BIOCHEMISTRY OF CARTILAGE

1. BIOCHEMISTRY OF CARTILAGE

2. DEFINITION Specialized form of connective tissuewith firm consistency of extra-cellular matrix, allow the tissue to bear mechanical stresseswithout permanent distortion and Support soft tissues. Sliding areas for joints to facilitate movement Provides a model for the formation of most of the bones in the body.

3. TYPES OF CARTILAGES HUMAN BODY HAS THREE TYPES OF CARTILAGES Hyaline Cartilage articularcartilage larynx rib and costal cartilage nasal septum Elastic Cartilage epiglottis Fibrocartilage Intervertebraldisk meniscus

8. The extracellular space in animal tissues is filled with a gel-like material, the extracellular matrix, also called ground substance, which holds the cells of a tissue together and provides a porous pathway for the diffusion of nutrients and oxygen to individual cells.

9. Epithelial cells extra-cellularmatrix Underlying cells

10. The extracellular matrix is composed of an interlocking meshwork of heteropolysaccharides and fibrous proteins.

11. Heteropolysaccharides in the body are the glycosaminoglycans (GAGs). These molecules are long unbranched polysaccharides containing a repeating disaccharide unit.

12. The disaccharide units contain either of two modified sugars, called amino sugars N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc), and an acidic sugar uronic acid such as glucuronic acid or iduronic acid.

13. GAGs are highly negatively charged molecules, with extended conformation that imparts high viscosity to the solution. GAGs are located primarily on the surface of cells or in the extracellular matrix (ECM).

14. Structure of Glycosaminoglycans GAGs in the body are linked to core proteins ( except hyaluronic acid), forming proteoglycans (also called mucopolysaccharides).

15. CHONDROCYTES Cells that synthesize and secrete Extracellular Matrix The cells are located in matrix cavity called Lacunae

16. CHONDROCYTES

17. EXTRACELLULAR MATRIX (25%) Fibers Collagen (II) Elastin fibrillin Ground substances Proteoglycan (Aggregan) Glycoprotein

18. The chains are linear (unbranched) They are linked to the protein core via a serine or threonine (O-linked) (except HA) forming Proteoglycan. Negative charge due to OH, COOH, and SO4, PG are hydrophillic and act as polyanion attract +ions (K and Na) Highly solvated and viscous.

19. FIBRES CREATES A FRAMEWORK THAT HOUSES THE OTHER COMPONENTS OF CARTILAGE

22. GROUNDSUBSTANCE Highly hydrated complex of mixture of proteoglycans and glycoproteins Proteoglycans are linear polysaccharides of repeating disaccharide units composed of hexosamine & uronic acid Glucosamine/Galactosamine Glucoronic acid/Iduronic acid

23. Linkage The linkage of GAGs to the protein core involves a specific trisaccharide composed of two galactose residues and a xylose residue (Gal-Gal-Xyl-O-CH2-protein).

27. PROTEOGLYCAN: PROTEIN WITH BOUND SIDE CHAINS (GLYCOSAMINOGLYCANS

28. HETERO POLYSACCHARIDES (GAG) OF THE EXTRA-CELLULAR MATRIX Hyaluronic acid - glassy and translucent lubricants in joints, cartilage, and tendons hyaluronidase in pathogenic bacteria and sperm

29. Hyaluronic acid (D-glucuronate + GlcNAc)

30. 2) Chondroitin sulfate(D-glucuronate + GalNAc sulfate)It is the most abundant GAG. cartilage, tendon, ligament, and walls of the aorta

31. Dermatan sulfate (L-iduronate + GlcNAc sulfate) Occurence : skin, blood vessels, heart valves

32. Heparin - natural anticoagulant made in mast cells bind antithrombin, then bind and inhibit thrombin

33. Keratan sulfate ( Gal + GlcNAc sulfate) Occurence : cornea, bone, cartilage ; Keratan sulfates are often aggregated with chondroitin sulfates.

34. Structure of proteoglycans The GAGs extend perpendicular from the core protein in a bottlebrush- like structure. The linkage of GAGs to the protein core involves a specific trisaccharide .The protein cores of proteoglycans are rich in Ser and Thr residues which allows multiple GAG attachment.

37. Much of the compressive strength of cartilage is derived from the glycosaminoglycan molecules in the extracellular matrix. • These molecules have abundant carboxyl and sulfate groups that are negatively charged under physiologic conditions

39. PROTEOGLYCAN FUNCTIONS Modulation of cell growth processes Binding of growth factor proteins by proteoglycans in the glycocalyx provides a reservoir of growth factors at the cell surface. Cushioning in joints Cartilage matrix proteoglycans absorb large amounts of water. During joint movement, cartilage is compressed, expelling water!

40. Some Functions of Glycosaminoglycans and Proteoglycans • Act as structural components of the ECM Have specific interactions with collagen, elastin, fibronectin, laminin, and other proteins such as growth factors • As polyanions, bind polycations and cations • Contribute to the characteristic turgor of various tissues • Act as sieves in the ECM Facilitate cell migration (HA)

41. Have role in compressibility of cartilage in weight-bearing (HA, CS) • Play role in corneal transparency (KS I and DS) • Have structural role in sclera (DS) • Act as anticoagulant (heparin) • Are components of plasma membranes, where they may act as receptors and participate in cell adhesion and cell-cell interactions (eg, HS) • Determine charge-selectiveness of renal glomerulus (HS) • Are components of synaptic and other vesicles (eg, HS)

42. When glycosaminoglycans are lost from the cartilage matrix, as occurs in trauma or osteoarthritis, the mechanical stiffness of the tissue is dramatically reduced, and the functional integrity of the cartilage is compromised. .

43. Maintaining and restoring glycosaminoglycans in adequate concentrations in the extracellular matrix are therefore important targets for therapeutic interventions. Understanding the loss and replenishment of glycosaminoglycans is potentially important in determining the correct diagnosis early, monitoring the disease, and selecting treatments