Cell and Molecular Biology Lecture 3: Extracellular Matrix

What is the collection of molecules (collagen fiber, elastic fiber, reticular fibers, hyaluron, proteoglycans, glyocoproteins, extracellular fluids) secreted by cells called?

Extracellular matrix

Where is the extracellular matrix located?

Spaces between cells; binds cells and tissues

What does the extracellular matrix do?

Provides structural and biochemical support to surrounding cells

What are the combination of glycoaminoglycans, proteoglycans, and glycoproteins called?

Ground substance

What is the collection of collagen fibers, reticular fibers, and elastic fibers called?

Fibrous proteins

What comprises the extracellular matrix?

Ground substance, fibrous proteins, extracellular fluid

What serves as a diffusion medium in the spaces around cells and fibers as well as determines the physical nature of a connective tissue?

Ground substance

What are the negatively charged, long, rod-like chains of repeating disaccharides in the extracellular matrix called?

Glycosaminoglycans

Why are glycosaminoglycans highly negatively charged?

Sulfate and carboxyl groups

What do glycosaminoglycans do in the ECM

Form gels that assist in restance to forces of compression; promote the ability of collagen fibers to retain moisture

What are the major types of glycosaminoglycans?

Hyaluron, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratin sulfate

What is the only non-sulfated simple glycosaminoglycan?

Hyaluronic acid (hyaluron)

What is the term for multiple glycosaminoglycans linked to a protein via the glycosaminoglycan side chains?

Proteoglycan

Which glycosaminoglycan does not bond covalently to a protein core to make proteoglycans?

Hyaluronic acid

How are proteoglycans formed?

Protein cores produced in rough endoplasmic reticulum; glycosaminoglycans covalently bound in Golgi apparatus

What do proteoglycans do?

1. Serve as a reservoir for nutrients, metabolites, hormones, and growth factors

2. Retard rapid movement of microorganisms and metastatic cells

3. Resist compression

4. Function as lubricants in synovial fluid

5. Store proteins and prevent them from degredation

What are polymer proteins that are covalently attached to small amounts of polysaccharides?

Glycoproteins

What are the structural glycoproteins?

Fibronectin, laminin, chondronectin, osteonectin

What type of protein is fibronectin?

Homodimeric

What type of cell produces fibronectin?

Fibroblasts

What is the role of fibronectin?

Mediate attachment of cells to the extracellular matrix

What formation facilitates the attachment of cells to the surface

RGD-Integrin complex

What type of protein is laminin?

Heterotrimeric (cross shaped)

What are the polypeptide chains in laminin and how are they oriented?

Alpha, beta 1, beta 2; beta chains wrap around alpha chain

Where is laminin located?

Basal membrane that separates the epithelial and connective tissues

What mediates the interaction of chondrocytes with their matrix via its binding directly with collagen?

Chondronectin

Where is chondronectin located?

Cartilage

What plays a significant role in bone mineralization?

Osteonectin

Where is osteonectin located?

Bone

What do fibrous proteins do?

Provide tensile strength and elasticity to the extracellular matrix

What is the most abundant protein in the body that comprises 25% the total protein mass in the body?

Collagen

What type of cells produce collagen?

Fibroblasts

What does collagen do in the extracellular matrix?

1. Maintain structural integrity

2. Provide tensile strength

3. Aid in cell differentiation, polarization, and migration

4. Tissue and organ development

What is the basic structure of collagen?

Three alpha chains forming triple helix

What are the most abundant amino acids in collagen?

Proline, glycine, hydroxyproline

How often does glycine occur in collagen amino acid sequences?

Every third position (G-P-H-G)

What is the function of glycine in the structure of collagen?

Allows the helical chains to pack tightly

What is the function of proline in the structure of collagen?

Packs the helices closely

What is the function of hydroxyproline in the structure of collagen?

Pro-Hyp stabilizes via h-bonding

How many types of collagen are there?

13

What is the most common type of collagen (90% of collagen in the body)?

Type I

Where is Type I collagen located?

CT proper, bones, dentin, tendons, cementum

Where is type II collagen located?

Matrix of cartilage (hyaline and elastic)

What is another name for type III collagen?

Reticular fibers

Where are type IV and type VII collagen found?

Basement membrane

Where is type V collagen found?

Placenta

What is the process for collagen synthesis?

1. Transcription of collagen gene in nucleus (mRNA formation)

2. Synthesis of pre-pro collagen in rough endoplasmic reticulum

3. Post-translational modification (removal of signal peptide, hydroxylation of proline and lysine residues, glycosylation of hydroxylysine, triple helix formation)

4. Transport of procollagen to the Golgi apparatus

5. Processed procollagens secreted by exocytosis

6. Removal of N- and C-terminal extensions by procollagen peptidases to generate tropocollagen

7. Assembly of tropocollagen to collagen fibrils and into fibers

What are elastic fibers composed of?

Elastin and fibrillin

What do elastic fibers do when the force/tension on them is released?

Return to their resting length

Where can elastic fibers be found?

Elastic cartilage, large arteries, bronchial tubes, skin

What is the difference between elastic fibers and collagen?

No hydroxylysine, triple helix, or repeating Gly-X-Y sequences, intermolecular desmosine crosslinks

What are the two unusual amino acids that elastin contains?

Desmosine and isodesmosine

What do desmosine and isodesmosine do in elastin?

Serve as intermolecular crosslinks

Which amino acids are most prevalent in elastin?

Glycine, lysine, alanine, valine, and proline

What protein is essential in the formation of normal elastic fibers?

Fibrillin

What syndrome is caused by a mutation in the fibrillin gene?

Marfan syndrome

How many genetic types does elastin have versus collagen?

One versus many

What type of crosslinks does collagen have versus elastin?

Aldol vs desmosine

Does elastin contain carbohydrate groups?

No

What is the main structural component of reticular connective tissue?

Reticular fibers

What is another name for reticular cells?

Fibroblasts

What type of collagen fibers are reticular fibers?

Type III

Where can reticular fibers be found?

Spleen, lymph node, liver

What are the main functions of reticular fibers?

1. Support soft organs

2. Assist in attaching epithelial cells to underlying connective tissue

What is the primary cause of scurvy?

Vitamin C deficiency

What happens to the collagen in individuals with scurvy?

Unstable triple helix formation; tropocollagen incapable of aggregation into collagen fibrils

What are the symptoms of scurvy?

Tiredness, muscle weakness, joint and muscle aches, bleeding around hair follicles/gums/under nails

What can be used to treat scurvy?

Consumption of increased vitamin C (foods or tablets)

What is the formal name for "Brittle Bone Disease"?

Osteogenesis imperfecta

Is osteogenesis imperfecta a group of genetic disorders?

Yes

What is the most common symptom of osteogenesis imperfecta?

Reduction in type I collagen causing brittle bones

Can osteogenesis imperfecta be cured?

No

What are some of the treatments that can be used to manage symptoms of osteogenesis imperfecta?

Medication, physiotherapy, surgery

What is the genetic disorder that results in a deficiency in the level of the enzyme lysyl hydroxylase resulting in abnormal collagen fiber formation?

Ehlers-Danlos Syndrome

What are the manifestations of Ehlers-Danlos Syndrome?

Over-flexible joints, hyper elastic skin

Where is the mutation in Marfan syndrome located?

Fibrillin (FBN1) gene

What causes overgrowth in those with Marfan syndrome?

Excess growth factor TGF-beta

What are the manifestations in adults with Marfan syndrome?

Tall and thin build, disproportionately long arms and legs, spinal curvature, chest sinking, crowded teeth, flat feet