Connective tissue Flashcards
What are the general features of connective tissue?
- Distributed throughout the body
- Composed of:
- Ground substance
- Structural proteins
- Specialised proteins
What are ground substances?
- Non-cellular, non-structural.
- Has proteoglycans that extracts H20 + ions and form viscous matrix in Extra cellular space
What are structural proteins?
- Collagen & elastin
- Secreted by Connective Tissue cells– fibroblasts, chondrocytes, osteoblasts
What are specialised proteins?
- Fibrillin - scaffold for deposition of Elastin
- Fibronectin - binds integrins, & other extracellular
matrix proteins - Laminin - basal lamina
What is the function of collagen?
- Support and strengthen (tendon)
- Intercellular binding (liver, muscles)
- Matrix for deposition of inorganic salts (bone, teeth)
Outline the properties for collagen.
Collagen:
- Present in all tissues, most abundant
- Fibrillar collagen: long & rigid, triple helical structure
- > 20 diff types
Outline the distribution for collagen.
Collagen:
1. Fibrils: ^ tensile strength. helical structure, collagen types I, II & III.
2. Network forming: 3D mesh (basement membrane, thin + sheet like, Collagen type IV, VII)
3. Fibril associated: Links fibrils to one another & other components of ECM, collagen types IX & XII
Outline the structure for collagen.
- Amino acid sequence:
- Repeating -Gly-X-Y- sequence, X = Proline, Y = hydroxyproline.
- Proline causes bending of chain
- Glycine fits into space made by triple helix - Triple helical structure:
- Exposed R-groups allow interactions with other collagen fibres. - Post-translational modification:
- Hydroxylation of Pro and Lys
- Hydroxyproline maximises inter-polypeptide H-bonds (triple helix stabilised)
- Glycosylation of hydroxylysine
Outline the synthesis for collagen.
Where:
- Fibroblasts, Osteoblasts & Chondrocytes
Go to:
- The extra cellular matrix (ECM)
Modification:
- product = mature collagen monomers aggregate & cross-link = Fibrils
How:
How does collagen cross-link?
- Lysyl oxidase deaminates some lys & hydroxy-lys
- Resulting reactive aldehydes (allylys & hydroxy-allylys)
- Reactive aldehydes covalently bond with lys or hydroxy-lys
Why is cross linking important?
- Essential for tensile strength
- Any mutations affecting cross- linking affects stability
Outline the degradation for collagen and elastin.
- T1/2= months
1. Collagenases: e.g. for type I cleavage at specific site 3⁄4 and 1⁄4 fragments
2. Matrix proteinases
What does pro-collagen peptidase do?
Procollagen peptidase is an endopeptidase involved in the processing of collagen. The proteases removes the terminal peptides of the pro-collagen
List the different types of collagen and where they are found.
How does vitamin c deficiency affect collagen?
- Vitamin c prevents auto-inactivation of lysyl and prolyl hyroxylase, two key enzymes in collagen biosynthesis.
- Collagen fibres cannot be cross-linked
- Decreased tensile strength
What is the molecular basis of the connective tissue disorder: Ehlers Danlos Syndrome
Defects in metabolism of fibrillar collagen:
1. Collagen processing enzyme deficiency
- Lysyl hydroxylase & Procollagen peptidase
2. Collagen sequence mutations
- Types I, III, V. III= v. serious, vascular problems.
Symptoms:
- hyper-mobile joints, hyper-elastic skin, CV complications (vessels & organs rupture), chronic pain
What is the molecular basis of the connective tissue disorder: Osteogenesis Imperfecta
‘Brittle bone disease’.
- Group of diseases & range of severities, disorder of type I collagen
Types:
1. Decreased Production: mild = OI type I
2. Altered structure: severe = OI type II, III, IV
Symptoms:
- Bone bend & # easily
- Slow wound healing
- Rotated & twisted spine- humped back
- Blue sclera
Discuss type 1 of Osteogenesis imperfecta.
Type 1: Osteogenesis imperfect tarda
- Most common, AD inheritance,
- Defect: Inactivation of 1 allele of a1 collagen gene,
- Result: decreased pro a1 synthesis, excess pro a2, deficiency in mature collagen (bone fragility)
- Symptoms: Blue sclera, frequent #, Conductive deafness
Discuss type 2 of Osteogenesis imperfecta.
Type 2: Osteogenesis imperfecta congenita
- Defect: Mutation in a1(I) or a2 collagen genes
- Result: Defective protein in normal amounts, > 75% of Type I collagen is abnormal, abnormal collagen degraded, extreme bone fragility.
- Symptoms: telescoping of long bones, multiple congenital #, perinatal lethal
Discuss type 3 of Osteogenesis imperfecta.
- Defect: Mutation in a1(I) or a2 collagen genes
- Result: Defective protein in normal amounts
- Symptoms: Progressively deforming, multiple congenital #, severe bone deformity, limited growth, blue sclera, hearing loss
Discuss type 4 of Osteogenesis imperfecta.
‘Norma lifespan’
- Defect: Mutation in a1(I) or a2 collagen genes
- Result: Defective protein in normal amounts
- Symptoms: #, limited growth, mild-moderate bony deformity, normal sclera*, hearing loss
What are the properties of elastin?
- Rubber like
- Stretch to several times its length and any direction
- Recoil to original shape
Distribution of elastin.
Location: lungs, large arterial walls, ligaments
Discuss the structure of elastin.
- Linear polypeptide (700 aa)
- Small non-polar aa e.g. Gly, Val, Ala. Rich in Pro and Lys
- Little hydroxy-pro, NO hydroxy-lys
- Secreted into ECM – interacts with Fibrillin
- Lysyl oxidase oxidatively deaminates lysyl side chains to ally-lys
- 3 allylysine & 1 lysyl cross-link tropoelastin
**Cross-linked Tropoelastin = elastin
Discuss elastin synthesis.
Discuss elastin degradation.
Degraded by elastase:
- Elastase secreted by neutrophils and inhibited by a1 anti-trypsin
*a1 anti-trypsin prevents inappropriate degradation of Elastin in the lungs.
What is the molecular basis of the connective tissue disorder: α1 anti-trypsin deficiency
Defect: Deficiency of a1-AT. Single allele not enough to cause disease.
Result: Premature Emphysema due to destruction of connective tissue in alveoli. Exacerbated by smoking
Treatment: a1-AT IV injections weekly
What is the molecular basis of the connective tissue disorder: Marfan syndrome
Defect: Mutation of fibrillin-1 gene (FBN1), defective fibrillin, Autosomal dominant
Result: classic presentation includes aortic aneurysm or dissection, long extremities, arachnodactyly, joint hyper-mobility, and subluxation of the lens of the eye.
- No causal tx but symptoms treated.
