Chapter 63 Collagens, Elastic Fibers, and Other Extracellular Matrix Proteins of the Dermis Flashcards
most of collagens have a modular structure, and composed of one, a few, or several copies of a limited set of individual structural modules, also called
domains
____ determines the biophysical properties of connective tissues
ECM
collagens approx ___% of the dry weight of the dermis
80%
Classical and 1st recognized physiologic role of collagens in the skin _________
provide tensile properties
first member of the collagens family, the most abundant collagens in the dermis and most other connective tissues
Type I collagen
______ the smallest amino acid, accounts for approximately 1/3 the total number of amino acids, evenly distributed along the polypeptide
glycine (Gly)
______ in every 3rd position are necessary for the triple-helical conformation of the collagens molecule, and ______ plays a critical role in stabilizing the triple helix at body temperature
glycine
hydroxyproline
Triple-helical conformation defines the so-called ______, and it gives type I collagens many of its unique properties
collagenous domain
_____ collagens represents approx 10% of the total collagens in the adult human dermis
Type III collagen
relatively high content of hydroxyproline and glycine and the presence of one cysteine residue
______ and _____form the relatively broad extracellular fibers that are primarily responsible for the tensile strength of the human dermis
collagen types I and III
_____ represents < 5% of the total collagens
Type V collagen
postulated to regulate the fiber diameter during fibrillogenesis
mutations in type V collagens genes in patients with classical autosomal dominant forms (types I and II) of Ehlers–Danlos syndrome
absence of _____ autosomal recessive form of Ehlers-Danlos syndrome
Tenascin X expression
_____ typical component of basement membranes, where it forms a lattice rather than the fibers characteristic of dermal collagens
collagen type IV
contain imperfect Gly-X-Y triplets, a feature that confers flexibility to the triple-helical domain of the molecule
A noncollagenous globular domain at the amino-terminal part of the molecule mediates dimer formation, while a short segment at the carboxyl-terminal region of the molecule allows for tetramer assembly, altogether resulting in the so-called “chicken-wire” assembly network for collagens type IV
mutation in _____ gene has been identified in a family with autosomal dominant porencephaly and infantile hemiparesis
mutation in the COL4A1 gene
mutations in the COL4A5 gene result in _____, an X-linked renal disease
Alport syndrome
Autoantibodies recognizing the collagens α3(IV) chain underlie ______
Goodpasture syndrome
______ collagen forms specific microfibrils in the dermis
Type VI collagens
_____ collagens forms the anchoring fibrils of the DEJ
type VII collagens
Mutations in each of the three type VI collagens genes can lead to different forms of _______
congenital muscular dystrophy
Alterations in the expression, structure, or molecular interactions of ____ with other basement membrane components could result in dystrophic epidermolysis bullosa (DEB)
type VII collagen
COL7A1
_____ collagen, Transmembrane protein anchored in the membrane of basal keratinocytes, with an intracellular domain and a large extracellular domain, or ectodomain, which is a component of the basement membrane at DEJ
type XVII collagen
initially identified as the 180-kDa bullous pemphigoid antigen (BPAG2), which was recognized by circulating autoantibodies in the sera of patients with bullous pemphigoid or herpes gestationis
mutations in the corresponding gene _____ that underlie a nonlethal variant of junctional epidermolysis bullosa, generalized atrophic benign epidermolysis bullosa
gene COL17A1
Collagens genes, like most eukaryotic genes, are large, multiexon genes interrupted at several points by noncoding DNA sequences called _____
introns
Precursor polypeptides of procollagen, so-called ______, are synthesized on the ribosomes of the rough endoplasmic reticulum in fibroblasts and related cells
pre-proa chains
The hydroxylation reactions are catalyzed by enzymes belonging to the prolyl and lysyl hydroxylase families
These enzymes require _____, _____, _____ and a reducing agent, such as _____ as cosubstrates or cofactors for the reactions
molecular oxygen
ferrous iron
α-ketoglutarate
ascorbate
critical amount of _______ is a prerequisite for the folding of α chains into the triple helix, the conformation required for secretion of procollagens molecules out of the cells
trans-4-hydroxy-l-proline
triple-helix formation takes place in the
cisternae of the rough endoplasmic reticulum
prolyl hydroxylase requires a reducing agent, such as ascorbate, for its activity, ascorbic acid deficiency leads to a decreased formation of collagens fibers.
