In simplest terms, the dermis provides structural stability and nutritional support to the skin. However, the simplicity ends with this description, as the dermis is a playground for complex interactions and processes involving multiple cell types and structures. The dermis is divided into the papillary and reticular layers. The papillary dermis is thinner, consisting of loose connective tissue containing capillaries, elastic fibers, reticular fibers and some collagen. The reticular dermis consists of a thicker layer of dense connective tissue containing larger blood vessels, closely interlaced elastic fibers and coarse bundles of collagen fibers arranged in layers parallel to the surface. Surrounding these components is the gel-like ground substance, composed of mucopolysaccharides (primarily hyaluronic acid), chondroitin sulfates, and glycoproteins. The fibroblast is the key cell type, able to produce and secrete procollagen and elastic fibers that ultimately form the dermal structural network. There are hair follicles with associated erector pili muscles, sebaceous and apocrine glands. Eccrine coils are also present, though these are not associated with hair follicles. Vessels and nerves course through the dermis to provide nutritional elements/immune cells and cutaneous sensation, respectively. There are also specialized nerve cells called Meissner’s and Vater-Pacini corpuscles that transmit the sensations of touch and pressure. As the dermis is clearly a vast and complicated domain, I will first begin by wrapping up the deepest portion of basement membrane zone, Zone IV, which will then lead into a review of the chief and major fibrous structural components of the dermal extracellular matrix, collagen and elastin. The biology of these components and associated pathologic states will be discussed.
Zone Four: Anchor Away
Below the lamina densa, there are fibrillar structures called anchoring fibrils that connect the lamina densa onto the dermal plaque-like structures.1 Anchoring fibrils are composed primarily of disulfide bonded dimers of type VII collagen, a 290-kDa protein synthesized and secreted by both keratinocytes and fibroblasts. 2 Type VII collagen is restricted to the basement membrane of stratified squamous epithelia, where it localizes to the sublamina densa in the upper papillary dermis. 3 Type VII collagen interacts with type IV collagen, laminin-5/laminin-6 complex, fibronectin and type I collagen in order to “anchor” the epidermis to the dermis. 4 The anchoring fibers are further supported in the sub-lamina densa by minor fibrillar structures such as elastin, fibrillins, fibulins and linkins. The gene encoding type VII collagen, COL7A1, is located on the short arm of chromosome 3. There are several mutations in the gene encoding type VII collagen resulting in various forms of dystrophic epidermolysis bullosa (EB) .3 Patients with recessive dystrophic EB typically have mutations in COL7A1 alleles that result in premature termination codons, resulting in no detectable type VII collagen mRNA or protein. Accordingly, these patients have no anchoring fibrils in their epidermal basement membrane and manifest extreme skin fragility, mutilating scars and an increased risk for cutaneous squamous cell carcinomas from which they often die in their early 20s. On the other hand, patients with dominant dystrophic EB typically have a mutation in only one COL7A1 allele that creates a dominant negative effect on protein derived from the normal COL7A1 allele. 5 Here, patients produce altered type VII collagen trimers, resulting in abnormal and/or reduced numbers of anchoring fibrils. The blistering these patients demonstrate is often less severe than that seen in patients with recessive dystrophic EB. 6 Epidermolysis bullosa acquisita (EBA) is an acquired autoimmune subepidermal bullous disease resulting from IgG directed against the NC1 domain of collagen VII. Patients with bullous systemic lupus erythematosus (SLE) can also have IgG antitype VII collagen autoantibodies directed at the same epitopes, as is seen in patients with EBA. 4 It is believed that these autoantibodies disrupt either anchoring fibril assembly or interactions of type VII collagen with other extracellular matrix molecules to ultimately create non-inflammatory subepidermal blisters, predominantly found in areas of mechanical trauma. 7
The Extracellular Matrix: A Brief Overview of a Functional Structure
