Chapter 63 Collagens, Elastic Fibers, and Other Extracellular Matrix Proteins of the Dermis

Question 1

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

Answer 1

domains

Question 2

____ determines the biophysical properties of connective tissues

Answer 2

ECM

Question 3

collagens approx ___% of the dry weight of the dermis

Answer 3

80%

Question 4

Classical and 1st recognized physiologic role of collagens in the skin _________

Answer 4

provide tensile properties

Question 5

first member of the collagens family, the most abundant collagens in the dermis and most other connective tissues

Answer 5

Type I collagen

Question 6

______ the smallest amino acid, accounts for approximately 1/3 the total number of amino acids, evenly distributed along the polypeptide

Answer 6

glycine (Gly)

Question 7

______ 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

Answer 7

glycine

hydroxyproline

Question 8

Triple-helical conformation defines the so-called ______, and it gives type I collagens many of its unique properties

Answer 8

collagenous domain

Question 9

_____ collagens represents approx 10% of the total collagens in the adult human dermis

Answer 9

Type III collagen

relatively high content of hydroxyproline and glycine and the presence of one cysteine residue

Question 10

______ and _____form the relatively broad extracellular fibers that are primarily responsible for the tensile strength of the human dermis

Answer 10

collagen types I and III

Question 11

_____ represents < 5% of the total collagens

Answer 11

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

Question 12

absence of _____ autosomal recessive form of Ehlers-Danlos syndrome

Answer 12

Tenascin X expression

Question 13

_____ typical component of basement membranes, where it forms a lattice rather than the fibers characteristic of dermal collagens

Answer 13

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

Question 14

mutation in _____ gene has been identified in a family with autosomal dominant porencephaly and infantile hemiparesis

Answer 14

mutation in the COL4A1 gene

Question 15

mutations in the COL4A5 gene result in _____, an X-linked renal disease

Answer 15

Alport syndrome

Question 16

Autoantibodies recognizing the collagens α3(IV) chain underlie ______

Answer 16

Goodpasture syndrome

Question 17

______ collagen forms specific microfibrils in the dermis

Answer 17

Type VI collagens

Question 18

_____ collagens forms the anchoring fibrils of the DEJ

Answer 18

type VII collagens

Question 19

Mutations in each of the three type VI collagens genes can lead to different forms of _______

Answer 19

congenital muscular dystrophy

Question 20

Alterations in the expression, structure, or molecular interactions of ____ with other basement membrane components could result in dystrophic epidermolysis bullosa (DEB)

Answer 20

type VII collagen

COL7A1

Question 21

_____ 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

Answer 21

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

Question 22

mutations in the corresponding gene _____ that underlie a nonlethal variant of junctional epidermolysis bullosa, generalized atrophic benign epidermolysis bullosa

Answer 22

gene COL17A1

Question 23

Collagens genes, like most eukaryotic genes, are large, multiexon genes interrupted at several points by noncoding DNA sequences called _____

Answer 23

introns

Question 24

Precursor polypeptides of procollagen, so-called ______, are synthesized on the ribosomes of the rough endoplasmic reticulum in fibroblasts and related cells

Answer 24

pre-proa chains

Question 25

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

Answer 25

molecular oxygen
ferrous iron
α-ketoglutarate
ascorbate

Question 26

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

Answer 26

trans-4-hydroxy-l-proline

Question 27

triple-helix formation takes place in the

Answer 27

cisternae of the rough endoplasmic reticulum

Question 28

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

Answer 28

scurvy

Question 29

decreased healing tendency of wounds and ulcers in peripheral tissues that are _____

Answer 29

anoxic due to relatively poor blood supply

Question 30

master regulator of hypoxia-inducible genes

Answer 30

α subunit of the hypoxia-inducible transcription factor

Question 31

glycosylation reactions use ______ as a source of the carbohydrate and require ____ as a cofactor