This explains some of the clinical manifestations in ____, such as poor wound healing and decreased tensile strength of the connective tissues
scurvy
decreased healing tendency of wounds and ulcers in peripheral tissues that are _____
anoxic due to relatively poor blood supply
master regulator of hypoxia-inducible genes
α subunit of the hypoxia-inducible transcription factor
glycosylation reactions use ______ as a source of the carbohydrate and require ____ as a cofactor
uridine diphosphate sugars
Mn2+
Deficiency of lysyl hydroxylase has been identified in patients with the
scoliotic form (type VI) of Ehlers–Danlos syndrome (hyperextensible skin, loose-jointedness, severe kyphoscoliosis, and ocular fragility)
association of proα1 and proα2 chains in a proper ___ ratio during the synthesis of type I procollagen
2:1
conversion of type I procollagens to collagens is catalyzed by two specific enzymes, ____ and _____ that separately remove the amino-terminal and carboxyl-terminal extensions, respectively
(1) procollagens N-proteinase and
(2) procollagens C-proteinase,
____ is required for the removal of the carboxyl-terminal extension from type I, II, III, and V procollagen, which allows the fully processed molecules to form functional fibers
C-proteinase
_____ catalyzing the conversion of type III procollagens to collagens
N-proteinase
______ caused by deficiency in N-proteinase activity
dermatosparaxis type of Ehlers–Danlos syndrome (type VIIc)
the arthrochalasia type of Ehlers–Danlos syndrome (types VIIa and VIIb), can be caused by mutations in the type I collagens genes (COL1A1 and COL1A2, respectively) at the cleavage site for the N-proteinase
these fibers do not attain the necessary tensile strength until the molecules are linked together by specific covalent bonds known as _______
cross-links
First step in the cross-linking of collagens is the enzymatic conversion of_______ to ______ by removal of the ε-amino groups
some of the lysyl and hydroxylysyl residues to the corresponding aldehyde derivatives
First step in collagens cross-linking, the oxidative deamination of certain lysyl and hydroxylysyl residues, is catalyzed by ____
lysyl oxidase
requires copper as a cofactor, and its activity is readily inhibited by nitriles, such as β-aminopropionitrile, which produce lathyrism in animals.
occipital horn syndrome (previously known as Ehlers–Danlos syndrome type IX), which results _______
from reduced lysyl oxidase activity
primary defect resides in perturbed copper metabolism caused by mutations in a copper transport enzyme protein, an adenosine triphosphatase encoded by the gene MNK-1 that is also involved in Menkes syndrome
_______ modulate type I collagens gene expression both in vitro and in vivo
Retinoids, such as all-trans- retinoic acid
_____ can induce the expression of other growth factors, in particular the expression of connective tissue growth factor in fibroblasts
TGF-β
_____ was the first enzyme of the MMP family to be discovered and was defined by its ability to break down triple-helical collagens that is resistant to most proteases
Interstitial collagenase (MMP-1)
MMP-1 contains intrinsic zinc in the active site and requires calcium for its activity and thermostabilization.
____ attacks collagens at the same site, as does human MMP-1, to produce the characteristic three-quarter/one-quarter collagens fragments.