The extracellular matrix of the skin consists of a large number of distinct macromolecules that play a pivotal role in providing homeostatic, physiologic properties to normal skin. Proteins and complex sugars form most of the dermal ECM, and they are arranged in an orderly network of fibers and ground substance. The chief and major fibrous components consists of collagen and elastic fibers, which exist in an interwoven network associated with proteoglycan/glycosaminoglycan complexes, and several non-collagenous glycoproteins, including fibronectin, fibrillins and fibulins. It is with the major components of the dermal frame that we begin our review. The Foundation: Collagen and Elastic Fibers Collagen The collagens, which comprise a family of genetically distinct proteins, play an important role in maintaining the integrity of most tissues. As many as 28 distinct collagen types have been identified. 8 All collagens consist of a triple-helical molecule composed of three subunit polypeptides. In each polypeptide chain, every third amino acid is glycine (Gly), and so the sequence can be expressed as (Gly-X-Y) n, where X and Y represent other amino acids and n varies according to the length of the chain. 9,10 The strength and rigidity of the peptide — and ultimately the collagen — is directly proportional to the number of consecutive three amino acid repeats. Interruption in these repeats by other amino acids allows for structural flexibility, an important feature depending on the function and location of the given collagen. 10 At least 12 different collagen types have been found in the human skin; each has an important functional role with respect to location. For example, as mentioned above, collagen VII is the major constituent of anchoring fibrils, which extend from the dermal-epidermal basement membrane to the upper papillary dermis. 11 Collagens represent approximately 80% of the dry weight and 20% and 30% of the volume of the dermis. Collagen fibrils are always mixtures of several collagens as well as other molecules such as proteoglycans. Collagen I is the major component of the dermal fibrils, while other collagens vary in the amount present. During fetal development and even wound repair, for example, type III collagen is highly prevalent, even equivalent to type I collagen content. 8, 10, 12, 13 Collagen biosynthesis involves a number of complex intra- and extra-cellular processes. Procollagen chains are synthesized intracellularly in the rough endoplasmic reticulum, following which prolyl and lysyl residues are hydroxylated — lysyl hydroxylase is dependent on vitamin C as a cofactor and deficiency will result in clinical disease (scurvy)! — and modified by glycosylation. Three chains come together to form a trimer and fold into a triple helix. 13 The newly formed, helical procollagen is secreted into the extracellular space, where specific components are cleaved by site-specific proteinases. The mature collagen molecules assemble to form mixed fibrils with other collagens, as mentioned above, as well as non-collagenous molecules for structural support and flexibility. These structures are finally stabilized via covalent cross-links. 10 The majority of collagens in the skin are generated by dermal fibroblasts, although there are a few exceptions, including types VIII and XVIII, which are produced by endothelial cells. Successful collagen formation is reliant on both the appropriate production of components and appropriate action of multiple enzymes, all of which can be disturbed or altered by a broad range of endogenous and exogenous factors. Disease phenotype can result from a defect in a distinct level at which collagen is either formed or metabolized. Ehlers-Danlos syndrome, a spectrum of clinical disease states sharing features such as hyperextensible skin, skin fragility and loose jointedness, highlights the diversity of pathology resulting from specific dysfunctional components of collagen synthesis. 10,12,14-17 Similarly, other heritable connective tissue diseases with cutaneous involvement are known to result from specific molecular defects in different collagen genes. In addition, defects leading to altered activities of enzymes, which modify collagen polypeptides, can result in clinical disease. There are numerous acquired and hereditary disease states resulting from both genes of enzymatic defects/dysfunction. Selected inherited diseases of collagen are highlighted in Table 1.1, 8, 10, 12, 14, 17-26 Elastic Fibers The elasticity and recoil of the skin is highly dependent on the proper functioning and appropriate composition of elastic fibers. Elastic fibers consist of two distinct components, elastin, a well characterized connective tissue protein, and elastic fiber microfibrils, which surround the elastin. 27 Although the exact makeup of the microfibrils is unclear, it is believed that fibrillins are a key ingredient in the microfibrillar composite. There are currently two described fibrillins, fibrillin 1 and fibrillin 2. 28 Defects in fibrillin 1 result in Marfan’s syndrome, characterized clinically by tall stature, arachnodactyly, upward dislocated ectopia lentis, elastosis perforans serpiniginosa, and heart defects such as mitral valve prolapse and, more seriously, aortic root dilatation. Congenital contractural arachnodactyly results from a defect in fibrillin 2, which is phenotypically similar to Marfans, but not as severe. 16, 29 The orientation of the elastic fibers depends on location. In the papillary dermis, the microfibrils insert vertically into the dermoepidermal junction and form the oxytalan fibers. Inferiorly, oxytalan fibers merge with other microfibrillar elements to become oriented parallel to the skin’s surface, termed elaunin fibers. Within the reticular dermis, the elastic fibers become thicker and are oriented parallel to the surface as they intertwine between collagen bundles. 