Answer 31

uridine diphosphate sugars

Mn2+

Question 32

Deficiency of lysyl hydroxylase has been identified in patients with the

Answer 32

scoliotic form (type VI) of Ehlers–Danlos syndrome
(hyperextensible skin, loose-jointedness, severe kyphoscoliosis, and ocular fragility)

Question 33

association of proα1 and proα2 chains in a proper ___ ratio during the synthesis of type I procollagen

Answer 33

2:1

Question 34

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

Answer 34

(1) procollagens N-proteinase and

(2) procollagens C-proteinase,

Question 35

____ 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

Answer 35

C-proteinase

Question 36

_____ catalyzing the conversion of type III procollagens to collagens

Answer 36

N-proteinase

Question 37

______ caused by deficiency in N-proteinase activity

Answer 37

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

Question 38

these fibers do not attain the necessary tensile strength until the molecules are linked together by specific covalent bonds known as _______

Answer 38

cross-links

Question 39

First step in the cross-linking of collagens is the enzymatic conversion of_______ to ______ by removal of the ε-amino groups

Answer 39

some of the lysyl and hydroxylysyl residues to the corresponding aldehyde derivatives

Question 40

First step in collagens cross-linking, the oxidative deamination of certain lysyl and hydroxylysyl residues, is catalyzed by ____

Answer 40

lysyl oxidase

requires copper as a cofactor, and its activity is readily inhibited by nitriles, such as β-aminopropionitrile, which produce lathyrism in animals.

Question 41

occipital horn syndrome (previously known as Ehlers–Danlos syndrome type IX), which results _______

Answer 41

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

Question 42

_______ modulate type I collagens gene expression both in vitro and in vivo

Answer 42

Retinoids, such as all-trans- retinoic acid

Question 43

_____ can induce the expression of other growth factors, in particular the expression of connective tissue growth factor in fibroblasts

Answer 43

TGF-β

Question 44

_____ 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

Answer 44

Interstitial collagenase (MMP-1)

MMP-1 contains intrinsic zinc in the active site and requires calcium for its activity and thermostabilization.

Question 45

____ attacks collagens at the same site, as does human MMP-1, to produce the characteristic three-quarter/one-quarter collagens fragments.

Answer 45

Human neutrophil interstitial collagenase (MMP-8)

higher degree of glycosylation than MMP-1

Question 46

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.

Answer 46

fibroblast collagenase

neutrophil collagenase

Question 47

______ 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

Answer 47

MT1–MMP complex

Question 48

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

Answer 48

collagenase-3

Question 49

elastin content is __% of the total dry weight of dermis

Answer 49

1-2%

Question 50

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

Answer 50

oxytalan fibers
elaunin fibers

elastin

Question 51

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.

Answer 51

first trimester

Question 52

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

Answer 52

desmosines
copper deficient diet
lathyrogens
β-aminopropionitrile

Question 53

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

Answer 53

tropoelastin

Question 54

____ accounts for about one-third of the amino acid residues in elastin

Answer 54

glycine

Question 55

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

Answer 55

hydroxyproline

Question 56

The two major cross-link compounds,____ and its isomer, _____, are structures that appear to be unique to elastin

Answer 56

desmosine

isodesmosine

Question 57

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

Answer 57

functional mRNA

Question 58

____ decreases elastin mRNA abundance primarily by suppressing promoter activity

Answer 58

TNF-α

Question 59

____ has been shown to upregulate the abundance of human elastin mRNA by up to approx 30-fold

Answer 59

TGF-β

Question 60

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

Answer 60

vitamin D3

Question 61

______ enhances elastin gene expression at the transcriptional level

Answer 61

insulin-like growth factor-1

Question 62

______ 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

Answer 62

smooth muscle cells

Question 63

____ may be the primary source of elastin in the dermis

Answer 63

fibroblasts

Question 64

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 ____

Answer 64

allysines

catalyzed by copper-requiring enzymes, lysyl oxidases
require copper and molecular oxygen as cofactors.

