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

Abstract 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.


| INTRODUC TI ON
In genetically susceptible individuals, chronic hyperglycaemia due to diabetes mellitus can cause tissue injury that may result in the development of fibrosis. 1 Fibrosis is characterized by dysregulation, accumulation and change in the quality of the extracellular matrix resulting from an abnormal or uncontrolled tissue repair response. The extracellular matrix provides mechanical support for cells and facilitates cell-cell communication through an insoluble network of collagen, elastins, structural glycoproteins, proteoglycans-hyaluronans and integrins. 1 The extracellular matrix is constantly being synthesized and degraded, and this turnover is important to ensure normal structure and function of organs and tissues. Fibrosis in people with diabetes can affect almost every organ in the body, including the heart, eyes, liver, kidney, skin and vascular system. 1 Many people with diabetes have arthropathies, such as thickened skin and limited mobility of the joints of the hands and fingers, leading to flexion contracture(s). 2 Endocrinologists may overlook limited joint mobility in people with diabetes or may not consider it a diabetes-related complication.
Dupuytren disease is a progressive fibrotic disorder of the fascia of the palm and fingers. Mean age at onset is 49 years for individuals with a family history, compared with 55 years for those without a family history of Dupuytren disease. 3 Nodules and cords fixed to the skin and palmar fascia disable normal movement of the hand and result in the pathology of Dupuytren contracture; a defect in wound repair is believed to initiate the fibrotic process of Dupuytren disease (in this review, 'Dupuytren disease' encompasses 'Dupuytren contracture'). [4][5][6] Several risk factors have been identified for Dupuytren disease, including diabetes, increasing age, being male, heavy alcohol consumption and smoking. 7,8 In people with diabetes and comorbid Dupuytren disease, the ring and middle fingers are typically affected, whereas in people with Dupuytren contracture but without diabetes, the ring and fifth ('pinkie') fingers typically are affected. A systematic review of 21 studies reported a relationship between Dupuytren disease and diabetes (overall odds ratio, 3.1; 95% confidence interval [CI], 2.7-3.5; Table 1, Dupuytren disease). 9 Furthermore, a strong association between both types of diabetes and Dupuytren disease was noted (Table 1). 9 Investigators have identified a significant relationship between diagnosis of Dupuytren disease and increasing HbA 1c levels in 3418 people with comorbid Dupuytren disease and diabetes. 10 A 2019 study reported a genome-wide genetic correlation between Dupuytren disease and type 2 diabetes, although at a local genetic level, there was no correlation or pattern suggestive of a causal relationship between the 2 conditions. 11 Peyronie's disease, which is thought to have a pathophysiology generally similar to that of Dupuytren disease, is a progressive fibrotic disorder causing plaques in the tunica albuginea of the penis. 12 The fibrotic plaques of Peyronie's disease can cause several abnormalities of the penis (eg curvature, shortening and narrowing), which can result in penile pain. 13 Risk factors for Peyronie's disease include penile trauma, smoking, obesity and hypertension. [14][15][16] Several studies have suggested a relationship between Peyronie's disease and diabetes (Table 1, Peyronie's disease). 14,17,18 In addition, a 2019 Iranian study reported a prevalence of Peyronie's disease of 3.8% among 317 men with type 2 diabetes. 19 In a retrospective study of 1622 men presenting to a urology health centre, the presence of type 2 diabetes (n = 387; 24%) was significantly associated with Peyronie's disease (P = .005); logistic regression analysis identified a significant association between glycated HbA 1c > 69 mmol/ mol (8.5%; eg poorly controlled) and Peyronie's disease (odds ratio of a systemic fibroproliferative pathologic process, the aim of this narrative review is to provide insights into commonalities in the genetics and pathogenesis of Peyronie's disease, Dupuytren disease and diabetes mellitus.