Human neutrophil interstitial collagenase (MMP-8)
higher degree of glycosylation than MMP-1
Although both fibroblast (MMP-1) and neutrophil (MMP-8) collagenases have similar affinities for type I and III collagens, _____ degrades soluble type III collagens with a higher turnover rate, whereas _____ degrades soluble type I collagens more rapidly.
fibroblast collagenase
neutrophil collagenase
______ anchored at the cell surface has profound implications concerning the generation of the forces required for cell locomotion, not only in the normal physiologic processes of tissue remodeling but also in pathologic processes, such as tumor invasion
MT1–MMP complex
unlike interstitial and neutrophil collagenases, _____ acts 5-10 times more rapidly on soluble type II collagens, a cartilage-specific collagens, than on types I and III
collagenase-3
elastin content is __% of the total dry weight of dermis
1-2%
In the papillary dermis, elastic fibers are present either as bundles of microfibrils ___ fibers or with small amounts of cross-linked elastin ____ fibers
In the reticular dermis, the elastic fibers consist primarily of ____, and they are oriented horizontally in a network with vertical extensions to the papillary dermis in the form of oxytalan fibers
oxytalan fibers
elaunin fibers
elastin
Elastic fibers that form during the ___ trimester of fetal development consist of bundles of microfibrils, which are thought to form a scaffold into which the elastin molecules will align while fetal age is increasing.
first trimester
insolubility of elastin is attributable to the presence of complex covalent cross-links, known as ____, whose formation can be prevented by maintaining the animals on a ____-deficient diet or by feeding them ____, such as _____, which inhibit elastin and collagens cross-linking
desmosines
copper deficient diet
lathyrogens
β-aminopropionitrile
Basic molecular unit of elastin is a linear polypeptide, known as ______, that consists of approximately 800 amino acids with a molecular mass of around 70 kDa
tropoelastin
____ accounts for about one-third of the amino acid residues in elastin
glycine
Elastin also contains some _____, but the relative content of this amino acid is considerably lower than that in collagens, and the values for hydroxyproline are variable
hydroxyproline
The two major cross-link compounds,____ and its isomer, _____, are structures that appear to be unique to elastin
desmosine
isodesmosine
Several lines of evidence suggest that the rate of elastin biosynthesis is largely regulated by the abundance of the ______, and consequently, assay of elastin mRNA levels allows measurements of the rate of elastin biosynthesis in tissues and cells
functional mRNA
____ decreases elastin mRNA abundance primarily by suppressing promoter activity
TNF-α
____ has been shown to upregulate the abundance of human elastin mRNA by up to approx 30-fold
TGF-β
incubation of fibroblasts with ______ results in an 80%–90% decrease in total accumulation of tropoelastin, accompanied by a parallel decrease in steady-state levels of the corresponding mRNA
vitamin D3
______ enhances elastin gene expression at the transcriptional level
insulin-like growth factor-1
______ in culture synthesize relatively large quantities of elastin, which suggests that they may be the major source of elastin in tissues rich in elastic fibers, such as vascular connective tissue
smooth muscle cells
____ may be the primary source of elastin in the dermis
fibroblasts
The formation of desmosines occurs in the extracellular space, and the first step is the oxidative deamination of lysyl residues to corresponding aldehydes, known as ____
allysines
catalyzed by copper-requiring enzymes, lysyl oxidases
require copper and molecular oxygen as cofactors.
