The document provides an overview of the extracellular matrix (ECM), detailing its definitions, functions, and components, including various types of collagen and elastic fibers. It also discusses diseases associated with ECM defects and autoimmune phenomena, such as Ehlers-Danlos syndrome and systemic sclerosis. Key processes involved in collagen biosynthesis are outlined, emphasizing the significance of ECM in tissue structure and function.

1. BIOLOGY OF
THE
EXTRACELLULA
R MATRIX
ABDULRAHMAN ALOMAIR
FIRST YEAR RESIDENT
JOINT DERMATOLOGY PROGRAM, RIYADH

2. OUTLINE
▸ Definitions
▸ Functions of the ECM
▸ Components of the ECM
▸ Diseases Related to Defects in ECM
▸ Diseases Related to Autoimmune Phenomena

3. DEFINITION
▸ ECM a three-dimensional network of extracellular
macromolecules, such as collagen, enzymes, and
glycoproteins, that provide structural and biochemical
support of surrounding cells.

4. FUNCTIONS OF THE ECM
▸ It maintains tissue architecture and mediating a number of
important biological events
▸ The Basement Membrane (BM) has important tissue specific
properties that allow for particular cell attachments; regulate
morphogenesis, differentiation, and barrier functions
▸ In the Dermis, the ECM maintains the elasticity, resilience, and
tautness of the skin
▸ At the Dermal-Epidermal junction, specific basement membrane-
associated strong aggregates ensure strong adhesion of the
epidermis to the dermis

5. FUNCTIONS OF THE ECM
▸ Attachment of tissue-specific cells, leukocytes, tumor
cells, and even micro-organisms
▸ Control cell proliferation, differentiation and migration.
▸ the ECM can function as a reservoir of information;
certain proteoglycans and proteins bind growth factors.
They will release and activate them as needed to control
cellular functions

6. COMPONENTS OF THE ECM

7. COMPONENTS OF THE ECM

8. COMPONENTS OF THE ECM: COLLAGEN
▸ The main structural component of the extracellular
protein of the human body
▸ The family currently includes 28 proteins , these proteins
contain at least 43 distinct polypeptide chains, each
encoded by a different gene
▸ 75% of the dry weight and 20–30% of the volume of the
dermis

9. COMPONENTS OF THE ECM: COLLAGEN
▸ All collagens consist of 3 polypeptide chains, known as α-
chains, which are folded into a triple helix
▸ In some collagens, the α-chains are identical
(homotrimers), while others contain two or three
different α-chains (heterotrimers)

10. COMPONENTS OF THE ECM: COLLAGEN
▸ In each chain, every third amino acid is glycine (Gly), and
the sequence of an α-chain can be expressed as (Gly-X-
Y)n where X and Y represent other amino acids
▸ The prototype collagen (type I) has an uninterrupted Gly-
X-Y repeat sequence

11. COMPONENTS OF THE ECM: COLLAGEN
▸ The synthesis of collagen has 2 steps:
▸ Intracellular
▸ Extracellular

12. BIOSYNTHESIS OF COLLAGEN:
INTRACELLULAR REACTIONS
1. Transcription of collagen α chain genes by mRNA
2. Translation of mRNA to polypeptide chain
3. Hydroxylation of certain Proline (Pro) and lysine (Lys) residues to 4-
HydroxyPro, 3-HydroxyPro (Hyp), and Hydroxylysine (Hyl) (This step
requires Vit C, if deficient —> Scurvy)
4. Glycosylation of some of the Hyl residues
5. formation of intra- and interchain disulfide bonds
6. folding of the triple helix
7. Secretion of Pro-Collagen from Golgi into outside of cell

13. BIOSYNTHESIS OF COLLAGEN:
EXTRACELLULAR REACTIONS
▸ Cleavage of N & C terminal by Pro-collagen N-proteinase
and Pro-collagen C-proteinase to form collagen.
▸ The formed collagen will be mixed with other collagens
and non-collagenous components, and formation of
covalent cross-links
▸ Cross-linking between collagen molecules involves
catalyzed by Lysyl Oxidase, this enzyme requires Copper
as a co-factor