Question 65

_____, 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

Answer 65

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

Question 66

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

Answer 66

fibrillins

Question 67

TGF-β is always secreted as a latent complex with _____ and this complex is bound to an LTBP

Answer 67

Latency-Associated Peptide (LAP)

Question 68

levels of LTBP1 are altered in a number of pathologic conditions, including ____

Answer 68

solar elastosis

Question 69

_____ are a family of ECM glycoproteins that contain tandem EGF-like repeats similar to fibrillins and LTBPs, and a common carboxyl-terminal globular domain

Answer 69

fibulins

Question 70

mutations in the ____ and ____ genes have been documented in some cases of cutis laxa

Answer 70

FBLN4 and FBLN5

Question 71

______ 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

Answer 71

microfibril-associated protein 1

Question 72

_____ are critical for the cross-linking and stabilization of the elastic fiber structures

Answer 72

lysyl oxidases

Question 73

Most distinguishing structural characteristic of proteoglycans is that they comprise both a ____ and covalently linked linear carbohydrate chains known as ____

Answer 73

core protein
GAGs

GAGs are highly polyanionic and bear a high charge density

Question 74

Prototypical proteoglycan consists of a _____ linked to one or more ____

Answer 74

single core protein

GAGs

Question 75

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 ______

Answer 75

iduronic acid or glucuronic acid

glucosamine or galactosamine

Question 76

This form of GAG contains a high proportion of iduronic acids in place of glucuronic acid and has more variable sulfation

Answer 76

dermatan sulfate (also known as chondroitin sulfate B)

Question 77

the simplest GAG, ____, is never sulfated

Answer 77

hyaluronic acid

Question 78

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

Answer 78

Golgi apparatus

Question 79

final product, core protein with attached GAG, defines the _______

Answer 79

proteoglycan

Question 80

_____ is the best-known intracellular proteoglycan and is found within the secretory granules of hematopoietic cells, including mast cells, leukocytes, and eosinophils

Answer 80

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

Question 81

On release, serglycin becomes a major source for the delivery of highly sulfated _____

Answer 81

heparan sulfate GAG

Question 82

_____ share the glycophosphatidyl inositol anchorage mechanism and a unique cysteine motif that is likely to impart a compact tertiary structure to the proteoglycans

Answer 82

glypicans

Six isoforms (glypican-1 to 6) have been described, and expression of some glypicans may be altered in inflamed skin and chronic wounds

Question 83

_______ consist of a short C-terminal cytoplasmic region, a transmembrane domain, and an extracellular region containing attachment sites for GAG chains.

Answer 83

syndecan core proteins

Unlike glypicans, syndecans span the plasma membrane and extend beyond the surface of the cell.

Question 84

During wound repair, ____ and ____ are highly induced in the dermis and granulation tissue

Answer 84

syndecan-1 and syndecan-4

Question 85

_____, 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

Answer 85

Aggrecan

Question 86

In the skin, fibroblasts produce large aggregating proteoglycans, the best known being _____

Answer 86

versican

Versican, like aggrecan, binds hyaluronic acid, which enables it to form large aggregates.

Question 87

In skin, versican has been identified in the dermis (fibroblasts) and epidermis (keratinocytes) and demonstrates selective upregulation in response to _____

Answer 87

TGF-β

Question 88

___ is a ubiquitous component of connective tissues and it is found in abundance in skin

Answer 88

Decorin

• One family is characterized by a leucine-rich repeat motif.
• The prototype of this family is decorin, an approx. 36-kDa secreted proteoglycan

Question 89

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.

Answer 89

dermatan sulfate chain

Question 90

closely associates w/ collagen fibrils.

This interaction is attributed to the ability of the decorin core protein to directly bind to ________

Answer 90

collagens type I

Question 91

______ is the predominant GAG in wound fluid and because it can bind a variety of growth factors, cytokines, and ECM proteins

Answer 91

dermatan sulfate

Question 92

_________, 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

Answer 92

Heparan sulfate-dependent growth factors

Question 93

Chondroitin sulfate and dermatan sulfate bind ____ and _____.