| ME THODS
A search of the PubMed database with no date restriction was conducted on 3 June 2019, using the following search terms: "diabetes" AND "Peyronie's disease"; and "diabetes" AND "Dupuytren." Searches were limited to human studies and English-language publi-

| G ENE TI C A SSO CIATI ON S AND B I O CHEMI C AL PATHWAYS LINK ED TO THE AE TI OLOGY OF FIB ROS IS
As part of the normal wound-healing process, myofibroblasts aid in wound closure through their contractile properties and secretion of growth factors and molecules that promote extracellular matrix formation. 30 At the end of the wound-healing process, myofibroblasts and vascular cells undergo apoptosis and are then removed from the wound site. 30 Tissue and organ fibrosis is believed to result from the lack of myofibroblast apoptosis, which leads to extracellular matrix overproduction, tissue contraction and scar formation in conditions such as Dupuytren disease. 31,32

| Genetics of Dupuytren disease and Peyronie's disease
Signalling pathways associated with the pathogenesis of fibrosis in Peyronie's disease and Dupuytren disease include wingless-type mammary-tumour virus integration site (WNT) signalling, extracellular matrix modulation and inflammation. 33-37

| Genetics of diabetes
TGF-β has been shown to promote renal cell hypertrophy and extracellular matrix accumulation in diabetes, 54,55 which is generally similar to the aetiologic processes of Dupuytren disease 57 and Peyronie's disease. 35,37 In a hyperglycaemic clamp study, increases in blood glucose levels in 13 healthy volunteers (mean age, 39 years) caused a sevenfold increase in urinary excretion of TGF-β1 (P = .002) compared with baseline, 68 and data suggest that increased blood glucose levels can activate TGF-β. 69 Decorin, an inhibitor of TGF-β1 that is upregulated in people with Peyronie's disease, 35 was also upregulated by 650% ± 60% of control values in the kidney tissue of people with diabetic nephropathy compared with healthy kidney tissue. 55 In advanced stages of diabetic nephropathy, decorin deposition was found in fibrotic areas and colocalized with type I collagen. 55 Dysregulation of MMP activity associated with breakdown of constituents of the extracellular matrix (Figure 1) 1,12  Fibroblasts, mesenchymal stem cells, pericytes, endothelial cells, epithelial cells 6,70,71 has been implicated in type 2 diabetes and in fibroproliferative complications associated with diabetes, 48 and it also has been implicated in the aetiology of Dupuytren disease 56  pants with type 1 diabetes versus controls (P = .07). 53 Significantly higher levels of MMP-9 also were seen when comparing participants with type 1 diabetes with, versus without, retinopathy (P < .05). 53 Evidence supports the theory that hyperglycaemia associated Participants who experienced complications due to microangiopathy during follow-up had significantly higher MMP-2 levels (P = .009) and enzymatic activity (P < .001) compared with participants without complications. 50 The significant differences seen in MMP-2 levels and activity between participants with type 1 diabetes and microangiopathic complications versus controls persisted for 5 years (P < .001 for both). 50 Systemic concentrations of MMP-2 and MMP-9 are increased in people with type 2 diabetes and peripheral arterial disease. 51 In a study of people with type 2 diabetes with (n = 51) or without Dickkopf-1 gene (Dkk-1): diabetes, 12.9 ± 10.3; control group, 9.1 ± 5.7; P < .05). 46 A significant difference in maximal carotid intima-media thickness (mean ± SD) was seen in the group with diabetes (0.9 ± 0.2 mm) compared with the control group (0.8 ± 0.1 mm; P < .05). 46 After adjusting for age, there was a significant negative univariate correlation between serum sclerostin and carotid intima-media thickness in the diabetes group (r = -0.42; P = .006) and between serum Dkk-1 and carotid intima-media thickness in the diabetes group (r = -0.48; P = .001); no significant correlations were seen between these serum markers and carotid intima-media thickness in the control group. 46 The investigators hypothesized that increased levels of these WNT pathway inhibitors could disrupt WNT pathway signalling, which is activated during atherosclerosis. 46

| Dupuytren disease
There is a lack of strong clinical evidence for the use of nonoperative treatments for early-stage Dupuytren disease (eg physiotherapy, splinting and local radiotherapy). 73 For patients with established flexion deformities, surgery is considered when hand function is affected and the digits are flexed ≥ 15°. 74  Procollagen type 1 was also significantly reduced compared with placebo (40-mg treatment group, 474 ± 84 pg/µg of total protein; placebo group, 817 ± 78 pg/µg of total protein; P = .019). 82 The results indicate that treatment with an anti-TNF antibody downregulates the myofibroblast phenotype and suggest that treatments targeting the WNT signalling pathway may be promising for the treatment of early-stage Dupuytren disease. 82

ACK N OWLED G M ENTS
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