14. BIOSYNTHESIS OF COLLAGEN

15. BIOSYNTHESIS OF COLLAGEN

16. BIOSYNTHESIS OF COLLAGEN

17. COLLAGEN FAMILY
▸ The ones in
bold are
present in the
skin

18. ▸ Type I collagens
▸ is the major component of the fibrils for approximately 80%of the
total collagens of adult human dermis
▸ Two identical α chains, α1 (I) and a third chain, called α2 (I)
▸ Type III collagens
▸ Form 10% of the total collagens in the adult human dermis
▸ It is composed of three identical α1 (III) chains
▸ During embryonic development and wound repair, the content of
collagen III is higher
IMPORTANT COLLAGEN TYPES

19. ▸ Type V collagens
▸ In dermis, type V collagens is associated with major
collagens fibers consisting of type I and III collagens
▸ Mutations in type V collagens genes in patients with
classical autosomal dominant forms (types I and
II) of Ehlers–Danlos syndrome
IMPORTANT COLLAGEN TYPES

20. IMPORTANT COLLAGEN TYPES
▸ Type IV Collagen
▸ is a typical component of basement membranes
▸ Type VI Collagen
▸ forms specific microfibrils in the dermis
▸ Type VII Collagen
▸ forms the anchoring fibrils of the dermal–epidermal
junction

21. IMPORTANT COLLAGEN TYPES
▸ Type XVII Collagen
▸ Also known as Bullous Pemphigoid Antigen 2
▸ It is a transmembrane collagen
▸ Component of the anchoring filaments that bind the
basal keratinocytes to the lamina densa (basement
membrane proper).

22. PRODUCTION OF COLLAGEN
▸ Most collagens in the skin are products of dermal fibroblasts.
Exceptions include:
▸ Collagen XVII
▸ a surface component of epidermal keratinocytes
▸ Collagen VII
▸ which can be synthesized by both Keratinocytes and fibroblasts
▸ Collagens VIII and XVIII
▸ which are produced by endothelial cells

23. COMPONENTS OF THE ECM: ELASTIC
FIBERS
▸ The elasticity of many tissues, including the skin,
depends upon the structure of elastic fibers.
▸ They can be stretched many times (by 100% or more) and
still return to their original form.
▸ The concentration of elastic fibers is highest in the aorta
and arterial blood vessels and in the lungs
▸ The main components of elastic fibers are ELASTIN and
MICROFIBRILS

24. COMPONENTS OF THE ECM: ELASTIC
FIBERS
▸ Forms 1%–2% of the total dry weight of dermis
▸ Lysyl oxidase, the same copper-dependent enzyme that
catalyzes collagen cross-linking, catalyzes the formation
of desmosine cross-links between elastin molecules,
which account for both the elasticity and insolubility of
elastic fibers.

25. COMPONENTS OF THE ECM: ELASTIC
FIBERS
▸ They insert into the basement membrane in a
perpendicular orientation and extend into the papillary
dermis
▸ Microfibrils consist mainly of fibrillins, but they also
contain and associate with other proteins

26. COMPONENTS OF THE ECM: THE EXTRA-
FIBRILLAR MATRIX
▸ It contains a number of proteoglycans and glycoproteins as well as
hyaluronic acid and water
▸ The functions of the extra-fibrillar matrix are adapted to the biologic
needs of each tissue
▸ GAGs are polysaccharides composed of sulfated and acetylated
sugars with negative charges that can bind large amounts of ions
and water
▸ The most prominent and ubiquitous protein-free GAG is
hyaluronic acid
▸ Proteoglycans comprise both a core protein and covalently linked
linear carbohydrate chains known as GAGs.

27. TEXT

28. TEXT
COMPONENTS OF THE ECM: THE EXTRA-
FIBRILLAR MATRIX
▸ Proteoglycans:
▸ Versican is the most important proteoglycan in the
dermis.
▸ It is associated with the elastic fiber system and
forms huge complexes with hyaluronic acid, which
provide the skin with its tautness
▸ Versican can be synthesized by fibroblasts, smooth
muscle cells and epithelial cells.