30, 31 Similarly to collagen, elastin fibrillogenesis involves numerous complicated steps, many of which are enzymatically mediated. Importantly, lysyl oxidase, a copper-dependent enzyme, mediates the oxidative deamination of certain lysyl residues. 30, 32, 33 This key step results in the formation of aldehyde derivates of lysine, known as allysines, which can participate in the formation of desmosines, complex crosslinks that stabilize the elastin molecules into a sound fiberous network. Defects in either lysyl oxidase or copper transport mechanisms can result in impaired elatic fiber production, clinically generating doughy skin (for example, Menkes kinky hair and occipital horn syndromes).34 Mature elastic fibers metabolism occurs in the extracellular space and is both a continual and relatively slow process. Degradation of elastic fibers can be markedly increased in a variety of pathological conditions. This process is initiated by elastases, a family of proteolytic enzymes capable of degrading elastic fibers. 35 The most significant and powerful elastolytic enzymes are present in neutrophils and monocyte/ macrophages, which both initiate elastin degradation in inflammatory processes, and can also be the source of delayed wound healing in the setting of persistent infection. It is likely apparent that disease can manifest from both abnormal elastin gene expression and defects/disruption of the elastic fiber biosynthetic pathway. As seen, both within the Ehlers-Danlos syndrome spectrum and other diseases of collagen, varying clinical pathology can occur depending on the level at which the defect in elastin fibrillogenesis ours. The prototypical skin disease of cutaneous elastic fibers is cutis laxa, characterized by redundant, sagging, folding, unrecoilable skin. There is considerable heterogeneity with respect to the severity and extent of disease depending on both mode of inheritance, but even more generally, whether the condition is acquired or congenital. Newborns presenting with cutis laxa more frequently demonstrate generalized connective tissue involvement, features including pulmonary emphysema and hip dislocation. Although most of the inherited cases suggest an autosomal recessive inheritance, there are reported examples of both autosomal dominant and X-linked recessive patterns. Furthermore, as mentioned above, the classic cutaneous changes can develop following both extensive cutaneous inflammation as well as from medication, which can disrupt elastic fiber biosynthesis, such as penicillamine.34, 36 Table 2 reviews the spectrum of elastic fiber-related disease states. 16,17,27,29, 34,36,37,38 Stay tuned for the next column, in which I will continue to review the various components and structures of the dermis and discuss function and dysfunction. Dr. Friedman is Clinical Instructor and Director of Dermatologic Research, Division of Dermatology, Albert Einstein College of Medicine in New York. Disclosure: Dr. Friedman has no conflicts of interest with any material in this column.
In simplest terms, the dermis provides structural stability and nutritional support to the skin. However, the simplicity ends with this description, as the dermis is a playground for complex interactions and processes involving multiple cell types and structures. The dermis is divided into the papillary and reticular layers. The papillary dermis is thinner, consisting of loose connective tissue containing capillaries, elastic fibers, reticular fibers and some collagen. The reticular dermis consists of a thicker layer of dense connective tissue containing larger blood vessels, closely interlaced elastic fibers and coarse bundles of collagen fibers arranged in layers parallel to the surface. Surrounding these components is the gel-like ground substance, composed of mucopolysaccharides (primarily hyaluronic acid), chondroitin sulfates, and glycoproteins. The fibroblast is the key cell type, able to produce and secrete procollagen and elastic fibers that ultimately form the dermal structural network. There are hair follicles with associated erector pili muscles, sebaceous and apocrine glands. Eccrine coils are also present, though these are not associated with hair follicles. Vessels and nerves course through the dermis to provide nutritional elements/immune cells and cutaneous sensation, respectively. There are also specialized nerve cells called Meissner’s and Vater-Pacini corpuscles that transmit the sensations of touch and pressure. As the dermis is clearly a vast and complicated domain, I will first begin by wrapping up the deepest portion of basement membrane zone, Zone IV, which will then lead into a review of the chief and major fibrous structural components of the dermal extracellular matrix, collagen and elastin. The biology of these components and associated pathologic states will be discussed.
