contracture, and there is a relationship between them. The study of the relationship between the three and their related signaling pathways provides a therapeutic target and a basis for the prevention and early treatment of palmar aponeurotic contracture.

Whole-Genome Sequencing Identifies Novel Heterozygous Mutation in ALMS1 in Three Men With Both Peyronie's and Dupuytren's Disease.

Peyronie's Disease (PD) is estimated to occur in up to 13% of males and has been associated with Dupuytren's Disease (DD). We identified 3 men with PD/DD and hypothesized that there may be a genetic association between the 2 diseases. Blood samples were collected from the participants and sent for whole genome sequencing. A rare non-synonymous mutation in the ALMS1 gene was identified in 3 men. Interestingly, ALMS1 is associated with TGF-b, and aberrant fibrosis. This pilot study generates the hypothesis that mutations in ALMS1 may predispose patients to development of PD/DD.

A vasculature niche orchestrates stromal cell phenotype through PDGF signaling: Importance in human fibrotic disease.

SignificanceTissue fibrotic diseases, for example of the liver and lung, represent a huge unmet medical need. In this study, using single-cell RNA sequencing, cytometry by time of flight (CyTOF), tissue imaging, and functional assays, we identify a complex vascular niche in Dupuytren's disease (DD), a common localized fibrotic condition of the palm, where early-disease-stage tissue can be accessed readily. We uncover a population of myofibroblast precursors within the pericyte compartment and demonstrate that the endothelium instructs the differentiation of functionally distinct stromal cells, thereby orchestrating discrete microenvironments in the fibrotic milieu. Together, these findings provide a basis for the concept of targeting blood vessel signaling to control the progression of human fibrosis.

Deciphering Mesenchymal Drivers of Human Dupuytren's Disease at Single-Cell Level.

Dupuytren's disease (DD) is a common, progressive fibroproliferative disease affecting the palmar fascia of the hands, causing fingers to irreversibly flex toward the palm with significant loss of function. Surgical treatments are limited; therefore, effective new therapies for DD are urgently required. To identify the key cellular and molecular pathways driving DD, we employed single-cell RNA sequencing, profiling the transcriptomes of 35,250 human single cells from DD, nonpathogenic fascia, and healthy dermis. We identify a DD-specific population of pathogenic PDPN+/FAP+ mesenchymal cells displaying an elevated expression of fibrillar collagens and profibrogenic genes. In silico trajectory analysis reveals resident fibroblasts to be the source of this pathogenic population. To resolve the processes governing DD progression, genes differentially expressed during fibroblast differentiation were identified, including upregulated TNFRSF12A and transcription factor SCX. Knockdown of SCX and blockade of TNFRSF12A inhibited the proliferation and altered the profibrotic gene expression of cultured human FAP+ mesenchymal cells, demonstrating a functional role for these genes in DD. The power of single-cell RNA sequencing is utilized to identify the major pathogenic mesenchymal subpopulations driving DD and the key molecular pathways regulating the DD-specific myofibroblast phenotype. Using this precision medicine approach, inhibition of TNFRSF12A has shown potential clinical utility in the treatment of DD.

Evaluation of WNT Signaling Pathway Gene Variants WNT7B rs6519955, SFRP4 rs17171229 and RSPO2 rs611744 in Patients with Dupuytren's Contracture.

Dupuytren's contracture (DC) represents a chronic fibroproliferative pathology of the palmar aponeurosis, which leads to flexion contractures of finger joints and hand disability. In recent decades, the WNT signaling pathway has been revealed to play a significant role in the manifestation and pathogenesis of DC. Our study aimed to evaluate the associations between Dupuytren's contracture and WNT-related single-nucleotide polymorphisms: Wnt Family Member 7B (WNT7B) rs6519955 (G/T), Secreted Frizzled Related Protein 4 (SFRP4) rs17171229 (C/T) and R-spondin 2 (RSPO2) rs611744 (A/G). We enrolled 216 patients (113 DC cases and 103 healthy controls), and DNA samples were extracted from the peripheral blood. Genotyping of WNT7B rs6519955, SFRP4 rs17171229 and RSPO2 rs611744 was performed using the Real-Time PCR System 7900HT from Applied Biosystems. WNT7B rs6519955 genotype TT carriers were found to possess a higher prevalence of DC (OR = 3.516; CI = 1.624-7.610; p = 0.001), whereas RSPO2 rs611744 genotype GG appears to reduce the likelihood of the manifestation of DC nearly twofold (OR = 0.484, CI = 0.258-0.908, p = 0.024). In conclusion, SNPs WNT7B rs6519955 and RSPO2 rs611744 are associated with the development of Dupuytren's contracture: WNT7B rs6519955 TT genotype increases the chances by 3.5-fold, and RSPO2 rs611744 genotype GG appears to attenuate the likelihood of the manifestation of DC nearly twofold. Findings of genotype distributions among DC patients and control groups suggest that SFRP4 rs17171229 is not significantly associated with development of the disease.

Fibroproliferative disorders and diabetes: Understanding the pathophysiologic relationship between Peyronie's disease, Dupuytren disease and diabetes.

Introduction: Fibrosis is characterized by dysregulation and accumulation of extracellular matrix. Peyronie's disease and Dupuytren disease are fibroproliferative disorders of the tunica albuginea of the penis and fascia of the hand, respectively. Chronic hyperglycaemia due to diabetes mellitus can also lead to tissue injury and fibrosis. A meta-analysis has shown a relationship between Dupuytren disease and diabetes (overall odds ratio, 3.1; 95% confidence interval, 2.7-3.5). This review explores commonalities in the pathogenesis of Peyronie's disease, Dupuytren disease and diabetes. Methods: A search of the PubMed database was conducted using the search terms "diabetes" AND "Peyronie's disease"; and "diabetes" AND "Dupuytren." Results: Genome-wide association and gene expression studies conducted with tissue from people with Peyronie's disease or Dupuytren disease identified signalling pathways associated with wingless-type mammary-tumour virus integration site signalling, extracellular matrix modulation and inflammation. Biochemical studies confirmed the importance of these pathways in the pathogenesis of fibrosis with Peyronie's disease and Dupuytren disease. Dysregulation of matrix metalloproteinase activity associated with extracellular matrix breakdown was implicated in fibroproliferative complications of diabetes and in the aetiology of Peyronie's disease and Dupuytren disease. A notable percentage of people with diabetes have comorbid Peyronie's disease and/or Dupuytren disease. Conclusions: Studies have not been performed to identify fibroproliferative pathways that all 3 conditions might have in common, but data suggest that common pathways are involved in the fibroproliferative processes of Peyronie's disease, Dupuytren disease, and diabetes.