Mechanobiological dysregulation of the epidermis and dermis in skin disorders and in degeneration

Ehlers–Danlos syndrome (cutis hyperelastica)

The EDS is a heterogeneous group of inherited connective tissue disorders caused by genetic defects in the synthesis of type I, III, or V collagen 4. There are at least 10 recognized types of EDS, and the current classification (Villefranche, 1997) categorizes them into six subtypes (classic, hypermobility, vascular, kyphoscoliosis, arthrochalasis and dermatosparaxis) 5. The severity of the collagen gene mutations can vary from mild to life-threatening ones in their expression. Treatment of affected individuals is unsatisfactory and mainly supportive while requiring close monitoring of the digestive, the excretory, and particularly the cardiovascular systems. The therapeutic approaches, including physical therapy and corrective surgery, differ according to the particular disease manifestations.

Abnormal collagen leads to increased skin elasticity. Physical examination of the skin might reveal a velvety texture, fragility with easy tearing or bruising, redundant folds, molluscoid pseudotumours especially on pressure points, subcutaneous spheroids and fatty growth on the forearms or shins. Moreover, wound healing and scarring are abnormal, with widened (broad) and atrophic (thin) scars described as ‘cigarette paper’ scarring, easy bruising and a propensity for cutaneous bleeding 6, 7. Abnormal wound healing and delayed wound healing, both associated with EDS are because of deficiencies in dermal ECM-based mechanobiological processes that result in a decrease in collagen production. This sequence of events might contribute to the reduced amount of fibronectin production observed in the cultured fibroblasts of EDS patients compared to normal fibroblasts 8.

Cutis laxa

While EDS is a deficiency of collagen fibres, cutis laxa is a deficiency of elastic fibres. The disease is inherited in most cases, but acquired forms are occasionally seen as well. Elastic fibres consist of elastin and play a fundamental role in skin structure and function 9. They are produced by fibroblasts and make up 2–5% of the dermis. As the dermal elastic network is a strong determinant of skin resilience, texture and quality 9, the state of the elastic fibres is closely related to the degree of cutaneous wrinkling and photoageing as well as to skin mechanobiology. Cutis laxa (also known as chalazoderma, dermatochalasia, dermatolysis, dermatomegaly, generalized elastolysis, generalized elastorrhexis and pachydermatocele) is a group of rare connective tissue disorders in which the skin becomes inelastic and hangs loosely in wrinkles and folds. The affected areas of skin may be thickened and dark. In addition, joints are loose (hypermobility) because of the lax ligaments and tendons 10. When cutis laxa is severe, it can also affect the internal organs, including a variety of severe impairments involving the lungs, heart, intestines and arteries 10. Patients also have cutaneous wound disruption and poor scarring, although cosmetic surgery procedures (face lifting) have been shown to be aesthetically and psychologically beneficial 11. The abnormal wound healing and scarring that occur in cutis laxa can also be considered dermal deficiencies in ECM-based mechanobiology.

Scleroderma

Scleroderma (systemic sclerosis) is a complex systemic autoimmune disease (primarily of the skin) characterized by extensive fibrosis, vascular alterations and autoantibodies 12. There are two major subgroups: limited cutaneous scleroderma and diffuse cutaneous scleroderma. The cutaneous manifestations of the limited type mainly affect the hands, arms and face. It was previously called CREST syndrome in reference to the associated complications: calcinosis, Raynaud's phenomenon, oesophageal dysfunction, sclerodactyly and telangiectasias 13. In addition, pulmonary arterial hypertension may occur in up to one third of patients and is the most serious complication of this form of scleroderma. Diffuse scleroderma is rapidly progressive, involving a large area of the skin and one or more internal organs, frequently the kidneys, oesophagus, heart and lungs. This form of scleroderma can be quite disabling.

The overproduction of ECM components by fibroblasts, the principal effector cells, plays a key role in the pathogenesis of scleroderma 14. Reich et al. 14 investigated whether these functional alterations are accompanied by changes in the mechanical properties and morphology of fibroblasts. Atomic force microscopy was used to assess dermal fibroblasts derived either from scleroderma patients or from healthy donors. Significant differences in the cellular stiffness of dermal fibroblasts derived from sclerodermal lesions were detected. The authors thus concluded that the altered stiffness of sclerodermal fibroblasts may be important in disease pathogenesis as it could lead to an abnormal cellular response to mechanical stimuli. Another explanation for the overproduction of ECM is the activation of fibroblasts in the profibrotic cellular milieu by cytokines and growth factors, developmental pathways, endothelin 1 and thrombin 15. Factors including innate immune signalling via Toll-like receptors, matrix-generated biomechanical stress signalling via integrins, hypoxia and oxidative stress seem to be implicated in perpetuating the process 15. These data support a close association between scleroderma and mechanobiology.