Zone Four: Anchor Away
Below the lamina densa, there are fibrillar structures called anchoring fibrils that connect the lamina densa onto the dermal plaque-like structures.1 Anchoring fibrils are composed primarily of disulfide bonded dimers of type VII collagen, a 290-kDa protein synthesized and secreted by both keratinocytes and fibroblasts. 2 Type VII collagen is restricted to the basement membrane of stratified squamous epithelia, where it localizes to the sublamina densa in the upper papillary dermis. 3 Type VII collagen interacts with type IV collagen, laminin-5/laminin-6 complex, fibronectin and type I collagen in order to “anchor” the epidermis to the dermis. 4 The anchoring fibers are further supported in the sub-lamina densa by minor fibrillar structures such as elastin, fibrillins, fibulins and linkins. The gene encoding type VII collagen, COL7A1, is located on the short arm of chromosome 3. There are several mutations in the gene encoding type VII collagen resulting in various forms of dystrophic epidermolysis bullosa (EB) .3 Patients with recessive dystrophic EB typically have mutations in COL7A1 alleles that result in premature termination codons, resulting in no detectable type VII collagen mRNA or protein. Accordingly, these patients have no anchoring fibrils in their epidermal basement membrane and manifest extreme skin fragility, mutilating scars and an increased risk for cutaneous squamous cell carcinomas from which they often die in their early 20s. On the other hand, patients with dominant dystrophic EB typically have a mutation in only one COL7A1 allele that creates a dominant negative effect on protein derived from the normal COL7A1 allele. 5 Here, patients produce altered type VII collagen trimers, resulting in abnormal and/or reduced numbers of anchoring fibrils. The blistering these patients demonstrate is often less severe than that seen in patients with recessive dystrophic EB. 6 Epidermolysis bullosa acquisita (EBA) is an acquired autoimmune subepidermal bullous disease resulting from IgG directed against the NC1 domain of collagen VII. Patients with bullous systemic lupus erythematosus (SLE) can also have IgG antitype VII collagen autoantibodies directed at the same epitopes, as is seen in patients with EBA. 4 It is believed that these autoantibodies disrupt either anchoring fibril assembly or interactions of type VII collagen with other extracellular matrix molecules to ultimately create non-inflammatory subepidermal blisters, predominantly found in areas of mechanical trauma. 7
The Extracellular Matrix: A Brief Overview of a Functional Structure
The extracellular matrix of the skin consists of a large number of distinct macromolecules that play a pivotal role in providing homeostatic, physiologic properties to normal skin. Proteins and complex sugars form most of the dermal ECM, and they are arranged in an orderly network of fibers and ground substance. The chief and major fibrous components consists of collagen and elastic fibers, which exist in an interwoven network associated with proteoglycan/glycosaminoglycan complexes, and several non-collagenous glycoproteins, including fibronectin, fibrillins and fibulins. It is with the major components of the dermal frame that we begin our review. The Foundation: Collagen and Elastic Fibers Collagen The collagens, which comprise a family of genetically distinct proteins, play an important role in maintaining the integrity of most tissues. As many as 28 distinct collagen types have been identified. 8 All collagens consist of a triple-helical molecule composed of three subunit polypeptides. In each polypeptide chain, every third amino acid is glycine (Gly), and so the sequence can be expressed as (Gly-X-Y) n, where X and Y represent other amino acids and n varies according to the length of the chain. 9,10 The strength and rigidity of the peptide — and ultimately the collagen — is directly proportional to the number of consecutive three amino acid repeats. Interruption in these repeats by other amino acids allows for structural flexibility, an important feature depending on the function and location of the given collagen. 10 At least 12 different collagen types have been found in the human skin; each has an important functional role with respect to location. For example, as mentioned above, collagen VII is the major constituent of anchoring fibrils, which extend from the dermal-epidermal basement membrane to the upper papillary dermis. 11 Collagens represent approximately 80% of the dry weight and 20% and 30% of the volume of the dermis. Collagen fibrils are always mixtures of several collagens as well as other molecules such as proteoglycans. Collagen I is the major component of the dermal fibrils, while other collagens vary in the amount present. During fetal development and even wound repair, for example, type III collagen is highly prevalent, even equivalent to type I collagen content. 