Connective tissue has a high ratio of ___ to cells in connective tissue.
ECM
What function does the ECM play in connective tissue?
Structural - provides architectural framework
What determines the physical properties of the connective tissue?
Composition of the matrix
The ECM provides support for what?
Cells and cell layers
The ECM acts as a barrier to what?
Cells
The ECM acts as a passive-selective ___-___ between tissue compartments.
Molecular sieve
What acts as a solid phase regulator of cell attachment, growth and differentiation?
ECM
ECM modulates what process?
Mineralization process
What are the three structural components of ECM?
Fibers
Amorphous ground substance
Basement membrane
What is a filament?
A threadlike structure (2-20 nm dia.)
Typically a single molecule or linear chain of molecules
Microfibrils are an aggregate of what?
Filaments
What is the typical diameter of a microfibril?
45-100 nm diameter
What is an aggregate of microfibrils called?
A fibril
What is the diameter of a fibril?
200-500 nm diameter
What is an aggregate of fibrils called?
A fiber
How big are fibers?
1-20 micrometers in diameter
What are the two types of fibers in the ECM?
Collagen
Elastic
How big are bundles?
20-100 micrometers in diameter
What makes up ground substance?
A complex mixture of glycoproteins, gags and proteoglycans
Ground substance helps bind cells to what of connective tissues?
Fibers
Ground substance fills the space between what?
Cells and fibers in connective tissue
What is a glycoprotein?
A protein with one or more attached sugars
A GAG is a family of what?
Heteropolysaccharides
GAGs are very ___ and very ___ ___.
Hydrated
Negatively charged
What is a proteoglycan composed of?
Protein core with many GAG chains attached
What glycoproteins are found in interstitial connective tissue?
Fibroconectins Elastin Fibrilins Tenascins Thrombospondins Microfibril-associated matrilins
What glycoproteins are found in basement membranes?
Laminins
Nidogen/entactin
Fibulin
What are the small leucine-rich proteoglycans?
Decorin Biglycan Fibromodulin Lumican Epiphycan
What are the modular proteoglycans involved in nonhyaluronan binding?
Prelecan
Agrin
Testican
What modular proteoglycans are involved in hyaluronan and lectin binding?
Aggrecan
Versican
Neurocan
Brevican
The large majority of the extracellular matrix is synthesized and secreted locally by what?
Neighboring cells
What makes most connective tissue?
Fibroblasts
What specialized CT cell makes dentin?
Odontoblasts
What specialized CT cells makes enamel?
Ameloblasts
Enamel is considered to be what?
Epithelial
What is the most abundant protein in the body?
Collagen
Collagen is about ___% of the protein in the body by weight
30%
The cornea is about ___% protein.
64%
What type of helix is collagen?
Left-handed
It is a specialized “collagen helix”, not a true alpha helix
What ring structure adds rigidity to collagen?
Proline
In mature form, collagen doesn’t have what two amino acids?
Cystein
Tryptophan
What is tropocollagen
3 helical strands of collagen wrapping around each other
How do tropocollagen fibrils arrange themselves?
In a staggered array of parallel bundles
What causes striations in collagen?
Alignment of every 4th molecule
What forms crosslinks in collagen?
Lysinonoreleucine
What enzyme does the production of lysinonorleucine require?
Lysyl amino oxidase
Lysyl amino oxidase requires which cofactor?
Vitamin B6 (pyridoxine)
What does each collagen molecule consist of?
Three alpha-chains
The collagen family has how many different alpha-chains?
34
Fibrillar collagens form ___ fibers with ___ strength.
Long
Tensile
Non-fibrillar collagens can partially organize into how many groups?
4
What are the 4 types of non-fibrillar collagens?
Basement membrane collagens
Fibril-associated collagen with interrupted triple helix
Multiplexins
Microfibrillar collagen
Which type of non-fibrillar collagen is the network forming collagen?
Basement membrane collagen
Which number types are the fibril-forming collagens?
I, II, III, V, XI
Fibrils can assemble into what?
Fibers
Fibers can assemble into what?
Bundles (ex. tendons)
Where are collagen types I, II, III, V, and XI found?
In interstitial connective tissue
What collagen types form the major stress bearing component of cartilage, tendons and ligaments?
Types I, II, III, V and XI
What type of collagen is the most abundant?
Type I
Where is type I collagen found?
In most connective tissue
Type I collagen is a major component of what structures?
Bone Tendon Skin Dentin Ligament Fascia Arteries Uterus
Type II collagen is a component of what type of cartilage?
Hylaine cartilage
Where is type III collagen found?
Skin
Arteries
Uterus
What type of collagen is prominent in periodontal ligament?
Type III collagen
Which type of collagen is absent or in very low levels in bone?
Type III collagen
What are the basement membrane collagens?
Types IV, VIII and X
What type of collagen is the most abundant structural component of basement membranes?
