connective tissue disorders by dr ashok kumar j

Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 1

Connective tissue disorders

Dr. Ashok Kumar J. International School of Medicine

Management and science universityMalaysia


OBJECTIVES : To learn …….

• What is a connective tissue? • Importance of connective tissue• Briefly about the composition of connective tissue• Disorders related to collagen and elastin synthesis and function• Scurvy and lathyrism• Important connective tissue disorders related to autoimmunity


Space between organs and tissues filled with connective tissueComposed of network of insoluble tough protein fibers1. Collagen (Glycoprotein ) 3. Fibrillin2. Elastin (Non glycoprotein )

embedded in a matrix of proteoglycans (ground substance), mainly secreted by fibroblasts

Connective Tissue

Connective tissue proteins and proteoglycans are synthesized by connective tissue cells

- Fibroblasts- Chondroblasts- Osteoblasts

Adipose tissue is a special form of connective tissue



• The unique property of each connective tissue

e.g:

Flexibility of skin

Rigidity of bone

Elasticity of large arteries

Strength of tendons

Depends upon the composition and organization of collagen and other matrix components

- Bind tissues together - Provide support to the organs and other structures

of the body


Collagen

tough and have high tensile strength

Component of Skin; Connective tissue; Blood vessel

walls Sclera of the cornea of eye


• Without collagen, a human being would be reduced to a clump of cells


Composed of three chains that form a trimer in the shape of a triple helix

polypeptide is characterized by a repeating sequence in

which glycine is in every third position (Gly-X-Y)

Prolyl residues in the Y-position are characteristically hydroxylated to produce hydroxyproline, which serves to stabilize the triple helix


• Inter and intrachain crosslinking by- non covalent bond hydrogen bond - covalent linkage involving the lysyl and

hydroxylysyl stabilize collagen

Hydroxylation necessary for crosslinking ;Cross-linking is one of the factor responsible for tensile strength of the collagen


allysine allysine

Aldol Cross link

Lysine residues

Aldehyde derivative

Lysyl oxidase O2

e


Defects in any one of the many steps in

collagen fiber synthesis or change in aminoacid

sequence

Inability of collagen to form fibers properly

Not provide tissues with the needed tensile strength normally

provided by collagen


Ehlers-Danlos syndrome (EDS):

Heterogeneous group of generalized connective tissue disorders

Result from inheritable defects in the metabolism of fibrillar collagen

molecules

Can result from a deficiency of collagen-processing enzymes

Lysyl hydroxylase deficiency procollagen peptidase deficiencyChange in the amino acid sequences of collagen


hypermobile and lax joints (Hyperextensible joints)

Stretchy skin of Ehlers-Danlos syndrome

Defects in collagen type I fibrilsResults in fragile, stretchy skin and loose joints


• Velvety skin• Rubber man syndrome;

• Mitral valve prolapse


Osteogenesis imperfecta (OI):

• Disease known as “brittle bone syndrome”• Heterogeneous group of inherited disorders• Distinguished by bones that easily bend and fracture• Retarded wound healing• Rotated and twisted spine leading to a “humped-back”

appearance


Type I osteogenesis imperfecta

• Type I is called osteogenesis imperfecta tarda • Decreased production of α1 and α2 chains• Presents in early infancy with fractures secondary to minor trauma• May be suspected if prenatal ultrasound detects bowing or fractures

of long bones


Type II osteogenesis imperfecta

• Type II is called osteogenesis imperfecta congenita• More severe form• Patients die of pulmonary hypoplasia in utero or during the neonatal

period• Most patients with severe “OI” have mutations in the gene coding for

pro-α of type I collagen• Most common mutations cause the replacement of glycine residues (in

-Gly–X–Y–) by amino acids with bulky side chains• Resultant structurally abnormal chains prevent the formation of the

required triple-helical conformation


Lethal from of osteogenesis imperfect:Fractures appear in utero


Alport syndrome

• Alport syndrome or hereditary nephritis • Named after a British doctor, Cecil A. Alport

- Presence of blood in the urine (hematuria) is almost always found- Affects the eyes causing eye abnormalities including cataracts, lenticonus, kerataconus, as well as retinal flecks in the macula and mid periphery


Alport syndrome• Mutation of genes - prevent the proper production

or assembly of the type IV collagen network• It is an important structural component of

basement membranes in the kidney, inner ear, and eye

• Basement membranes are thin, sheet-like structures that separate and support cells in many tissues

• Basement membranes of the kidneys are not able to filter waste products from the blood

• allow blood and protein into the urine


Scurvy


Vitamin C deficiency

Bleeding spongy gums

Subcutaneous hemorrhage

Delayed wound healing

Biochemical basis:Vitamin C is required for prolyl hydroxylase

and lysyl hydroxylase involved in hydroxylation of proline and lysine of collagen chain

http://www.google.com.my/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=cKl658jDPZf-GM&tbnid=F5u4AQQVLm-E4M:&ved=0CAUQjRw&url=http://openwetware.org/wiki/BME494_Project_Group7&ei=sn6WU5O5EdCVuAS34oHwCg&psig=AFQjCNFuVQRLm_80f9Gr_dcegWsbkYQEfg&ust=1402457989882409