8, 10, 12, 13 Collagen biosynthesis involves a number of complex intra- and extra-cellular processes. Procollagen chains are synthesized intracellularly in the rough endoplasmic reticulum, following which prolyl and lysyl residues are hydroxylated — lysyl hydroxylase is dependent on vitamin C as a cofactor and deficiency will result in clinical disease (scurvy)! — and modified by glycosylation. Three chains come together to form a trimer and fold into a triple helix. 13 The newly formed, helical procollagen is secreted into the extracellular space, where specific components are cleaved by site-specific proteinases. The mature collagen molecules assemble to form mixed fibrils with other collagens, as mentioned above, as well as non-collagenous molecules for structural support and flexibility. These structures are finally stabilized via covalent cross-links. 10 The majority of collagens in the skin are generated by dermal fibroblasts, although there are a few exceptions, including types VIII and XVIII, which are produced by endothelial cells. Successful collagen formation is reliant on both the appropriate production of components and appropriate action of multiple enzymes, all of which can be disturbed or altered by a broad range of endogenous and exogenous factors. Disease phenotype can result from a defect in a distinct level at which collagen is either formed or metabolized. Ehlers-Danlos syndrome, a spectrum of clinical disease states sharing features such as hyperextensible skin, skin fragility and loose jointedness, highlights the diversity of pathology resulting from specific dysfunctional components of collagen synthesis. 10,12,14-17 Similarly, other heritable connective tissue diseases with cutaneous involvement are known to result from specific molecular defects in different collagen genes. In addition, defects leading to altered activities of enzymes, which modify collagen polypeptides, can result in clinical disease. There are numerous acquired and hereditary disease states resulting from both genes of enzymatic defects/dysfunction. Selected inherited diseases of collagen are highlighted in Table 1.1, 8, 10, 12, 14, 17-26 Elastic Fibers The elasticity and recoil of the skin is highly dependent on the proper functioning and appropriate composition of elastic fibers. Elastic fibers consist of two distinct components, elastin, a well characterized connective tissue protein, and elastic fiber microfibrils, which surround the elastin. 27 Although the exact makeup of the microfibrils is unclear, it is believed that fibrillins are a key ingredient in the microfibrillar composite. There are currently two described fibrillins, fibrillin 1 and fibrillin 2. 28 Defects in fibrillin 1 result in Marfan’s syndrome, characterized clinically by tall stature, arachnodactyly, upward dislocated ectopia lentis, elastosis perforans serpiniginosa, and heart defects such as mitral valve prolapse and, more seriously, aortic root dilatation. Congenital contractural arachnodactyly results from a defect in fibrillin 2, which is phenotypically similar to Marfans, but not as severe. 16, 29 The orientation of the elastic fibers depends on location. In the papillary dermis, the microfibrils insert vertically into the dermoepidermal junction and form the oxytalan fibers. Inferiorly, oxytalan fibers merge with other microfibrillar elements to become oriented parallel to the skin’s surface, termed elaunin fibers. Within the reticular dermis, the elastic fibers become thicker and are oriented parallel to the surface as they intertwine between collagen bundles. 30, 31 Similarly to collagen, elastin fibrillogenesis involves numerous complicated steps, many of which are enzymatically mediated. Importantly, lysyl oxidase, a copper-dependent enzyme, mediates the oxidative deamination of certain lysyl residues. 30, 32, 33 This key step results in the formation of aldehyde derivates of lysine, known as allysines, which can participate in the formation of desmosines, complex crosslinks that stabilize the elastin molecules into a sound fiberous network. Defects in either lysyl oxidase or copper transport mechanisms can result in impaired elatic fiber production, clinically generating doughy skin (for example, Menkes kinky hair and occipital horn syndromes).34 Mature elastic fibers metabolism occurs in the extracellular space and is both a continual and relatively slow process. Degradation of elastic fibers can be markedly increased in a variety of pathological conditions. This process is initiated by elastases, a family of proteolytic enzymes capable of degrading elastic fibers. 