Answer 93

fibronectin and laminin

Question 94

In fetal skin, the high relative content of _______ has been associated with the ability of fetal skin to heal without scar

Answer 94

hyaluronan

Question 95

______ 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.

Answer 95

Integrins

Question 96

mutations in the fibrillin genes.

Heterozygous mutations that affect the structure or lead to a reduced synthesis are the cause of the ______

Answer 96

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.

Question 97

deficiency of decorin core protein has been described as the cause of a variant form of ______

Answer 97

Ehlers–Danlos syndrome

Question 98

decrease in _______ explains diminished skin turgor

Answer 98

hyaluronic acid

Question 99

Deposition of calcium apatite crystals, excessive accumulation of glycosaminoglycans on elastic fibers; d-penicillamine treatment; mutations in the ABCC6 gene

Answer 99

Pseudoxanthoma elasticum

Yellowish papules coalescing into plaques
Inelastic skin
Cardiovascular and ocular abnormalities

Accumulation of pleomorphic and calcified elastic fibers in the middermis

Question 100

Increased desmosine content in the skin; mutations in the LEMD3

Answer 100

Buschke–Ollendorf syndrome

Dermatofibrosis lenticularis disseminata
osteopoikilosis

accumulation of interlacing elastic fibers int the dermis

Question 101

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

Answer 101

cutis laxa

Loose, sagging, inelastic skin
Pulmonary emphysema
Tortuosity of aorta
Urinary and gastrointestinal tract diverticuli

Fragmentation and loss of elastic bers

Question 102

Reduced elastin mRNA levels

Answer 102

De-Barsy syndrome

Cutis laxa-like skin changes
Mental retardation
Dwarfism

rudimentary fragmented elastic fibers

Question 103

Decreased number and length of elastic fibers

Answer 103

Wrinkly skin syndrome

Decreased elastic recoil of the skin
Increased number of palmar and plantar creases

Question 104

Fragmentation and loss of elastin in the middermis

Answer 104

middermal elastolysis

Inlammatory; sun exposure

Fine wrinkling of the skin, primarily in exposed areas

Question 105

Reduced desmosine content in the lesions; often secondary to inflammatory lesions

Answer 105

anetoderma

Localized areas of atrophic, sac like lesions

loss and fragmentation of elastic fibers in the dermis

Question 106

d-penicillamine-induced abnormalities in elastin cross-linking

Answer 106

elastosis perforans serpiginosa

Hyperkeratotic papules, commonly on the face and neck

Accumulation and transepidermal elimination of elastic fibers

Question 107

Accumulation of pleomorphic elastotic material without

calcification in the mid and lower dermis and the subcutaneous tissue

Answer 107

elastoderma

Loose and sagging skin with loss of recoil

Question 108

Accumulation of thick elastic fibers in the dermis

Answer 108

isolated elastomas

dermal papules or nodules

Question 109

Accumulation of globular elastic structures encased in collagenous meshwork

Answer 109

Elastofibroma dorsi

Deep subcutaneous tumor, usually on subscapular area

Trauma on the lesional area

Question 110

Accumulation of irregularly thickened elastic fibers in upper dermis

Answer 110

actinic elastosis

Thickening and furrowing of the skin
Long-term sun exposure

Question 111

Mutations in the FBN1 gene

Answer 111

marfan syndrome

Skeletal, ocular, and cardiovascular abnormalities
Hyperextensible skin Striae distensae

Fragmentation of the elastic structures in the aorta

Question 112

Mutations in the FBN2 gene

Answer 112

congenital contractural arachnodactyly

camptodactyly and joint contractures

Question 113

Allelic deletion of the ELN gene; contiguous gene deletion syndrome

Answer 113

williams syndrome

Supravalvular aortic stenosis Velvety skin
Dysmorphic facies

Disruption of smooth muscle and matrix relationship a ecting blood vessels