Connective tissue disorders by Dr Ashok Kumar J

Connective tissue disorders
Dr. Ashok Kumar J.
International School of Medicine
Management and science university
Malaysia
Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 1

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 tissue
Composed of network of insoluble tough protein fibers
1. Collagen (Glycoprotein ) 3. Fibrillin
2. 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

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

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

Prolyl residues in the Y-position
are characteristically
hydroxylated to produce
hydroxyproline, which serves
to stabilize the triple helix
polypeptide is characterized
by a repeating sequence in
which glycine is in every third
position (Gly-X-Y)
Composed of three chains
that form a trimer in the
shape of a 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 Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 12

Lysine residues
Lysyl oxidase O2
Aldehyde derivative
allysine allysine
Aldol Cross link
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 deficiency
Change in the amino acid sequences of collagen Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 15

Collagen
containing
mutant chains
is not secreted
Degraded or
accumulated to
high levels in
intracellular
compartments
- Collagen type III
is an important
component of the
arteries
- Potentially lethal
vascular problems
occur

Defects in collagen type I fibrils
Results in fragile, stretchy skin and loose joints
Stretchy skin of Ehlers-Danlos
syndrome
hypermobile and lax joints
(Hyperextensible 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 Dr. Ahok Kumar J; IMS; Biochemistry; MSU. 24

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
Scurvy
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

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 glycoprotein
Elastin core
Microfibrils

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

Marfan’s Syndrome
Inherited
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
• 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

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
• 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
• Defect in the elastin synthesis
• low nasal bridge
• developmental delay
• coupled with strong language
skills
• supravalvular aortic stenosis

Rheumatoid Arthritis
[An immune mediated inflammatory disease (IMID)]
• Women are affected twice as often as men
• Peak incidence is
• between the fourth and sixth decades
• morning stiffness, symmetric polyarthritis,
inflammatory
synovitis, and the presence of rheumatoid
factor (RF)

LUPUS ERYTHEMATOSES
It exists in two forms :
a) Systemic lupus erythematosus
b) Discoid lupus erythematosus
Clinical features: Erythematous patches on face (cheeks and
bridge of nose), neck, upper arm, shoulder and fingers
Kidney –fibrous thickening of glomerular capillaries
Heart-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

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