Mixed connective tissue disease

Mixed connective tissue disease, also known as Sharp's syndrome 16, combines the features of scleroderma, myositis, systemic lupus erythematosus and rheumatoid arthritis and is thus considered an overlap syndrome. It commonly causes joint pain/swelling, malaise, Raynaud phenomenon, Sjögren's syndrome, muscle inflammation and sclerodactyly (thickening of the skin of the finger pads) 16. As in scleroderma, matrix-generated biomechanical stress signalling via integrins is thought to be associated with the cutaneous chronic inflammation and delayed wound healing.

Keloids and hypertrophic scars

Keloids and hypertrophic scars are fibroproliferative disorders of the skin, which in affected individuals appear red and show elevated scars with chronic inflammation at the affected sites. Several studies 17, 18 have determined a genetic predisposition, such as single nucleotide polymorphisms, to the development of keloids and hypertrophic scars 18. There is also increasing evidence that the local microenvironment plays a significant role 19, 20. Keloids show a marked preference for particular locations on the body and commonly adopt distinct site-specific shapes. These features have been shown to be highly dependent on local factors, especially mechanical force distribution 20. Thus, keloids usually occur at sites that are constantly or frequently subjected to mechanical forces (such as the anterior chest and scapular regions), but seldom occur in areas where stretching/contraction of the skin is rare (such as the parietal region or anterior lower leg), even in patients with multiple keloids. Moreover, the typical butterfly, crab's claw, or dumbbell shapes of keloids appear to be largely determined by the direction of the mechanical forces on and around the wound site 19. Thus, deficiencies in mechanosignalling pathways have been suggested to explain the formation of keloids and hypertrophic scars 21. As these lesions develop in the dermis, an understanding of dermal mechanobiology will be essential to unravelling their underlying mechanisms.

Moreover, hyperreactivity or derangement of the MS nociceptors of nerve fibres has been suggested to cause or contribute to the generation of keloid and hypertrophic scars 22. MS nociceptors on unmyelinated axons (C-fibres and Aδ-fibres) can be stimulated while the skin is stretched. In addition, axonal reflexes and the stimulation of antidromic sensory nerves result in the release of vasodilatory factors, including neuropeptides such as substance P and calcitonin gene-related peptide, which in turn induce local erythema. These neuropeptides may also up-regulate the expression of genes encoding growth factors, such as transforming growth factor β and nerve growth factor, in fibroblasts and other dermal cells. Therefore, neurogenic inflammation is a mediator that plausibly connects mechanical forces with the development of abnormal scar progression and/or generation.

Bullous pemphigoid

This is an acute or chronic autoimmune skin disease involving a reaction against structural components of the hemidesmosome, resulting in subepidermal blistering, more appropriately known as bullae, within the space between the epidermis and dermis. Destruction of the hemidesmosomes is followed by the loss of epidermal adhesion and by the development of blisters between the keratinocyte layer and the dermis 23, 24.

Typically, there is a linear deposit of IgG at the basement membrane zone accompanied by the presence of circulating antibodies to BP230 and BP180 23. Iwata et al. 25 presented evidence that pathogenic autoantibodies against BP180 decrease the strength of keratinocyte adhesion to the cell matrix in the absence of complement and neutrophils 23.

Hemidesmosomes are very small stud- or rivet-like structures on the inner basal surface of epidermal keratinocytes. While desmosomes link two cells together, hemidesmosomes bind a cell to the ECM and thus play an important role in epidermal mechanobiology, specifically in cell-matrix adhesion 26. The breakdown of the epidermal mechanobiological environment is the main reason for the appearance of clinical symptoms.

Neurofibromatosis

The NF is a genetically inherited disorder in which neurofibromas, which may be benign, may nonetheless cause serious damage by compressing nerves and other tissues. In NF type 1 (NF-1, also known as von Recklinghausen disease), unremarkable scars are produced after injury or surgery and progression to keloid or hypertrophic scar formation is rare 27. Miyawaki et al. 27 analysed 101 cases of NF or solitary neurofibroma recorded in centres from five different countries. The clinical diagnosis was NF-1 in 57 cases, solitary neurofibroma in 35, plexiform neurofibroma in four and no distinct clinical diagnosis in five. No patient in the NF group developed keloids or hypertrophic scars, whereas two patients in the solitary neurofibroma group had hypertrophic scarring 27. Given the obvious association between scar formation and mechanobiology 28, 29, the results of this study suggest that in NF the mechanobiological cutaneous environment is disrupted. Two possible pathways for this disruption have been suggested: (i) via neuropeptides or peripheral nerves and (ii) via the matrix.