_____, a specific elastolytic enzyme, was first obtained from study of the pancreas, and since then elastolytic enzymes have been detected in several other tissues, as well as in a variety of cell types, including PMN leukocytes, monocytes/macrophages, and platelets
elastase
classic elastases are serine proteases that degrade insoluble elastic fibers at neutral or slightly alkaline pH
inhibited by serum factors, such as α1-antitrypsin and α2-macroglobulin
largest, and perhaps the most important microfibrillar proteins for biology and pathology of the dermis, are the ____, 350-kDa glycoproteins that form an integral part of the microfibril structure
fibrillins
TGF-β is always secreted as a latent complex with _____ and this complex is bound to an LTBP
Latency-Associated Peptide (LAP)
levels of LTBP1 are altered in a number of pathologic conditions, including ____
solar elastosis
_____ are a family of ECM glycoproteins that contain tandem EGF-like repeats similar to fibrillins and LTBPs, and a common carboxyl-terminal globular domain
fibulins
mutations in the ____ and ____ genes have been documented in some cases of cutis laxa
FBLN4 and FBLN5
______ is remarkable in that it is extremely acidic, with glutamic acid comprising 23% and aspartic acid 6% of the residues
extremely acidic nature of the protein suggests that it may have an important function in the assembly of the very basic tropoelastin molecules
microfibril-associated protein 1
_____ are critical for the cross-linking and stabilization of the elastic fiber structures
lysyl oxidases
Most distinguishing structural characteristic of proteoglycans is that they comprise both a ____ and covalently linked linear carbohydrate chains known as ____
core protein
GAGs
GAGs are highly polyanionic and bear a high charge density
Prototypical proteoglycan consists of a _____ linked to one or more ____
single core protein
GAGs
GAG chains = assembly of sugars
These sugars are organized as disaccharide pairs that usually consist of an acidic sugar that is either an ______ or ______ alternating with a hexosamine that is either _____ or ______
iduronic acid or glucuronic acid
glucosamine or galactosamine
This form of GAG contains a high proportion of iduronic acids in place of glucuronic acid and has more variable sulfation
dermatan sulfate (also known as chondroitin sulfate B)
the simplest GAG, ____, is never sulfated
hyaluronic acid
Synthesis of GAGs (with the exception of hyaluronan) occurs in the ____, and the sequence information is determined by the activity and location of multiple specific enzymes along this pathway
Golgi apparatus
final product, core protein with attached GAG, defines the _______
proteoglycan
_____ is the best-known intracellular proteoglycan and is found within the secretory granules of hematopoietic cells, including mast cells, leukocytes, and eosinophils
Serglycin
heparan sulfate form is found in serosal mast cells and is a major source from which heparin is pharmacologically derived
serglycin peptide core is composed primarily of tandem serine– glycine repeats
On release, serglycin becomes a major source for the delivery of highly sulfated _____
heparan sulfate GAG
_____ share the glycophosphatidyl inositol anchorage mechanism and a unique cysteine motif that is likely to impart a compact tertiary structure to the proteoglycans
glypicans
Six isoforms (glypican-1 to 6) have been described, and expression of some glypicans may be altered in inflamed skin and chronic wounds
_______ consist of a short C-terminal cytoplasmic region, a transmembrane domain, and an extracellular region containing attachment sites for GAG chains.
syndecan core proteins
Unlike glypicans, syndecans span the plasma membrane and extend beyond the surface of the cell.
During wound repair, ____ and ____ are highly induced in the dermis and granulation tissue
syndecan-1 and syndecan-4
_____, a large proteoglycan found in cartilage, has a core protein containing a region with over 100 serine–glycine dipeptides that serve as attachment sites for up to 130 GAG chains
Aggrecan
In the skin, fibroblasts produce large aggregating proteoglycans, the best known being _____
versican
Versican, like aggrecan, binds hyaluronic acid, which enables it to form large aggregates.
In skin, versican has been identified in the dermis (fibroblasts) and epidermis (keratinocytes) and demonstrates selective upregulation in response to _____
TGF-β
___ is a ubiquitous component of connective tissues and it is found in abundance in skin
Decorin
- One family is characterized by a leucine-rich repeat motif.
- The prototype of this family is decorin, an approx. 36-kDa secreted proteoglycan
Decorin core protein has a single _______ covalently bound to a serine residue at amino acid position 4 and, like many other proteoglycans, also has N-linked oligosaccharides.
dermatan sulfate chain
closely associates w/ collagen fibrils.
This interaction is attributed to the ability of the decorin core protein to directly bind to ________
collagens type I
______ is the predominant GAG in wound fluid and because it can bind a variety of growth factors, cytokines, and ECM proteins
dermatan sulfate
_________, such as members of the fibroblast growth factor family, are induced in healing wounds and influence the wound repair process through the stimulation of keratinocyte proliferation, fibroblast growth, and angiogenesis
Heparan sulfate-dependent growth factors
Chondroitin sulfate and dermatan sulfate bind ____ and _____.
fibronectin and laminin
In fetal skin, the high relative content of _______ has been associated with the ability of fetal skin to heal without scar
hyaluronan
______ have a short cytoplasmic domain, a single stretch transmembrane domain, and a large extracellular domain interacting with specific proteins of the ECM or with counter-receptor present on the surface of circulating cells, including microbial proteins.
