COLLAGEN a fibrous protein, like elastin elastin is rich in glycine, proline, and alanine collagen is the most abundant protein in mammals, approx 30% of total body prot both found in skin, CT, BV's, scler and cornea of eye the major fibrous component of CT (connective tissue) collagen may be dispersed as a gel (vitreous humor) or bundled paralell (tendon) in the cornea collagen is stacked to transmit light w/o scattering bone collagen fibers are angled to each other TYPES 20+ types types of collagen distinguished by different amino acid chains used: alpha 1, 2, 13, etc. types I, II, III are fibrillar, rope-like, linear type I collagen in skin, bone, tendon has greatest tensile strength, 80% more than type III type II more cartilaginous type III more distensible, found in BVs, early scar tissue types IV and VII form 3D mesh, are major part of basement membranes types IX and XII bind to sfc of collagen fibrils, linking them to each other and more STRUCTURE prevalent aminos: glycine (1/3), proline approximately half of the collagen sequence is not glycine, proline or hydroxyproline proline or hydroxyproline constitute about 1/6 of the total sequence proline facilitates helical formation because it causes kinks in the chain usual sequence is GLY - X - Y where X is usu proline and Y is often hydroxyproline or hydroxylysine thus (GLY - PRO - HYP - ) x 333 = one chain chain: structural components approx 1,000 aminos long a triple helix (L handed, unlike DNA) of cross-linked alpha chains helix held together by hydrogen bonding among amino acids some amino acid side chains on surface to allow binding with neighboring monomers-->long fiber hydroxyproline and hydroyxline not seen in most prots made by hydroxylation of proline and lysine after their incorporation into the polypeptide hydroxyl group of hydroxylysine may be enzymatically glycosylated often gluc & galact attached before triple helix formation (does this happen more with high serum glucose levels?) MANUFACTURE OF COLLAGEN protein chains assembled in nucleus of fibroblasts, osteoblasts, chondroblasts delivered to rough endoplasmic reticulum for cleavage, hydroxylation enzymes: prolyl oxidase and lysyl hydroxylase (requires oxygen and vitamin C) after hydroxylation is glycosylation disulfide bonds on C-terminal extensions line up chains for twisting you then have procollagen procollagen exported from cell via Golgi apparatus-->secretory vesicles-->release into ECM after export procollagen is cleaved by N- and C-procollagen peptidases now have triple-helical tropocollagen molecules which spontaneously associate to form fibrils a regular staggered but parallel pattern fibrillar array is substrate for LYSYL OXIDASE (contains copper) this enzyme oxidatively deaminates some lysyl and hydroxylysyl residues aldehydes resulting are reactive and condense with lysyl or hydroxylysyl residues in neighbors forming covalent cross-links-->mature collagen DEGRADATION OF COLLAGEN very stable molecule, half life is years breakdown depends on collagenases type I collagen has specific cleavage site WOUND REPAIR BY FIBROSIS occurs when injury is severe or persistent tissue in 3rd deg burn cannot be restored to normal dt loss of skin, BM, CT structure WOUND HEALING BY FIRST INTENTION day 1: fibrin clot, neuts come in to liquefy injuried tissue, increased mitotic activity of basal cells in squamous epithelium around wound margines day 2: squamous cells from neighboring basal cell layer migrate under the fibrin clot and seal off the wound after 48 hours, macrophages come in day 3: granulation tissue begins to form. Initial deposition of type III collage begins but does not bridge incision site. macrophages replace neutrophils. days 4-6: granulation tissue formation peaks, collagen bridges incision site week 2: collagen compresses BV's in fibrous tissue, reducing blood flow, tensile str = 10% month 1: collagenase (Zn cofactor) remodeling of wound occurs with replacement of type III collagen by type I. Tensile strength increases. Scar tissue is devoid of adnexal structures (hair, glands) and inflammatory cells SECOND INTENTION different healing more intense inflammatory rxn increased granulation tissue formation wound contraction caused by increased numbers of myofibroblasts PATHOLOGIES OF COLLAGEN FORMATION SCURVY vitamin C (ascorbic acid) deficiency lysyl-oxidase is the enzyme that crosslinks collagen strands vitamin C-->hydroxylation of proline and lysine in initial collagen synthesis by fibroblasts sites of hydroxylation are anchor sites for cross links between triple helix of alpha chains collagen is weak gums bleed, poor wound healing EHLERS-DANLOS SYNDROME a group of mendelian disorders defects in type I and III fibrillar collagen synthesis/structure enzymes that may be deficient incl: lysyl hydroxylase, procollagen peptidase also can result from mutations of aa sequences in types I, III, or V (III most imp) mutant collagen is not secreted and accumulates in fibroblast arteries are weakened Sx: hypermobile joints, ecchymoses, poor wound healing, hyperelasticity of skin aortic dissection is mc cause of death ...now I understand why some of those circus performers can do the stuff they can do. OSTEOGENESIS IMPERFECTA aka brittle bone syndrome bones esaily bend and fracture delayed wound healing rotated and twisted spine, humpback common type I OI is osteogenesis imperfecta tarda presents in early infancy wiht fractures dt minor trauma may have prenatal bowing or fractures type II OI is osteogenesis imperfecta congenita more severe, pts die of pulmonary hypoplasia in uteria or during neonatal period KELOID bulky overformed scars excess type III collagen formation common in African Americans may occur dt 3rd degree burns microscopic: irreg, thick collagen bundles extending beyond border of injury SYSTEMIC SCLEROSIS (see ch3) mc cause of death is lung dz excessive collagen production dt auto-immune rxn mostly in skin but also GI (esophagus), lungs, kidneys women of childbearing age small vessel EC damage-->BV fibrosis and ischemic injury T-cells release cytokines-->excessive collagen synthesis Sx: Raynaud's is 1st sign, skin atrophy and tissue swelling begins in fingers and extends proximally, parchment-like appearance, extensive dystrophic calcifications in subcu, tightened facial features, dysphagia for solids and liquids (bottom 2/3 of esph smooth m replaced by collagen), small bowel looses villi-->malabsorption, wide-mouthed diverticuli-->bacterial overgrowth, interstitial fibrosis of lungs, renal vasculitis of arterioles and glomeruli (hyperplastic arteriolosclerosis), infarctions, malignant HTN LABS: serum ANA+ 70-90%, anti-topoisomerase Ab+ in 15-40% CREST syndrome: calcific, centomere ab, raynauds, esoph dysmot, sclerodactyly, telangiectasias crest shows anti-centomere ab's in 30% IDIOPATHIC PULMONARY FIBROSIS ~15% of cases of chronic interstitial lung dz more common in males usu over 40 years, up to 70 repeated cycles of alveolitis triggered by unknown agent release of cytokines-->interstitial fibrosis-->proximal dilation of small airways honeycomb appearing lung tissue NOT COLLAGEN PATHOLOGY MARFAN SYNDROME autosomal dominant weakness of elastic tissue defect in fibrillin = component of elastic tissue fibrillin is a leukocyte adhesion molecule (integrins and selectins are made of it) ocular: dislocated lens twisted humped spine much like OI aortic dissection SOURCES Rapid Review Pathology, Goljan Wikipedia Biochemistry; Lippincott's Illustrated Reviews