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Types of ECM Molecules
- Collagens
- Proteoglycans
- Matricellular Proteins (Adhesive Glycoproteins)
- Integrins
- Cadherins
- CAMs (Cell Adhesion Molecules)
- Elastic fibers (Elastin)
- Matrix Metalloproteases (MMPs)
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Collagens
- provide structural integrity for bone and cartilage; also major component of basement membranes
- •Type I: fibril-forming & found almost everywhere (bONE especially)
- •Type II: fibril-forming & almost exclusively in cartilage (car-two-lage)
- •Type IV: network/sheet-forming type that plays a role in basement membranes (basal lamina)
- •Type XVIII: basal lamina around blood vessels
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•Type I + II = connective tissue collagens
- •Type II = cartilage collagen
- •Type IV = epithelial basement membrane/basal lamina collagens
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Endostatin
- fragment of Type XVIII (18) Collagen that inhibits angiogenesis
- • likely anti-cancer by inducing apoptosis in endothelial cells
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Diseases of Collagen Defects
- 1. Goodpasture’s Syndrome
- 2. Alport Syndrome
- 3. Menke’s Disease
- 4. Ehler-Danlos Syndrome
- 5. Scurvy
- 6. Osteogenesis Imperfecta
- - G A M ED S OI -
- O(i)MG SE(d)A! OMG SEA!
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Goodpasture’s Syndrome
- autoimmune disease in which antibodies to Type IV collagen destroy the basement membrane in the lungs and kidneys
- •this is the one where you have to consider which is worse, losing kidney or lung function?
- •treatment = corticosteroids, immunosuppressants
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Alport Syndrome
•genetic disorder in which type IV collagen is absent or non-functional --> KIDNEY failure
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Menke’s Disease
- X-linked recessive disease --> causes a deficiency in copper utilization --> results in faulty collagen cross-linking
- •causes developmental delays, seizures, failure to thrive, & characteristically kinky, colorless, & easily broken hair
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Ehler-Danlos Syndrome
- a connective tissue disorder --> results from a defect in collagen synthesis & assembly
- •without the collagen to stabilize the connective tissue, tissues become more elastic (bendy fingers)
- •has consequences in both the musculoskeletal & vascular system
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Scurvy
Vitamin C deficiency prevents cross-linking of collagens; deficiency leads to spots on the skin, spongy gums, & bleeding from mucous membranes
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Osteogenesis Imperfecta
- autosomal dominant disorder --> causes a mutation in Type I collagen
- •mutated collagen in bones results in brittle bones & multiple fractures (case study where girl was taken away from her parents)
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Major Functions of Proteoglycans:
- 1) Regulate hydration state of tissues, especially cartilage
- 2) Provide resistance to impact (shock absorbers) in cartilage
- 3) Act as reservoirs for growth factors and cytokines
- It’s the carbs that count!
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Chondrodysplasias
- •can be caused by either 1) defective proteoglycans or 2) defective Collagen II
- •clinical correlate: collagen II OR chondroitin proteoglycans
- •flattened nose bridge and malformed legs, feet, toes, forearm & fingers
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Matricellular Proteins
- •secreted and bound tightly to cell surface through interactions with integrins; help attach cells to each other and the ECM
- •they help regulate proliferation, motility, and differentiation because they're attached to cytoskeleton & signaling pathways
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What are 3 examples of matricellular proteins?
- 1) fibronectin
- 2) laminin
- 3) CCN proteins
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fibronectin
type of matricellular protein found in connective tissue/mesenchymal matrices (glue for attaching cells)
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laminin
matricellular protein found in basement membranes
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Integrins
- Receptors for fibronectin, laminins, CCN proteins as well as other molecules; often connect to cell signaling and cytoskeletal machinery via tightly complexed proteins on cytoplasmic side of membranes
- •"they're everywhere"
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Glanzmann's Thrombasthenia*
- •clinical correlate: integrin
- •defect of integrins in platelets; inability to clot properly
- •autosomal recessive
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Elastin
major component of the elastic laminae of large artery walls; cross-linked by fibrillin
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Marfan’s syndrome
- •clinical correlate: elastin
- •defective fibrillin fails to cross-link elastin
- •people with Marfan's are really tall --> seen in a few basketball players
- •upon overexertion aneurism can occur in athletes with Marfan's
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Cadherins
- cell adhesion molecules important in maintaining tissue integrity (ie, skin) by connecting desmosomes of adjacent skin cells (require Ca 2+)
- •defects in cadherins connecting desmosomes can weaken/destroy integrity of the skin and cause sloughing and blistering
- •(critical in embryonic development)
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Pemphigus
- •autoimmune blistering disease, therefore clinical correlate: cadherins
- •antibodies against cadherins destroy desmosomes and hemidesmosomes, resulting in blisters
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CAMs (Cell Adhesion Molecules)
- •basically play a role in bringing immune response to an infected EC
- •leukocytes roll along endothelium by sticking weakly to P-selectin (a matricellular protein)
- •if a tissue is inflamed, the endothelial cells in that area express Platelet Activating Factor (PAF), which binds to the PAF receptor ON the leukocyte --> stronger binding
- •this binding additionally activates an integrin ON the leukocyte which itself binds tightly to ICAM-1 back to the EC membrane
- •leukocyte stops and invades the tissue
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Matrix Metalloproteinases (MMPs)
- enzymes in the matrix that bind metal ions and are responsible for breaking down collagen and the ECM
- •required for stimulating and inhibiting angiogenesis, cancer cell metastasis, tissue remodeling, & wound healing
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Metastatic Cancer
- clinical correlate: MMPs (+ fibronectin, laminin, matrix-degrading enzymes)
- •cancer that has spread from the place where it first started to another place in the body
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positional control is another way to say:
cell-matrix interactions
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Cardiovascular Disease: Arteriosclerosis and Restenosis
related to most things discussed in CellBio proteoglycans, CAMs, etc)
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