29. DISEASES RELATED TO DEFECTS
IN ECM

30. EHLERS-DANLOS SYNDROME
▸ A group of genetic connective tissue diseases
▸ There can be cutaneous and extra-cutaneous
involvement
▸ The classic type of EDS (Types I and II) mainly (50%)
caused by COL5A1 and COL5A2 mutations of collagen V
▸ Defects in COL3A1 gene encoding collagen III causes the
vascular type of EDS (Also called type IV)

32. MENKES SYNDROME
▸ Also called Kinky Hair Syndrome

33. CUTIS LAXA
▸ Characterized by genetic heterogeneity and clinical
variability.
▸ In all cases, the primary diagnostic feature is: loose, hyper
extensible skin
▸ “Too large skin” appearance and premature aging
▸ Extra-cutaneous manifestations:
▸ Pulmonary emphysema, bladder diverticula and
pulmonary artery stenosis

34. CUTIS LAXA

35. EPIDERMOLYSIS BULLOSA
▸ Diverse group of hereditary diseases characterized by mechanical
fragility of the skin that results in cutaneous blister formation
▸ Mutations in the collagen VII gene (COL7A1) cause both dominant
and recessive forms of dystrophic EB
▸ cleavage occurs in the uppermost dermis (just below the lamina
densa)
▸ Mutations in the collagen XVII gene (COL17A1) can cause junctional
EB
▸ cleavage within the lamina lucida of the epidermal basement
membrane

36. EPIDERMOLYSIS BULLOSA

37. MARFAN SYNDROME
▸ Caused by Fibrillin -1 mutation (Fibrillin-1 is a component
of microfibrils)
▸ An autosomal dominant disorder
▸ Connective tissue weakness of the: skin, skeletal, ocular
and cardiovascular Systems
▸ The main cutaneous manifestations: striae and elastosis
perforans serpiginosa

38. MARFAN SYNDROME

41. DISEASES RELATED TO
AUTOIMMUNE PHENOMENA

43. SYSTEMIC SCLEROSIS (SCLERODERMA)
▸ ANA, anti-Centomere, topoisomerase I, and anti-fibrillin
I
▸ Characterized by symmetric hardening of the skin of the
fingers, hands and face that may generalize
▸ Raynaud phenomenon is common and digital ulcers may
develop
▸ Internal organ involvement is frequent and affects the
lungs, gastrointestinal tract, heart and kidneys

45. LICHEN SCLEROSIS
▸ Most commonly affects female or male genitalia, less
often extra-genital skin, no systemic manifestations
▸ May cause scarring of the vaginal introitus or phimosis
▸ Severe pruritus may occur
▸ Autoantibodies against extracellular matrix protein 1
(ECM-1)
▸ The extracellular matrix-1 (ECM-1) protein is mutated in
patients with lipoid proteinosis

47. LICHEN SCLEROSIS
▸ On the lower back

48. MCQS
1. What is the most abundant amino acid in collagen’s
structure?
A. Lysine
B. Proline
C. Glycine
D. Valine

49. MCQS
2. Which of these collagens is not present in the skin ?
A. I
B. II
C. III
D. IV

50. MCQS
3. Autoantibodies targeting Fibrillin I lead to?
A. Marfan syndrome
B. Scleroderma
C. Goodpasture Syndrome
D. Lichen Sclerosis

51. MCQS
4. Dystrophic EB involves a defect in which of the
following?
A. collagen VII
B. Collagen VIII
C. Collagen XVII
D. Collagen XVI

52. MCQS
5. Classical Ehlers Danlos syndrome involves a defect in
which of the following?
A. Collagen II
B. Fibrillin I
C. Collagen Type V
D. Elastin

53. MCQS
6. Which of the following enzymes requires Vit C as a
cofactor?
A. prolyl-4-hydroxylase
B. Procollagen N-proteinas
C. Lysyl oxidase
D. Galactosyl transferase

54. ▸ Thank You