Elastin• Protein with rubber-like properties• Elastic fibers composed of elastin and glycoprotein microfibrils • Found in the lungs, the walls of large arteries, and elastic ligaments, in

the uterus, skin• Peripheral microfibrillar network that surrounds the core consists largely

of fibrillin, a glycoproteinElastin core

Microfibrils


• Can be stretched to several times their normal length• Recoil to their original shape when the stretching force is relaxed


Marfan’s SyndromeInherited

defects in

fibrillin

formation of abnormal

elastic fibers

Marfan’s

syndrome

Disorder characterized by impaired structural integrity in the skeleton, the eye, and the cardiovascular system


Long thin extremities

associated with other skeletal deformities

Reduced vision as a result of

dislocation of the lenses (ectopia

lentis)

Aortic aneurysms that typically

begins at the base of the aorta

Characterized by triad of features


Skeletal Abnormalities and high arched pallet


• Elastin is an insoluble protein polymer • Synthesized from a precursor, tropoelastin• Is a linear polypeptide• Contains primarily small and nonpolar amino acids

(for example, glycine, alanine, and valine)

• Elastin is also rich in proline and lysine

Elastin


Role of α1-antitrypsin in elastin degradation

• Blood and other body fluids contain a protein, α1-antitrypsin (α1-AT, AAT, currently also called α1-antiproteinase)

• Originally named α1-antitrypsin because it inhibits the activity of trypsin synthesized by the pancreas

• Important physiologic role is to inhibit neutrophil elastase • Elastase is a powerful protease that is released into the extracellular

space by neutrophils• It degrades elastin of alveolar walls as well as in other tissues


• Most of the α1-AT found in plasma is synthesized and secreted by the liver

• The remainder is synthesized by several tissues including monocytes and alveolar macrophages

• α1-AT is important in the prevention of local tissue injury by elastase.


Role of α1-AT in the lungs:

• In the normal lung- Alveoli are chronically exposed to low levels of neutrophil

elastase released from activated and degenerating neutrophils

- Proteolytic activity can destroy the elastin in alveolar walls if unopposed by the inhibitory action of α1-AT

- Destruction of the connective tissue of alveolar walls

- Lung tissue cannot regenerate – results in emphysema


• Smoking causes the oxidation and subsequent inactivation of that methionine residue, thereby rendering the inhibitor powerless to neutralize elastase

• Smokers with α1-AT deficiency, therefore, have a considerably elevated rate of lung destruction and a poorer survival rate than nonsmokers with the deficiency.

• The deficiency of elastase inhibitor can be reversed by weekly intravenous administration of α1-AT

• The α1-AT diffuses from the blood into the lung


Epidermolysis bullosa

• Characterized by severe blistering of the skin and epithelial tissue

• Defect in the structure of type VII collagen


Lathyrism

• Diet induced disease• Due to inhibition of lysyl oxidase by the

β aminopropionitrile of Lathyrus odoratous seeds ( sweet pea) or β oxalylaminoalanine found in kesari dal

• Affects cross-linking of collagen • Characterized by deformation of spine ,

dislocation of joints, demineralization of bines, aortic aneurysm and joint hemorrhage


Williams Syndrome

• Defect in the elastin synthesis• low nasal bridge• developmental delay • coupled with strong language

skills• supravalvular aortic stenosis

• Rare genetic condition. The clinical manifestations include a distinct facial appearance, cardiovascular anomalies that may be present at birth or may develop later in life, idiopathic hypercalcemia


Rheumatoid Arthritis

• Women are affected twice as often as men• Peak incidence is• between the fourth and sixth decades• morning stiffness, symmetric polyarthritis,

inflammatorysynovitis, and the presence of rheumatoid

factor (RF)

[An immune mediated inflammatory disease (IMID)]


LUPUS ERYTHEMATOSES

It exists in two forms :a) Systemic lupus erythematosusb) Discoid lupus erythematosusClinical features: Erythematous patches on face (cheeks and

bridge of nose), neck, upper arm, shoulder and fingersKidney –fibrous thickening of glomerular capillariesHeart-atypical endocarditis.Oral manifestations:-superficial ulceration and bleeding of

oral mucosa, commonly buccal mucosa,palate and tongue.Tongue shows atrophy of papillae


It is a multiple organ disease and almost always associated with Raynaud`s phenomenon

The fibroblasts are defective with accentuated fibrillogenesis (abnormal diameter of fibers) increase in type VI collagen

Skin takes a waxy appearance due to hardening and cannot be wrinkled. Hands become claw like

Scleroderma


• Thank you

connective tissue disorders by dr ashok kumar j

Health & Medicine

ashok kumar j

connective tissue disordersdr

connective tissuee

collagen glycoprotein

osteogenesis imperfecta

osteogenesis imperfecta

severe form patients

ehlersdanlos syndrome