35 The most significant and powerful elastolytic enzymes are present in neutrophils and monocyte/ macrophages, which both initiate elastin degradation in inflammatory processes, and can also be the source of delayed wound healing in the setting of persistent infection. It is likely apparent that disease can manifest from both abnormal elastin gene expression and defects/disruption of the elastic fiber biosynthetic pathway. As seen, both within the Ehlers-Danlos syndrome spectrum and other diseases of collagen, varying clinical pathology can occur depending on the level at which the defect in elastin fibrillogenesis ours. The prototypical skin disease of cutaneous elastic fibers is cutis laxa, characterized by redundant, sagging, folding, unrecoilable skin. There is considerable heterogeneity with respect to the severity and extent of disease depending on both mode of inheritance, but even more generally, whether the condition is acquired or congenital. Newborns presenting with cutis laxa more frequently demonstrate generalized connective tissue involvement, features including pulmonary emphysema and hip dislocation. Although most of the inherited cases suggest an autosomal recessive inheritance, there are reported examples of both autosomal dominant and X-linked recessive patterns. Furthermore, as mentioned above, the classic cutaneous changes can develop following both extensive cutaneous inflammation as well as from medication, which can disrupt elastic fiber biosynthesis, such as penicillamine.34, 36 Table 2 reviews the spectrum of elastic fiber-related disease states. 16,17,27,29, 34,36,37,38 Stay tuned for the next column, in which I will continue to review the various components and structures of the dermis and discuss function and dysfunction. Dr. Friedman is Clinical Instructor and Director of Dermatologic Research, Division of Dermatology, Albert Einstein College of Medicine in New York. Disclosure: Dr. Friedman has no conflicts of interest with any material in this column.
In simplest terms, the dermis provides structural stability and nutritional support to the skin. However, the simplicity ends with this description, as the dermis is a playground for complex interactions and processes involving multiple cell types and structures. The dermis is divided into the papillary and reticular layers. The papillary dermis is thinner, consisting of loose connective tissue containing capillaries, elastic fibers, reticular fibers and some collagen. The reticular dermis consists of a thicker layer of dense connective tissue containing larger blood vessels, closely interlaced elastic fibers and coarse bundles of collagen fibers arranged in layers parallel to the surface. Surrounding these components is the gel-like ground substance, composed of mucopolysaccharides (primarily hyaluronic acid), chondroitin sulfates, and glycoproteins. The fibroblast is the key cell type, able to produce and secrete procollagen and elastic fibers that ultimately form the dermal structural network. There are hair follicles with associated erector pili muscles, sebaceous and apocrine glands. Eccrine coils are also present, though these are not associated with hair follicles. Vessels and nerves course through the dermis to provide nutritional elements/immune cells and cutaneous sensation, respectively. There are also specialized nerve cells called Meissner’s and Vater-Pacini corpuscles that transmit the sensations of touch and pressure. As the dermis is clearly a vast and complicated domain, I will first begin by wrapping up the deepest portion of basement membrane zone, Zone IV, which will then lead into a review of the chief and major fibrous structural components of the dermal extracellular matrix, collagen and elastin. The biology of these components and associated pathologic states will be discussed.
Zone Four: Anchor Away
Below the lamina densa, there are fibrillar structures called anchoring fibrils that connect the lamina densa onto the dermal plaque-like structures.1 Anchoring fibrils are composed primarily of disulfide bonded dimers of type VII collagen, a 290-kDa protein synthesized and secreted by both keratinocytes and fibroblasts. 2 Type VII collagen is restricted to the basement membrane of stratified squamous epithelia, where it localizes to the sublamina densa in the upper papillary dermis. 3 Type VII collagen interacts with type IV collagen, laminin-5/laminin-6 complex, fibronectin and type I collagen in order to “anchor” the epidermis to the dermis. 4 The anchoring fibers are further supported in the sub-lamina densa by minor fibrillar structures such as elastin, fibrillins, fibulins and linkins. The gene encoding type VII collagen, COL7A1, is located on the short arm of chromosome 3. There are several mutations in the gene encoding type VII collagen resulting in various forms of dystrophic epidermolysis bullosa (EB) .3 Patients with recessive dystrophic EB typically have mutations in COL7A1 alleles that result in premature termination codons, resulting in no detectable type VII collagen mRNA or protein. Accordingly, these patients have no anchoring fibrils in their epidermal basement membrane and manifest extreme skin fragility, mutilating scars and an increased risk for cutaneous squamous cell carcinomas from which they often die in their early 20s. On the other hand, patients with dominant dystrophic EB typically have a mutation in only one COL7A1 allele that creates a dominant negative effect on protein derived from the normal COL7A1 allele. 