Integrins
mutations in the fibrillin genes.
Heterozygous mutations that affect the structure or lead to a reduced synthesis are the cause of the ______
Marfan syndrome
analysis of mouse models with similar molecular defects revealed that the mutations in the fibrillin gene are associated with increased TGF-β signaling.
deficiency of decorin core protein has been described as the cause of a variant form of ______
Ehlers–Danlos syndrome
decrease in _______ explains diminished skin turgor
hyaluronic acid
Deposition of calcium apatite crystals, excessive accumulation of glycosaminoglycans on elastic fibers; d-penicillamine treatment; mutations in the ABCC6 gene
Pseudoxanthoma elasticum
Yellowish papules coalescing into plaques
Inelastic skin
Cardiovascular and ocular abnormalities
Accumulation of pleomorphic and calcified elastic fibers in the middermis
Increased desmosine content in the skin; mutations in the LEMD3
Buschke–Ollendorf syndrome
Dermatofibrosis lenticularis disseminata
osteopoikilosis
accumulation of interlacing elastic fibers int the dermis
Decreased desmosine content and reduced elastin mRNA levels; increased elastase activity in some cases;
d-penicillamine treatment, inflammatory and urticarial skin lesions (e.g., drug reaction);
mutations in the ELN, EBLN4FBLN4, or FBLN5, LTBP4, or PYCR15 gene in limited cases
cutis laxa
Loose, sagging, inelastic skin
Pulmonary emphysema
Tortuosity of aorta
Urinary and gastrointestinal tract diverticuli
Fragmentation and loss of elastic bers
Reduced elastin mRNA levels
De-Barsy syndrome
Cutis laxa-like skin changes
Mental retardation
Dwarfism
rudimentary fragmented elastic fibers
Decreased number and length of elastic fibers
Wrinkly skin syndrome
Decreased elastic recoil of the skin
Increased number of palmar and plantar creases
Fragmentation and loss of elastin in the middermis
middermal elastolysis
Inlammatory; sun exposure
Fine wrinkling of the skin, primarily in exposed areas
Reduced desmosine content in the lesions; often secondary to inflammatory lesions
anetoderma
Localized areas of atrophic, sac like lesions
loss and fragmentation of elastic fibers in the dermis
d-penicillamine-induced abnormalities in elastin cross-linking
elastosis perforans serpiginosa
Hyperkeratotic papules, commonly on the face and neck
Accumulation and transepidermal elimination of elastic fibers
Accumulation of pleomorphic elastotic material without
calcification in the mid and lower dermis and the subcutaneous tissue
elastoderma
Loose and sagging skin with loss of recoil
Accumulation of thick elastic fibers in the dermis
isolated elastomas
dermal papules or nodules
Accumulation of globular elastic structures encased in collagenous meshwork
Elastofibroma dorsi
Deep subcutaneous tumor, usually on subscapular area
Trauma on the lesional area
Accumulation of irregularly thickened elastic fibers in upper dermis
actinic elastosis
Thickening and furrowing of the skin
Long-term sun exposure
Mutations in the FBN1 gene
marfan syndrome
Skeletal, ocular, and cardiovascular abnormalities
Hyperextensible skin Striae distensae
Fragmentation of the elastic structures in the aorta
Mutations in the FBN2 gene
congenital contractural arachnodactyly
camptodactyly and joint contractures
Allelic deletion of the ELN gene; contiguous gene deletion syndrome
williams syndrome
Supravalvular aortic stenosis Velvety skin
Dysmorphic facies
Disruption of smooth muscle and matrix relationship a ecting blood vessels
