First identification of resident and circulating fibrocytes in Dupuytren's disease shown to be inhibited by serum amyloid P and Xiapex.

Dupuytren's disease (DD) is a common progressive fibroproliferative disorder causing permanent digital contracture. Proliferative myofibroblasts are thought to be the cells responsible for DD initiation and recurrence, although their source remains unknown. DD tissue has also been shown to harbor mesenchymal and hematopoietic stem cells. Fibrocytes are circulating cells that show characteristics of fibroblasts and they express surface markers for both hematopoietic and mesenchymal stromal cells. Fibrocytes differentiate from peripheral CD14+ mononuclear cells, which can be inhibited by serum amyloid P (SAP). In this study we have demonstrated the presence of fibrocytes in DD blood and tissue, moreover we have evaluated the effects of SAP and Xiapex (Collagenase Clostridium histolyticum) on fibrocytes derived from DD. H&E staining showed typical Spindle shaped morphology of fibrocytes. FACS analysis based on a unique combination of 3 markers, revealed the increased presence of fibrocytes in blood and tissue of DD patients. Additionally, immunohistology of DD nodule and cord tissue showed the presence of collagen 1+/CD34+ cells. No difference in plasma SAP levels was observed between DD and control. Higher concentrations of SAP significantly inhibited fibrocytes differentiated from DD derived monocytes compared to control. DD fascia derived fibrocytes showed resistance to growth inhibition by SAP, particularly nodule derived fibrocytes showed robust growth even at higher SAP concentrations compared to control. DD derived fibrocytes were positive for typical fibrocyte dual markers, i.e. Collagen 1/LSP-1 and collagen 1/CD34. Xiapex was more effective in inhibiting the growth of nodule derived cells compared to commercially available collagenase A. Our results show for the first time the increased presence of fibrocytes in DD patient's blood and disease tissue compared to control tissue. Additionally, we evaluate the response of these fibrocytes to SAP and Xiapex therapy.

DNA copy number variations at chromosome 7p14.1 and chromosome 14q11.2 are associated with dupuytren's disease: potential role for MMP and Wnt signaling pathway.

BACKGROUND: Dupuytren's disease is a common fibroproliferative disorder with an unknown etiology. Emerging evidence suggests a strong genetic component involved in the manifestation of the disease. This study aims to investigate the potential involvement of copy number variations in Dupuytren's disease pathogenesis. METHODS: Array-based comparative genomic hybridization (NimbleGen Human CGH 2.1 M) was utilized to compare DNA from (1) nodules versus internal control (patient's blood; n = 4) and (2) nodules (n = 4) versus external control (commercial reference DNA pooled from 10 donors). Analysis was carried out using Nexus 5.1 (BioDiscovery, El Segundo, Calif.) with the inclusion of additional results from previously published array-based comparative genomic hybridization. Copy number variations were considered to be common in Dupuytren's disease if the overlap was statistically significant and they were present in the majority (75 to 87.5 percent when compared with controls) of Dupuytren's disease nodules. The copy number variations loci were also compared with recently published genome wide-association studies. Common copy number variations were further validated using quantitative polymerase chain reaction. DNA from 25 Dupuytren's disease cases and 30 external controls were used in the quantitative polymerase chain reaction validation. In addition, gene expression was compared between Dupuytren's disease nodules and internal controls (transverse palmar fascia; n = 7). RESULTS: Five common copy number variations, on chromosome 17q12, 1p31.1, 20p13, 7p14.1, and 14q11.2, were identified by array-based comparative genomic hybridization. Significantly higher copy numbers of copy number variations at chromosome 7p14.1 and 14q11.2 in Dupuytren's disease were confirmed in quantitative polymerase chain reaction validation. Matrix metalloproteinase-14 and secreted frizzled-related protein 4 (near a polymorphism recently associated with Dupuytren's disease) were significantly up-regulated in nodules. CONCLUSION: This study demonstrated an association between Dupuytren's disease and copy number variations at chromosomes 7p14.1 and 14q11.2.

Revised Tubiana's staging system for assessment of disease severity in Dupuytren's disease-preliminary clinical findings.

There are few objective staging systems to assess severity of Dupuytren's disease (DD). Previous methods to assess severity of DD were based primarily on the degree of contracture of an affected digit measured using a goniometer. Nonetheless, this method of assessment alone may be incomplete, and other factors should be considered. White (n = 92) patients diagnosed with DD from northwest of England were assessed for DD. Objective criteria for evaluating severity incorporated quantified variables. The revised severity stage was correlated to a known staging system of DD (Tubiana's staging system) which measures total flexion deformity for a single affected digit. Total revised severity staging scores ranged between 4 and 53 (mean = 18.7) and revealed significant positive correlation to Tubiana's original staging system (r (2) = 0.8, p < 0.001). There was significant difference between severity staging scores in those with a positive family history compared to those without (p < 0.01). In current practice, often, the degree of contracture in an affected digit is used solely as a measure of disease severity. Additional objective clinical information may provide useful prognostic indices for disease progression as well as postoperative outcome.