Biology of the ExtraCellular Matrix - Functions of the ECM, Components of the ECM, Diseases Related to Defects in ECM

Definitions
Functions of the ECM
Components of the ECM
Diseases Related to Defects in ECM
Diseases Related to Autoimmune Phenomena

1. Biology of the ExtraCellular 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 Transcription of collagen α chain genes by mRNA Translation of mRNA to polypeptide chain 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) Glycosylation of some of the Hyl residues formation of intra- and interchain disulfide bonds folding of the triple helix 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 K eratinocytes 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 P roteoglycans 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)

31. Menkes Syndrome Also called Kinky Hair Syndrome

32. 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

33. Cutis laxa

34. 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

35. Epidermolysis Bullosa

36. 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

37. Marfan syndrome

38. Diseases Related to Autoimmune Phenomena

39. 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

40. 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

41. Lichen Sclerosis On the lower back

42. MCQs What is the most abundant amino acid in collagen’s structure? Lysine Proline Glycine Valine

43. MCQs Which of these collagens is not present in the skin ? I II III IV

44. MCQs Autoantibodies targeting Fibrillin I lead to? Marfan syndrome Scleroderma Goodpasture Syndrome Lichen Sclerosis

45. MCQs Dystrophic EB involves a defect in which of the following? collagen VII Collagen VIII Collagen XVII Collagen XVI

46. MCQs Classical Ehlers Danlos syndrome involves a defect in which of the following? Collagen II Fibrillin I Collagen Type V Elastin

47. MCQs Which of the following enzymes requires Vit C as a cofactor? prolyl-4-hydroxylase Procollagen N-proteinas Lysyl oxidase Galactosyl transferase

48. Thank You