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Journal of Hand Surgery (British and European Volume), Vol. 30, No. 6,
557-562 (2005)
DOI: 10.1016/J.JHSB.2005.07.002
Dupuytren’s Contracture: An Update of Biomolecular Aspects and Therapeutic Perspectives
A. CORDOVA,
M. TRIPOLI,
B. CORRADINO,
P. NAPOLI and
F. MOSCHELLA
From the Dipartimento di Discipline Chirurgiche ed Oncologiche, Cattedra di Chirurgia Plastica e Ricostruttiva Università di Palermo, Via del Vespro, Palermo, Italy
Correspondence: Massimiliano Tripoli, Via Andrea Costa no 4–90125 Palermo, Italy. Tel.: +91 6472965. E-mail: matripoli{at}yahoo.it
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Abstract
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The so-called fibrogenic cytokines, able to induce the growth of fibroblasts and their differentiation into myofibroblasts and to stimulate their production of extracellular matrix, are involved in the genesis of Dupuytren’s contracture. Although many studies have been made of biomolecular aspects of palmar fibromatosis, practical applications from them are still far from imminent because of the real difficulty of blocking their action in vivo, even in a chronic, progressive lesion such as Dupuytren’s disease. Consequently, surgical excision of the palmar fascia still remains the treatment of choice.
Key Words: Dupuytren’s contracture • flexion • transforming growth factor-beta • alternatives to surgery
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INTRODUCTION
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In the 1970s, the pathogenetic role of a cellular element present in the aponeurotic tissue, viz. the myofibroblast, was identified. In more recent years, attention has been focused on the search for molecular factors involved in the control of myofibroblasts, such as free radicals and cell growth factors. Research on other fibrotic diseases, such as hepatic cirrhosis, pulmonary fibroses, atherosclerosis and the glomerulonephritides, as well as research in cell biology, have made an innovative contribution to the understanding of the development of Dupuytren’s contracture. Some molecular factors are now recognized to be involved in the genesis of Dupuytren’s contracture. Specifically, some cytokines and growth factors, with their respective receptors (Table 1), have been identified.
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BIOMOLECULAR FACTORS INVOLVED IN THE GENESIS OF DUPUYTREN’S DISEASE
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The concept of a cell able to produce and secrete growth factors which subsequently bind to the receptors exposed on its surface constitutes an autocrine modality of control of cell growth. There exists a complex system of various growth factors balancing one another which can function individually or in association with others. A characteristic of the normal repair process induced by growth factors is that, once homeostasis has been achieved, the autocrine and/or paracrine mechanisms return to the normal condition. A classic example of this process is wound healing.
Various researchers have demonstrated that Dupuytren’s contracture and fibromatoses, in general, are the result of abnormal and altered fibroblast proliferation, linked to anomalous expression of the growth factors themselves (Kloen, 1999) The factors able to stimulate the growth of fibroblasts are probably also able to induce their differentiation into myofibroblasts and to stimulate the production of extracellular matrix. The most likely candidates for control of cellular growth of myofibroblasts of the palmar fascia are the so-called fibrogenic cytokines: transforming growth factor beta (TGF-β), transforming growth factor alpha (TGF- ), platelet derived growth factor (PDGF) and granulocyte macrophage-colony stimulating factor (GM-CSF). Many of these cytokines also induce proliferation of endothelial cells, allowing another important process for tissue growth and repair, viz. angiogenesis.
(a) Transforming growth factor beta (TGF-β)
TGF-β is a member of a family of proteins regulating the proliferation, proliferative inhibition and differentiation of a large variety of cells. Structurally, it is a homodimer with a molecular weight of 25 kDa, made up of 112 amino acids. The gene by which it is produced is on chromosome 19q13. Seven isoforms of TGF-β are known. Depending on the type of cell, it can stimulate proliferation, inhibit it, have both functions or neither. For example, TGF-β is able to stimulate the growth of mesenchymal cells like fibroblasts, as well as connective tissue. A recent study by Meek et al. (1999) has demonstrated that TGF-β, combined with mechanical stress, is able to promote differentiation of fibroblasts into myofibroblasts, which subsequently contract through the effect of thrombin.
