Mechanical forces in skin disorders

Abstract

Mechanical forces are known to regulate homeostasis of the skin and play a role in the pathogenesis of skin diseases. The epidermis consists of keratinocytes that are tightly adhered to each other by cell junctions. Defects in keratins or desmosomal/hemidesmosomal proteins lead to the attenuation of mechanical strength and formation of intraepidermal blisters in the case of epidermolysis bullosa simplex. The dermis is rich in extracellular matrix, especially collagen, and provides the majority of tensile force in the skin. Keloid and hypertrophic scar, which is the result of over-production of collagen by fibroblasts during the wound healing, are associated with extrinsic tensile forces and changes of intrinsic mechanical properties of the cell. Increasing evidences shows that stiffness of the skin environment determines the regenerative ability during wound healing process. Mechanotransduction pathways are also involved in the morphogenesis and cyclic growth of hair follicles. The development of androgenetic alopecia is correlated to tensile forces generated by the fibrous tissue underlying the scalp. Acral melanoma predominantly occurs in the weight-bearing area of the foot suggesting the role of mechanical stress. Increased dermal stiffness from fibrosis might be the cause of recessive dystrophic epidermolysis bullosa associated squamous cell carcinoma. Strategies to change the mechanical forces or modify the mechanotransduction signals may lead to a new way to treat skin diseases and promote skin regeneration.

Melanoma in the Eyes of Mechanobiology

“…Keratinocytes are the predominant cell type in the epidermis, most of them (90%) being located at the outmost epidermis layer (McGrath et al, 2004). Keratinocytes are connected to each other through actin cell junctions (Hsu et al, 2018).…”

“…Elastin fibers contribute to cyclic stretching during life; collagen fibers contribute to the tissue stiffness and mechanical strength of tissues and GAGs affect ECM viscoelasticity, forming bridges between the collagen fibers and contributing to the compressive tissue stiffness. Cells sense the forces exerted by the ECM, converting these stimuli into intracellular signal pathway, which further downstream regulate transcriptional changes (Hsu et al, 2018). Several mechanosensors are identified in cells: glycocalyx, lipid raft/caveolin-1, cell adhesion structures (integrin, hemidesmosomes and focal adhesion), ion channels (calcium-sensing receptor), transient receptor potential channels, connexins, intercellular complexes (desmosomes or cadherin) and the cytoskeleton (particularly the actin filaments) (Hsu et al, 2018).…”

The Desmosome is a Mesoscale Lipid Raft-Like Membrane Domain

“…Among these structures, adherens junctions and desmosomes play overlapping but distinct roles in cell adhesion, signaling, and morphogenesis (Garcia et al, 2018). Desmosomes are particularly abundant in tissues exposed to mechanical stress, including the skin and heart (Amagai and Stanley, 2012;Delmar and McKenna, 2010;Hsu et al, 2018). These adhesive complexes are characterized by highly organized and dense arrangements of desmosomal proteins that can be visualized by electron microscopy (Al-Amoudi et al, 2007;Delva et al, 2009;Harmon and Green, 2013).…”

“…The desmosomal cadherins are coupled to the intermediate filament cytoskeleton through adaptor proteins such as plakoglobin, plakophilins, and the cytolinker protein desmoplakin (Al-Amoudi et al, 2011;Delva et al, 2009;Jones et al, 2017). These interactions form an electron dense plaque that couples the adhesive interactions of the desmosomal cadherins to the intermediate filament cytoskeleton of adjacent cells, thus conferring tissue resilience to mechanical stress (Hsu et al, 2018;Thomason et al, 2010). Loss of desmosome function results in skin (Hsu et al, 2018;Payne et al, 2004) and heart (Delmar and McKenna, 2010;Samuelov and Sprecher, 2015) diseases characterized by tissue fragility.…”

“…These interactions form an electron dense plaque that couples the adhesive interactions of the desmosomal cadherins to the intermediate filament cytoskeleton of adjacent cells, thus conferring tissue resilience to mechanical stress (Hsu et al, 2018;Thomason et al, 2010). Loss of desmosome function results in skin (Hsu et al, 2018;Payne et al, 2004) and heart (Delmar and McKenna, 2010;Samuelov and Sprecher, 2015) diseases characterized by tissue fragility. In the skin, loss of desmosomal adhesion manifests clinically as epidermal blisters and erosions (Brooke et al, 2012;Payne et al, 2004), and in some disorders, aberrant thickening of the epidermis (Has and Technau-Hafsi, 2016;Stahley and Kowalczyk, 2015).…”