10.2. Features of metabolism of extracellular matrix Catabolism of extracellular matrix proteins

In the catabolism of extracellular matrix proteins metalloproteinase plays a major role. It is Ca-dependent, zinc-binding endopeptidase. Regulators of their activity are the tissue inhibitors of metalloproteinases, and cytokines.

Collagens are slowly metabolized proteins: their half-life time is measured in weeks or months. Half-life time of elastin in the tissues of humans is about 75 years.

Collagenase cuts all three peptide chains of collagen between glycine and leucine residues. The resulting fragments are denatured and hydrolyzed by different peptide hydrolases. The content of hydroxyproline in the blood and urine reflects the balance of the rate of collagen and hydroxyproline catabolism. During some diseases associated with the damage of connective tissue, such as hyperparatyroidism excretion of hydroxyproline is increased due to accelerated breakdown of collagen.

Proteoglycans metabolize at high rate. Half-life time of extracellular proteoglycans matrix is days or weeks, of the cell surface – are hours. Proteoglycans are destroyed in lysosomes.

Cortisone and its analogs inhibit the biosynthesis of collagen by fibroblasts, inhibit the biosynthesis of glycosaminoglycans. They activate the enzymatic catabolism of collagen. Aldosterone and deoxycorticosterone increase the biosynthesis of inoglia. Thyroxine causes depolymerization of hyaluronic acid, and somatotropic hormone of anterior pituitary stimulates inclusion of proline into a polypeptide chain of tropocollagen.

Reparation of damage of the extracellular matrix in norm

In the matrix, there may be isolated focuses of damage (e.g., accidental proteolysis). Metalloproteinases are activated in the area of violations. There is a degradation of damaged and improperly oriented molecules. The basement membrane serves as a template for the assembly of new membrane, which replaces the damaged.

In wound healing a number of cytokines is involved, but the special role is belongs to transforming growth factor (TGF). TGF induces the synthesis of collagen, fibronectin, laminin, glycosaminoglycans and inhibits their degradation. TGF stimulates the synthesis of integrins that regulate the formation of extracellular matrix components.

Biochemical changes of connective tissue with aging

With aging there is a decrease of water content and the ratio of the main substance / fiber due to increase of collagen content and decreased concentration of glycosaminoglycans, particularly hyaluronic acid. A number of cross-links in collagen is increased, its elasticity is decreased (the process of "maturation" of fibrillar structures of connective tissue). This is the normal outcome of metabolic processes occurring in the body.

The lesions of connective tissue

Scurvy is a disease caused by an acute lack of vitamin C. This leads to disruption of collagen synthesis, the connective tissue loses its strength. Symptoms are weakness, fatigue, weakening of muscle tone, rheumatic pain, loosening and loss of teeth; the fragility of the blood vessels leads to bleeding gums, bleeding in the skin. Treatment and prevention is normal providing of the body with vitamin C.

Collagenoses (connective tissue disease) are rheumatism, rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma, dermatomyositis. There is damage of all the structural components of connective tissue. All collagenoses are characterized by multiple organ lesions, vasculitis (inflammation and necrosis of the vascular wall), arthritis and immunity disorders.

The greatest recognition has the theory of infectious-allergic origin, in particular – the concept of autoimmune origin.

Corticosteroid hormones and a variety of immunosuppressive drugs have the therapeutic effect.

Fibrosis is an abnormal growth of fibrous component of connective tissue, excessive accumulation of extracellular matrix with the appearance of scars of various organs. It is preceded by a sufficiently long phase of inflammatory disease, usually related to chronic action of damaging factors (ethanol in cirrhosis of the liver, inhalation of dust from pulmonary fibrosis, hyperglycemia in diabetic nephropathy, etc.).

Mucopolysaccharidosis (MPS) is a group of hereditary diseases of connective tissue due to metabolic disorders of glycosaminoglycans as a result of genetically determined deficiency of enzymes involved in their cleavage. Glycosaminoglycans are accumulated in large amounts in organs and tissues.

The main manifestations of MPS are the systemic failure of the skeleton, delayed physical development. The nervous system, eyes and internal organs are affected. There is a severe disturbance of child development and reducing life expectancy.

For the treatment hormones are prescribed: ACTH (adrenocorticotropic hormone) to inhibit the synthesis of mucopolysaccharides, thyreoidinum, prednisolone. Large doses of vitamin A and cardiac medications are used; there are attempts to treat with cytostatic agents.

More than 400 mutations of collagen are known; they are related to chondrodysplasia, some forms of osteoporosis and osteoarthritis.

Osteogenesis imperfecta is a rare disorder of connective and supporting tissue. The basis of the disease is mutations in one of two genes encoding collagen type I. The disease is characterized by abnormal fragility of the bones. In severe lesions multiple fractures occur already in utero, including fractures of the ribs. Many patients suffer from a shortened, deformed limbs, and fragile bell or barrel-shaped chest. In mild cases, there are some broken limbs, but often there are compression fractures of the spinal column.

Test Questions

1. List the functions of the extracellular matrix.

2. Describe the structure and biological role of main proteins of the extracellular matrix.

3. What enzymes play a major role in the catabolism of extracellular matrix proteins?

4. Explain the reasons for increased bleeding with a deficiency of vitamin C.

5. What compounds are called glycosaminoglycans? Give examples.

6. What role do proteoglycans in the cartilage of the articular surfaces?

7. Describe the biochemical changes of connective tissue with aging.