A study by Badalamente et al. (1996), on samples of pathological palmar tissue, has demonstrated that (1) TGF-β 1 has a high concentration in myofibroblasts and fibroblasts at all stages of Dupuytren’s contracture, (2) Normal fibroblasts of the palmar fascia also express TGF-β 1, but at a lower concentration, (3) TGF-β 2 is localized in the myofibroblasts of patients in the proliferative phase of Dupuytren’s disease but absent in the myofibroblasts of the residual phase and in those of the normal palmar fascia, (4) Addition of TGF-β 1 or 2, or both, to culture terrains containing myofibroblasts significantly increases proliferation of these cells, above all in areas with higher cell density. Another recent study also demonstrated the association between Dupuytren’s disease and a polymorphism on the 5'–untranslated region of the TGF-β 2 gene: the variability of the gene could modulate myofibroblast activity, proliferation and induction of extracellular matrix synthesis, resulting in fibromatous tissue genesis (Bayat et al., 2002).
It is known that TGF-β induces significant effects, both in vitro and in vivo, in wound healing models, e.g. an increase in type III collagen and glucosaminoglycans, excessive formation of granulomatous tissue (fibromatosis) and stimulation of angiogenesis, as found in Dupuytren’s contracture. Seeing these similarities, an approach to the treatment of Dupuytren’s fibromatosis might involve inhibition of myofibroblast proliferation, induced by TGF-β in the early phases of the disease. This could be possible with more complete knowledge of the receptor for TGF-β expressed by myofibroblasts, of the second messengers and of the stimulus for collagen synthesis.
(b) Zinc-Finger 9 protein (ZF9)
Recently, a possible genetic predisposition for Dupuytren’s contracture has been evaluated. Of interest is biomolecular research which has highlighted the relationship between the ZF9 and the synthesis of the growth factor most involved in the aetiology and pathogenesis of fibromatosis, i.e. TGF-β (Bayat and Watson, 2003). The ZF9 protein is a transcription factor synthesized inside the cell nucleus, whose main role consists in binding to the promoter sequence of the gene of TGF-β 1, TGF-β 2 and their respective receptors, promoting transcription of the RNA-messenger of all these molecules. The gene by which the protein is synthesized is localized in chromosome 10p15. The experimental study was carried out on 138 patients, all affected by palmar fibromatosis and on 255 persons not affected by the disease (healthy controls). A sample of venous blood was taken from each patient and DNA was extracted from the cells, subsequently amplified by means of polymerase chain reaction. Then the gene by which the ZF9 protein is synthesized was identified and the nucleotide sequence was codified. It was shown that, at position 1140 on the above-mentioned chain, it was possible to find two different nucleotides, i.e. guanine (the so-called "G" allele) and adenine (the "A" allele). The former allele was present in 70% of patients with the disease and in 59% of controls. The "A" allele was only found in 30% of patients and 41% of controls. So allele "G" is more frequent in both patients and controls than the allele "A". Hence, it appears likely that, unlike the one containing adenine, the gene of the ZF9 protein containing the nucleotide guanine at position 1140 synthesises an unstable form of this proteinic molecule, which appears to be directly responsible for increased synthesis of TGF-β 1, TGF-β 2 and their respective receptors in serum and tissue.
(c) Epidermal growth factor (EGF)
In the early phase of Dupuytren’s disease, different cytokines are involved in controlling proliferating myofibroblasts and their deposition of collagen Type III in the intercellular space. It is accepted that EGF stimulates migration, division and differentiation of connective tissue cells and, also, plays an active role in control of apoptosis and angiogenesis. In a recent study, it was shown that there were different concentrations of EGF in different degrees of palmar fibromatosis (Augoff et al., 2005). The experimental study was carried out on fragments of fibromatous palmar fascia of 68 patients treated surgically for Dupuytren’s disease and on 14 fragments of normal fascias of persons treated for carpal tunnel syndrome (healthy controls). In this study, Iselin’s four degree scale was used to identify the clinical progression of the disease, viz. first degree –palmar nodules and small cords without signs of contracture; second degree – contracture of the meta-carpophalangeal joint only; third degree – contracture affecting the proximal interphalangeal joint also; fourth degree – severe contracture of the metacarpophalangeal and proximal interphalangeal joints, with hyperextension of the distal interphalangeal joint, together with advanced secondary lesions in the skeleton (Augoff et al., 2005). It was observed that (1) there was a low EGF concentration in pathological tissues from first and third degree disease compared with the control value. (2) there was an increase of EGF concentration in pathological tissues from second degree disease linked to significant increase of cellular density and activity. (3) there was an increase of EGF concentration in pathological tissues from fourth degree disease linked to the neoangiogenesis process and the beginning of apoptosis by eliminating myofibroblasts from the aponeurosis. It is clear that EGF plays an important role in the development of Dupuytren’s contracture, especially in the advanced stages of the disease.