Type IV
What makes type VIII collagen?
Endothelial cells
What make type X collagen?
Chondrocytes during endochondral ossification
What are the two types of multiplexins?
XV
XVIII
Where are types XV and XVIII found?
In basement membranes
What type of domains to multiplexins have?
Triple helix domains and interruptions
What are fibril associated collagens with interrupted triple helices (FACIT)?
Large multidomain molecules with 2 or more short helical rods, separated by small, non-triple helical domains
FACIT collagens have large what?
N-terminal non-collagen-helix-domain
What are the FACIT collagen numbers?
IX XII XIV XVI XIX
Where is type IX collagen found?
Cartilage and certain embryonic tissues
Where is type XII collagen found?
Similar to type I collagen, so it is found in many connective tissues
What types of cllagens have several fibrocectin and von Willebrand domains?
XII and XIV
What shape is type VI collagen?
Dumbell-shaped with short helical domain and large globular domain at each end
Where are type VI collagens found?
Ubiquitous in connective tissue
Where are type VI collagens especially abundant?
Cornea
What is the longest type of collagen with a triple helix?
Type VII
Where are type VII collagens found?
Anchoring fibrils of basement membrane underlying stratified epithelia
Collagens are ___ ___.
Secreted proteins
Where does translation of collagen alpha-chain mRNAs take place?
On the rough ER
What are the steps of collagen synthesis?
- Nascent polypeptide chain enters lumen of RER
- Signal peptide cleaved off to give procollagen alpha-chain
- Hydroxylation of proline and lysine in RER lumen
- Hydroxylated lysines can be glycosylated
- 3 alpha-chains linked by disulfide bonds at C-terminal; starts procollagen triple helix formation
- Procollagen molecules packaged into secretory granules and secreted
In collagen synthesis, what occurs in the preprocollagen to procollagen step?
Signal peptide cleaved Registration peptides Attach OH to Pro & Lys Attach sugars to hydroxy-lys Form triple helix Package into vesicles
In collagen, what occurs in the procollagen to tropocollagen step?
Registration peptides cleaved to form insoluble tropocollagen
Tropocollagen aggregates to form fibrils
Fibrils crosslink
What are N and C terminals in collagens?
Extension called registration peptides that must be proteolytically removed by extracellular enzymes
What do procollagen registration peptides prevent?
Further assembly of collagen molecules into multimers prior to secretion
After secretion, what removes registration peptides?
Specific procollagen N and C peptidases
How is a mature collagen molecule yielded?
After secretion, the registration peptides must be removed
What is a mature collagen molecule called?
Tropocollagen
What can crosslink the modified lysine side chains of collagen?
Lysyl oxidase
What is needed for full strength in collagen?
Cross-links
Do cells only secrete one type of fibrillar collagen type?
No - they can secrete multiple types
With heterogeneous fibrils it is believed that there are 3 types of collagen involved. What are they and how are they structured?
Collagen V is the core of the fibril
Types I & II polymerize around it
What forms the fiber core of collagen II fibrils?
Type XI collagen
What regulates fibril morphogenesis?
Core collagens
What give mechanical strength to fibrils?
Bulk collagens
What type of domain does collagen IV have?
Relatively long triple helical domain
How is flexibility generated in collagen IV?
Sever small interruptions generate flexible rod
What is assembly of collagen VI?
assembles into beaded filaments
What does collagen VI promote?
attachment of fibroblasts and binding to other collagens (widely distributed)
What are the beaded filaments associated with in collagen VI?
globular domains
What does collagen VII do?
dimerizes by antiparallel overlapping
How are dimers arranged in collagen VII?
dimers associated laterally to form 800nm long bundles of fibrils (microfibrils) in basement membrane
What type of collagen has an N-terminal domain at each end of that fan out and interact with other ECM components?
collagen VII
What type of unique collagen is found in hemidesmosomes of epidermal-dermal junctions?
collagen XVII
What kind of protein is collagen XVII?
a transmembrane protein
When are tissues remodeled?
during normal development, bone growth, and wound healing
How do enzymes degrade collagen?
specific collagenases hydrolyze collagen peptide bonds that causes fragments to denature and release single chain fragments
What type of peptide is much more susceptible to degradation?
an open conformation peptide
What is cleaved denatured collagen called?
gelatin
What are gelatinases?
denatured collagen that has been further degraded by a variety of enzymes
What are some examples of matrix metalloproteinases (MMPs)?
collagenase, gelatinase, stromelysin (proteoglycans)
What is fibronectin?
a ubiquitous ECM glycoprotein
What are some characteristics of fibronectin?
soluble form in body fluids, insoluble form in ECM, especially basement membranes
Where does fibronectin play a major role?
in embryogenesis, wound healing, hemostasis, thrombosis
Fibronectin is a modular protein that is comprised of what three different modules?
Fn1, Fn2, Fn3