5 Here, patients produce altered type VII collagen trimers, resulting in abnormal and/or reduced numbers of anchoring fibrils. The blistering these patients demonstrate is often less severe than that seen in patients with recessive dystrophic EB. 6 Epidermolysis bullosa acquisita (EBA) is an acquired autoimmune subepidermal bullous disease resulting from IgG directed against the NC1 domain of collagen VII. Patients with bullous systemic lupus erythematosus (SLE) can also have IgG antitype VII collagen autoantibodies directed at the same epitopes, as is seen in patients with EBA. 4 It is believed that these autoantibodies disrupt either anchoring fibril assembly or interactions of type VII collagen with other extracellular matrix molecules to ultimately create non-inflammatory subepidermal blisters, predominantly found in areas of mechanical trauma. 7
The Extracellular Matrix: A Brief Overview of a Functional Structure
The extracellular matrix of the skin consists of a large number of distinct macromolecules that play a pivotal role in providing homeostatic, physiologic properties to normal skin. Proteins and complex sugars form most of the dermal ECM, and they are arranged in an orderly network of fibers and ground substance. The chief and major fibrous components consists of collagen and elastic fibers, which exist in an interwoven network associated with proteoglycan/glycosaminoglycan complexes, and several non-collagenous glycoproteins, including fibronectin, fibrillins and fibulins. It is with the major components of the dermal frame that we begin our review. The Foundation: Collagen and Elastic Fibers Collagen The collagens, which comprise a family of genetically distinct proteins, play an important role in maintaining the integrity of most tissues. As many as 28 distinct collagen types have been identified. 8 All collagens consist of a triple-helical molecule composed of three subunit polypeptides. In each polypeptide chain, every third amino acid is glycine (Gly), and so the sequence can be expressed as (Gly-X-Y) n, where X and Y represent other amino acids and n varies according to the length of the chain. 9,10 The strength and rigidity of the peptide — and ultimately the collagen — is directly proportional to the number of consecutive three amino acid repeats. Interruption in these repeats by other amino acids allows for structural flexibility, an important feature depending on the function and location of the given collagen. 10 At least 12 different collagen types have been found in the human skin; each has an important functional role with respect to location. For example, as mentioned above, collagen VII is the major constituent of anchoring fibrils, which extend from the dermal-epidermal basement membrane to the upper papillary dermis. 11 Collagens represent approximately 80% of the dry weight and 20% and 30% of the volume of the dermis. Collagen fibrils are always mixtures of several collagens as well as other molecules such as proteoglycans. Collagen I is the major component of the dermal fibrils, while other collagens vary in the amount present. During fetal development and even wound repair, for example, type III collagen is highly prevalent, even equivalent to type I collagen content. 8, 10, 12, 13 Collagen biosynthesis involves a number of complex intra- and extra-cellular processes. Procollagen chains are synthesized intracellularly in the rough endoplasmic reticulum, following which prolyl and lysyl residues are hydroxylated — lysyl hydroxylase is dependent on vitamin C as a cofactor and deficiency will result in clinical disease (scurvy)! — and modified by glycosylation. Three chains come together to form a trimer and fold into a triple helix. 13 The newly formed, helical procollagen is secreted into the extracellular space, where specific components are cleaved by site-specific proteinases. The mature collagen molecules assemble to form mixed fibrils with other collagens, as mentioned above, as well as non-collagenous molecules for structural support and flexibility. These structures are finally stabilized via covalent cross-links. 10 The majority of collagens in the skin are generated by dermal fibroblasts, although there are a few exceptions, including types VIII and XVIII, which are produced by endothelial cells. Successful collagen formation is reliant on both the appropriate production of components and appropriate action of multiple enzymes, all of which can be disturbed or altered by a broad range of endogenous and exogenous factors. Disease phenotype can result from a defect in a distinct level at which collagen is either formed or metabolized. Ehlers-Danlos syndrome, a spectrum of clinical disease states sharing features such as hyperextensible skin, skin fragility and loose jointedness, highlights the diversity of pathology resulting from specific dysfunctional components of collagen synthesis. 