(d) Transforming growth factor alpha (TGF-) and epidermal growth factor receptor (EGF-R)
The varying expression of TGF- and EGF-R in different phases of fibromatosis has been highlighted (Magro et al., 1997). Both are present in the myofibroblasts of hypercellular nodules in the proliferative phase, while they later disappear from the hypocellular and fibrotic nodules in the involutionary and residual phases. This explains why myofibroblasts produce and release TGF-, which, with an autocrine and paracrine mechanism (binding to EGF-R), stimulates cell proliferation (proliferative phase), with a consequent increase in the number of cells and formation of hypercellular areas. Later, TGF- inhibiting factors, which have not yet been isolated, reduce their expression, leading to a hypocellular condition. The contractile capacity of the myofibroblasts will determine palmar contracture.
(e) Platelet-derived growth factor (PDGF)
The association between PDGF and myofibroblasts has been known for some time. It seems that PDGF is able to induce proliferation of these cells. There have been experimental demonstrations of an increase in the expression of this growth factor in fibromatous areas in Dupuytren’s contracture and other fibromatoses in which high expression of TGF-β is found. This gives rise to the hypothesis that the mitogenic effects of PDGF are controlled by TGF-β itself, by means of a paracrine mechanism, which, once again, suggests a very important role for this growth factor in fibromatosis (Badalamente et al., 1996). An ultrastructural study showed the effect of blockade of PDGF and TGF-β with neutralizing antibodies on myofibroblasts, in vitro. The proliferation, chemotaxis and collagen deposition of these cells was decreased (Li et al., 2001).
(f) Granulocyte macrophage-colony stimulating factor (GM-CSF)
This is a factor stimulating the formation of granulocyte and macrophage colonies, known for its proliferative effects on haematopoietic cells and on the inflammatory process. In a experimental model, it was demonstrated that, after transferring to rat lung GM-CSF gene, an overexpression of this cytokine is able to induce release of TGF-β1 and pulmonary fibrosis formation (Xing et al., 1997). So far, TGF-β1 and GM-CSF are the only cytokines able to induce -actin synthesis in myofibroblasts of the cutis, in vivo, and the ones which probably activate myofibroblasts in Dupuytren’s contracture, although there are, as yet, no data regarding a possible relationship between GM-CSF and Dupuytren’s contracture itself.
In conclusion, among all the growth factors and cytokines which have, so far, been studied in order to detect their possible participation in the development of Dupuytren’s contracture, TGF-β seems to play a fundamental role and the others a minor one, at all events dependent on TGF-β.
(g) Free radicals
The theory of free radicals advanced by some researchers suggests a relationship between palmar ischaemia and the superoxide radical (O2–), hydrogen peroxide (H2O2) and the hydroxylic radical (OH–) (Kloen, 1999). Progressive restriction of capillaries with age, smoking and other environmental factors lead to a condition of localized hypoxia. This causes increases in levels of xanthine oxidase, which allows the synthesis of free radicals.
For the treatment and prevention of Dupuytren’s contracture, some researchers in the past had turned their attention to the possible clinical-therapeutic role of allopurinol (Murrel et al., 1987), which inhibits xanthine oxidase and prevents free radical formation. However, experimental studies have shown that this role is absolutely insignificant (Hurst and Badalamente, 1999).
(h) Metalloproteinases and tissue inhibitors of metalloproteinases (MMP–TIMP)
MMP are zinc-dependent endopeptidases produced by cells involved in wound healing, including myofibroblasts, macrophages, endothelial cells and keratinocytes. The best-known are MMP 1 (interstitial collagenases), MMP 2 (collagenase type IV from 72 kDa-gelatinase A), and MMP 9, (72 kDa-gelatinase B). The activity of these enzymes depends on their conversion from the proteinic form to the catalytic one by means of "tissue inhibitors" of metalloproteinases. Four serum forms of TIMP, arising from the same gene, have been identified. TIMP-1 is the most important inhibitor. In numerous carcinomas, there is hyper-expression of MMP by tumour cells, allowing them to digest connective fibres and to make their way to the nearest blood or lymphatic vessel. A study was carried out on the effects of administering a synthetic inhibitor of MMP, referred to as MARIMASTAT, in 24 patients with inoperable gastric adenocarcinomas: 12 patients who had shown encouraging results after the first weeks continued to be given treatment for over a month and three of them developed fibrosis of the palm of the hand, very similar to Dupuytren’s disease, with the formation of cords and nodules. Unfortunately, no biopsies were taken of these lesions. It has been hypothesized that this condition, similar to Dupuytren’s disease, was due to a reduction in MMP function, caused by an increase in the systemic concentration of the synthetic inhibitor of MMP (Hutchinson et al., 1998).
