Metabolic and structural abnormalities of collagen, elastin and proteoglycans. Mucopolysaccharidoses
Collagen
Collagen is the main fibrous component of skin, bone, tendons and cartilage, in total it is a third of our total protein.
Collagen is made of 3 polypeptide alpha chains coiled in a right handed triple helix. There are 3 amino acids per turn, and Glycine occupies every third position in the repeating sequence. Additionally, collagen has a high content of proline and hydroxyproline and is further stabilised by inter-chain hydrogen bonds.
There are 28 types of collagen, but there are five main ones we should concern ourselves with:
- Collagen I - skin, tendon, vascular ligature, organs, bone
- Collagen II - cartilage
- Collagen III - reticulate
- Collagen IV - forms basal lamina
- Collagen V - cell surface, hair and placenta
Collagen disorders are generally the product of genetic defects or nutritional deficiencies that affect biosynthesis, there are in effect three categories of disorder:
- Increased collagen synthesis (fibrosis)
- Abnormal structure of collagen
- Abnormal collagenolysis
Increased collagen synthesis
- Fibrosis is the product of increased activity of fibroblasts, the cells that lay down connective tissue (collagen and glycosaminoglycans)
- The process is initiated when immune cells such as macrophages stimulate fibroblasts
- The most well known one is TGF beta, so released by macrophages
- Fibrosis is generally the product of inflammation or damage, examples include:
- Pulmonary fibrosis (e.g. Cystic fibrosis)
- Liver Cirrhosis
- Atrial/Endomyocardial fibrosis
- Glial scarring (in the brain)
- Macroscopically there is a decrease in organ size and an increase in density
- Microscopically there is an increase in collagen in the ECM, visible with Van Gieson staining (collagen stains red)
Abnormal structure
This is generally the product of genetic defects which result in abnormal structure, there are two main conditions to consider:
- Marfan’s syndrome
- AD disorder, affecting fibrillin 1, a major component of microfibrils found in ECM, including elastins
- Product of FBN1 gene mutation
- Morphologically shows Arachnodactyly (spider fingers), hyperextensibility of joints, spinal deformities, bilateral dislocation/subluxation of the lens and mitral valve regurgitation with congestive heart failure
- Ehlers-Danlos syndrome
- Defects in synthesis or assembly of collagen, comes in 6 variations
- Produces structurally abnormal collagen
- Pathophysiology
- Deficiency in lysyl hydroxylase enzyme
- Deficient synthesis of type III collagen, result of COL3A1 gene mutation
- Morphology shows fragile, hyperextensible skin, poor wound healing, hypermobility of joints and rupture of internal organs