10,12,14-17 Similarly, other heritable connective tissue diseases with cutaneous involvement are known to result from specific molecular defects in different collagen genes. In addition, defects leading to altered activities of enzymes, which modify collagen polypeptides, can result in clinical disease. There are numerous acquired and hereditary disease states resulting from both genes of enzymatic defects/dysfunction. Selected inherited diseases of collagen are highlighted in Table 1.1, 8, 10, 12, 14, 17-26 Elastic Fibers The elasticity and recoil of the skin is highly dependent on the proper functioning and appropriate composition of elastic fibers. Elastic fibers consist of two distinct components, elastin, a well characterized connective tissue protein, and elastic fiber microfibrils, which surround the elastin. 27 Although the exact makeup of the microfibrils is unclear, it is believed that fibrillins are a key ingredient in the microfibrillar composite. There are currently two described fibrillins, fibrillin 1 and fibrillin 2. 28 Defects in fibrillin 1 result in Marfan’s syndrome, characterized clinically by tall stature, arachnodactyly, upward dislocated ectopia lentis, elastosis perforans serpiniginosa, and heart defects such as mitral valve prolapse and, more seriously, aortic root dilatation. Congenital contractural arachnodactyly results from a defect in fibrillin 2, which is phenotypically similar to Marfans, but not as severe. 16, 29 The orientation of the elastic fibers depends on location. In the papillary dermis, the microfibrils insert vertically into the dermoepidermal junction and form the oxytalan fibers. Inferiorly, oxytalan fibers merge with other microfibrillar elements to become oriented parallel to the skin’s surface, termed elaunin fibers. Within the reticular dermis, the elastic fibers become thicker and are oriented parallel to the surface as they intertwine between collagen bundles. 30, 31 Similarly to collagen, elastin fibrillogenesis involves numerous complicated steps, many of which are enzymatically mediated. Importantly, lysyl oxidase, a copper-dependent enzyme, mediates the oxidative deamination of certain lysyl residues. 30, 32, 33 This key step results in the formation of aldehyde derivates of lysine, known as allysines, which can participate in the formation of desmosines, complex crosslinks that stabilize the elastin molecules into a sound fiberous network. Defects in either lysyl oxidase or copper transport mechanisms can result in impaired elatic fiber production, clinically generating doughy skin (for example, Menkes kinky hair and occipital horn syndromes).34 Mature elastic fibers metabolism occurs in the extracellular space and is both a continual and relatively slow process. Degradation of elastic fibers can be markedly increased in a variety of pathological conditions. This process is initiated by elastases, a family of proteolytic enzymes capable of degrading elastic fibers. 35 The most significant and powerful elastolytic enzymes are present in neutrophils and monocyte/ macrophages, which both initiate elastin degradation in inflammatory processes, and can also be the source of delayed wound healing in the setting of persistent infection. It is likely apparent that disease can manifest from both abnormal elastin gene expression and defects/disruption of the elastic fiber biosynthetic pathway. As seen, both within the Ehlers-Danlos syndrome spectrum and other diseases of collagen, varying clinical pathology can occur depending on the level at which the defect in elastin fibrillogenesis ours. The prototypical skin disease of cutaneous elastic fibers is cutis laxa, characterized by redundant, sagging, folding, unrecoilable skin. There is considerable heterogeneity with respect to the severity and extent of disease depending on both mode of inheritance, but even more generally, whether the condition is acquired or congenital. Newborns presenting with cutis laxa more frequently demonstrate generalized connective tissue involvement, features including pulmonary emphysema and hip dislocation. Although most of the inherited cases suggest an autosomal recessive inheritance, there are reported examples of both autosomal dominant and X-linked recessive patterns. Furthermore, as mentioned above, the classic cutaneous changes can develop following both extensive cutaneous inflammation as well as from medication, which can disrupt elastic fiber biosynthesis, such as penicillamine.34, 36 Table 2 reviews the spectrum of elastic fiber-related disease states. 16,17,27,29, 34,36,37,38 Stay tuned for the next column, in which I will continue to review the various components and structures of the dermis and discuss function and dysfunction. Dr. Friedman is Clinical Instructor and Director of Dermatologic Research, Division of Dermatology, Albert Einstein College of Medicine in New York. Disclosure: Dr. Friedman has no conflicts of interest with any material in this column.