Another study made it possible for the very first time to determine the serum concentrations of the metallo-proteinases, MMP 1, MMP 2 and MMP 9, and of the tissue inhibitors, TIMP-1 and TIMP-2, in patients with Dupuytren’s contracture, at the involutionary and residual proliferative stage (Ulrich et al., 2003). This study revealed a significant increase in the serum TIMP-1 level in patients with palmar fibromatosis in the proliferative phase compared to the control group, while TIMP-2, MMP-1, MMP-2 and MMP-9 concentrations showed no significant differences between these two groups. TIMP-1 was raised in the serum of patients in the proliferative phase more than in ones in the involutionary-residual phase. The study showed that, in patients with Dupuytren’s disease, the physiological balance between MMP and their antagonist endogens is altered. The high systemic concentration of TIMP-1 associated with a reduction in decay of the extracellular matrix may represent a very important pathogenic mechanism responsible for palmar fibromatosis and other proliferative disorders.
(i) Collagen and fibronectine
The cell matrix is made up of collagen, fibronectine and proteoglycans, which constitute a structure to which cells attach themselves by means of their receptors, called integrins. The cell matrix is a dynamic structure which is constantly destroyed and reconstructed. A high level of total collagen in palmar tissue in a patient with fibromatosis is considered very typical. The reason for the different types of collagen and their potential role in fibromatous tissue compared to healthy tissue has not been fully clarified. For example, some authors (Brickley-Parson et al., 1981) believe that type III collagen is linked to a higher degree of severity of disease while others disagree on this. A time-protracted increase in type III collagen has been demonstrated in the palmar fascia of patients with stabilized Dupuytren’s contracture. Another constituent of the matrix is fibronectine, involved in cell migration, morphological modification, adhesion and differentiation. Fibronectine concentration increases under the stimulus induced by TGF-β. In Dupuytren’s contracture, its presence has been demonstrated (using indirect immunofluorescence) in the form of oncofoetal fibronectine, thus assimilating fibromatosis to normal processes of immature granulation tissue formation during tissue repair (Ignotz and Massague, 1986). A recent experimental study on samples of palmar fascia from patients with Dupuytren’s contracture compared to samples of normal fascia showed a higher concentration of two proteins regulating the wound healing process, viz. heat shock protein 47 (Hsp47) and oncofoetal fibronectine (isoform IIICS) (Howard et al., 2004).
(j) The immune system
Dupuytren’s disease is a familial disorder. A genetic study demonstrated a statistically significant association between palmar fibromatosis and the human leucocyte antigens complex (HLA). In particular, there is a relative risk of 2.94 of persons with HLA-DR3 developing the disease (Neumuller et al., 1994). The presence of HLA-DR3 may determine autoimmune reactions and the formation of autoantibodies against components of the extracellular matrix. The autoantibodies may, also, induce release of profibrotic cytokines by immune system cells. Macrophages, for example, secrete large quantities of cytokines, including TGF-β and GM-CSF, which, as mentioned, play a role in fibromatosis.
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ALTERNATIVES TO SURGERY
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The existence of cases with regression and complete spontaneous healing without any surgical treatment has led to a search for possible alternatives to surgery, such as the use of creams based on vitamin E, dimetilsulphoxides, drugs inducing hypouricaemia and therapy with ultrasounds (Hurst and Badalamente, 1999). However, many of these therapies have not led to any clinical improvement and have not made it possible to stabilize the disease in the long term. In vitro, the injection of steroids and  -interferon have given better results. An experimental study (Meek et al., 2002) compared the effects of a steroid (Depo-Medrone) on cultured Dupuytren’s fibroblasts and on control ones. Depo-Medrone is able to reduce the rate of fibroblast proliferation and to increase apoptosis of these cells and inflammatory cells.
Recently it was discovered that interferon -2b and interferon , in vitro, are able to reduce expression of the RNA messenger for cytoplasmic β-actin and -actin in fibroblasts of the palmar fascia in cell cultures, inhibiting the replication, differentiation and synthesis of collagen in the cultures (Sanders et al., 1999). These studies suggest a possible use of these substances therapeutically, in Dupuytren’s contracture.