An excess accumulation of neuropeptides is found in patients with pathological scarring 30. Hingtgen et al. 31 demonstrated that the capsaicin-stimulated release of neuropeptides is three- to fivefold higher in spinal cord slices from Nf1+/− mice than in wild-type mouse tissue. Extrapolated to NF-1 patients, while neuropeptides are produced in abundance, scarring is unremarkable. Nonetheless, controversy remains as to the underlying pathological mechanism. The absence of scarring in NF tissue can perhaps be explained by the fact that the disease instead develops in the deep dermis, 32 where the resulting structural changes may alter the cutaneous mechanobiology.

Leprosy

Leprosy, also known as Hansen's disease, is a chronic condition caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis 33. A loss of sensation and the destruction of the intra-epidermal innervation are the characteristic findings 34. An interesting feature of the disease is the absence of extensive scarring 34, which suggests that MS nociceptors involved in initiating the scarring process are denervated in these patients.

Diabetic skin ulcers

Diabetes causes neuropathy, which inhibits nociception and the perception of pain. Consequently, diabetes patients often fail initially to notice small wounds involving the legs and feet and may therefore fail to prevent infection or repeated injury. Furthermore, diabetes causes immune compromise while the characteristic damage to small blood vessels prevents adequate tissue oxygenation, potentially resulting in chronic wounds. Pressure (compression) also plays a role in the formation of diabetic ulcers, as does infection. Regarding the mechanobiological aspects of the disease, fibronectin gene expression was shown to be enhanced in hypertrophic scars, but decreased in diabetic foot ulcers compared with normal skin 35. A deficiency of the MS nociceptors of nerve fibres has also been postulated as a cause or contributing factor in the generation of diabetic ulcers. Damage to sensory nerve fibres can lead to ‘neurogenic inflammation’, with the release of neuropeptides by sensory fibres and thus the accelerated production of cytokines by various activated cell types. Neurogenic inflammation is a form of mechanical stress-induced inflammation in which there is cutaneous antidromic vasodilatation and plasma extravasation. It is mediated by the release of neuropeptides from sensory nerve endings. Under normal conditions, the combined neurovascular control and neurogenic inflammation promote cutaneous wound healing, whereas this is not the case in diabetic patients 36.

Lymphoedema

Lymphoedema, also known as lymphatic obstruction, is a condition of localized fluid retention and tissue swelling caused by a compromised lymphatic system. The lymphatic system returns the interstitial fluid to the thoracic duct and then to the bloodstream, where it is recirculated back to the tissues. In lymphoedema patients, the malfunction of this system results in an elevated risk of infection. Recently, an effective therapeutic approach consisting of lymphaticovenular anastomosis has been described 37.

Lymphatic fluid returns to the blood circulation through the force of osmosis acting on the venous capillaries. Prior to its return, the proteins, cellular debris and bacteria contained in the lymph are filtered through lymph collectors, which are blind-ended and epithelial-lined. Once the lymph enters the valved lymphatic vessels, the primary driving force for its movement is the rhythmic peristaltic-like pumping action of the smooth muscle cells lining the lymphatic vessel walls. A complex network of innervation regulates this system. Thus, lymphoedema can be considered a mechanobiological dysfunction involving osmosis and fluid pressure within the lymphatic system.

Ageing

Skin changes, including wrinkles, laxity and pigmentary irregularities, are among the most visible signs of ageing. The ageing process may be induced by environmental factors, such as sun exposure and smoking, or by chronological (intrinsic) factors 38, 39. The major feature of aged skin is the degeneration and fragmentation of the dermal collagen matrix, including collagen and elastic fibres (solar elastosis). Destruction of the ECM in aged skin further leads to the collapse of fibroblasts within the dermis, as these cells thereby no longer receive mechanical information. Consequently, collagen production is decreased while that of collagen-degrading enzymes (matrix metalloproteinases) is increased 40-42.

In vivo stimulation of de novo collagen production has been achieved by the injection of cross-linked hyaluronic acid dermal filler into photodamaged human skin 43, thereby restoring mechanical tension to the dermal matrix. At the surrounding sites of hyaluronic acid deposition, an increase in the number of fibroblasts has been demonstrated. Interestingly, these fibroblasts, which show a distinct, elongated stretched appearance, express high levels of type I procollagen together with an increased level of signalling molecules, such as transforming growth factor β and connective tissue growth factor 43, 44.