Improvements are also achieved with percutaneous enzymatic aponeurotomy, 10,000 units of collagenase diluted in hydrochloric acid being injected into the cords through the skin (Badalamente and Hurst, 2002). First of all, it is necessary to carry out ultrasonography in order to establish the depth of the underlying tendons, so as to avoid damaging them with the injection. The day after the injection, the patient is submitted to light manipulation of the finger, which is, often, able to correct the flexion contracture. In the ensuing 4 months, he, or she, then has to do exercises to restore flexion and extension and, at night, wear an extension splint. In this way, fair results are achieved in over 90% of contractures of the metacarpophalangeal joint and in over 66% of contractures of the proximal interphalangeal joint (Hurst and Badalamente, 1999). At present, no long-term results with this type of treatment are known.
A recent study have suggested a possible role of 5–fluorouracil in patients with Dupuytren’s disease in reducing the recurrence rate after limited excision of fibromatous tissue, through its control of proliferation, differentiation and contractility of fibroblasts (Bulstrode et al., 2004) . In this study, a double-blind prospective randomized clinical trial was performed. After an 18 months follow-up, it was demonstrated that there were no significant differences between the two groups with, and without, intraoperative application of 5–fluorouracil.
A study which reported a 5-year follow-up on 57 patients, suggested that ortho voltage radiotherapy is able to prevent disease progression, but only if applied in the early stages (Keilholz et al., 1996). Forty-four patients (77%) treated had no disease progression but 13 (23%) did progress. Another study of radiotherapy treatment, with a 7-year follow-up, reported no difference between the treated group and the untreated one (Hurst and Badalamente, 1999). Today, radiotherapy is not commonly used for benign diseases because of its side effects, such as lymphatic occlusions, actinic nerve lesions, with reduction of motor strength and sensory reinnervation, and various skin changes, such as radio-dermatitis, sclerosis of the dermis, friable nails, ulceration and necrosis (Brenner and Rayan, 2003).
It is known that Dupuytren’s disease has a higher incidence in male patients. The presence of androgen receptors on fibroblasts from Dupuytren’s nodules suggests fibroblast metabolism may be regulated, partly, by androgen (Pagnotta et al., 2002). A recent experimental study has tested the responsiveness of Dupuytren’s fibroblasts to the active form of testosterone, 5-dihydrotestosterone (5-DHT) (Pagnotta et al., 2003). It was demonstrated that 5-DHT stimulated Dupuytren’s fibroblasts to proliferate in cultures, while androgen receptor expression decreased with a lower concentration of 5-DHT. It is clear that palmar fascia is a target tissue for androgen hormones. These studies appear particularly promising from a practical point of view. For example, a pharmacological inhibition of the enzyme 5-reductase, which converts testosterone to its active form, 5-DHT, may control progression of Dupuytren’s contracture.
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CONCLUSION
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The processes inducing the series of cascading events leading to excessive proliferation and synthesis of cell matrix are still not very clear and many questions remain unanswered. These include whether palmar fibromatosis is pathogenically similar to fibrotic diseases; whether, once the disease has been diagnosed, it is possible to modulate the myofibroblast apoptosis mechanism; whether the fibromatous process starts from local hypoxia, as would seem to be the case in smokers and diabetics, or from continual and repeated micro-traumas stimulating an inflammatory response with macrophages and/or platelets, producing specific fibrogenic cytokines; or whether it is a gene defect with alteration of the apoptotic mechanism.
Recent experimental research has concentrated on local gene therapy, which can control the expression of some growth factors through the use of antibodies blocking the binding of ligands to their respective receptors, or, when binding has already occurred, by blocking the receptor–ligand complex. Local application of antibodies against TGF-β has shown a decrease of adhesion formation in rabbit flexor tendons repair and histological evaluation of tissue has shown a reduction of collagen production (Zhang et al., 2004).
Identification of the alteration of the balance between MMP and their TIMP antagonists, with the demonstration of an increase in the TIMP concentration in patients with palmar or visceral fibromatosis, has made it possible to discover pathogenic phases common to different fibroses.
It has become evident that palmar fibromatosis is a complicated process comprising a series of cascading molecular events. Among the molecular factors involved, TGF-β plays an essential role. Secondarily, an increase in fibromatosis leads to local hypoxia, which amplifies TGF-β expression. This complicated process may also include free radical synthesis. Elements such as the presence or absence of myofibroblasts, type I and type III collagen, epilepsy and diabetes are important in the patient’s medical history, but, so far, have not proved useful in identifying effective non-surgical treatment for Dupuytren’s disease.
Although many studies have been made on the biomolecular aspects of palmar fibromatosis, which has various aspects in common with anomalous processes of overabundant cicatrization and visceral fibroses, practical applications of the results of these studies are still far from close. Consequently, surgical excision of the palmar fascia still remains the treatment of choice.
Received for publication March 22, 2005.
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Abstract
INTRODUCTION