Collagen Synthesis & Defects PDF

Collagen Synthesis & its defects By: Dr. Moustafa Al Sawy Dr. Shaimaa Mohamed Amer MBBCH, M.SC. M.D HISTOLOGY MBBCH, M.SC. M.D HISTOLOGY Associate Professor of Histology & Cell Bio...

Collagen Synthesis & its defects By: Dr. Moustafa Al Sawy Dr. Shaimaa Mohamed Amer MBBCH, M.SC. M.D HISTOLOGY MBBCH, M.SC. M.D HISTOLOGY Associate Professor of Histology & Cell Biology Associate Professor of Histology & Cell Biology Certified Medical Educator Learning objectives Knowledge: Learning Objectives At the end of the lecture , each student will be able to: 1.Discuss collagen biosynthesis & its defect. 2. Mention different types of collagen.  Types of Collagen Collagen is the most abundant protein in the body. It enters in the structure of our hair, skin, nails, bones, ligaments and tendons. Collagen is a protein made up of a group of amino-acids as glycine, proline, hydroxyproline. It is secreted mainly by fibroblast. There are about 46 types collagen that numbered in the order from 1 to 46.  Synthesis of collagen Many cells are responsible for collagen synthesis; 1.Fibroblast, chondroblast, osteoblast , odontoblast produce collagen type I. 2.Chondroblast also form collagen type II 3.Smooth muscle, reticular cells, Schwann cells, hepatocytes form type III. 4.Endothelial, epithelial cells, muscle cells, Schwann cells form type IV. *Collagen contains two characteristic amino acids: Hydroxyproline Hydroxylysine  Synthesis of Collagen (Inside the cell) 1.Messenger RNA (mRNA) is synthesized from a template of DNA in the fibroblast nucleus. 2.mRNA molecules enter the cytoplasm and attach to ribosomes of the rER. 3.Translation of mRNA in rough endoplasmic reticulum produces an amino acid sequence preprocollagen. 4.The preprocollagen is released into the lumen of the RER and Modified to pro-alpha chains.  Collagen Biosynthesis 5. Hydroxylation of proline and lysine of polypeptide chains occurs. This step requires vitamin C as a cofactor. 6.Glycosylation (addition of sugar) of hydroxylysine residues occurs. 7.Formation of procollagen: Three polypeptide chains around one another to from a triple helix. 8. Procollagen is transported into the Golgi apparatus, where it is packaged and secreted by exocytosis.  Synthesis of Collagen (Outside the cell) 1.Cleavage: Procollagen peptidases remove the registration peptides & transform soluble procollagen into insoluble tropocollagen (collagen molecule). 2.Assembly : Tropocollagen aggregates to form collagen fibrils.  Synthesis of Collagen (Outside the cell) In collagen I the fibrils form fibers that form bundles. It is the most abundant & present in bones, dentin, tendons, dermis. In collagen II occurs as fibrils only. In collagen III, the fibrils form fibers (not form bundles).  Shape of Collagen By EM, collagen fibers display cross-banding at regular intervals of 67 nm. These fibers are formed from parallel aggregates of thinner fibrils. The fibrils themselves are fashioned from a highly regular subunits called tropocollagen molecules, each about 300 nm long and 1.5 nm in diameter. Individual tropocollagen molecules are composed of three polypeptide chains, called α-chains, wrapped around each other in a triple helical configuration. Each α-chain possesses about 1000 amino acid residues. Every third amino acid is glycine and most of the remaining amino acids are composed of proline, hydroxyproline, and hydroxylysine. Triple helix (3polypeptide α- chains)  Examples of clinical disorders resulting from defects in collagen synthesis Disorder Defect Symptoms Ehlers-Danlos type IV Faulty transcription or translation of Aortic and/or intestinal rupture collagen type III Ehlers-Danlos type VI Faulty lysine hydroxylation Augmented skin elasticity, rupture of eyeball Ehlers-Danlos type VII Decrease in procollagen peptidase Increased articular mobility, frequent activity luxation Scurvy Lack of vitamin C (cofactor for Ulceration of gums, hemorrhages prolyl hydroxylase) Osteogenesis imperfecta Change of one nucleotide in genes Spontaneous fractures, cardiac for collagen type I insufficiency  Osteogenesis Imperfecta (Brittle Bone Disease) *Symptoms of osteogenesis imperfecta include: Easily broken bones Bone deformities, such as bowing of the legs Discoloration of the white of the eye (sclera), may be blue or gray in color. A barrel-shaped chest A curved spine A triangle-shaped face Loose joints Muscle weakness Skin that easily bruises Hearing loss in early adulthood Soft, discolored teeth.  Ehlers-Danlos syndrome *There are several types of EDS that may share some symptoms. *These include: 1.An increased range of joint movement (joint hypermobility). 2. Stretchy skin. 3. Fragile skin that breaks or bruises easily. Ehlers Danlos Syndrome  Medical Application ▪Keloid, also known as keloidal scar, is the formation of scar composed mainly of type III (early) then type I (late) collagen. ▪It is a result of an overgrowth of granulation tissue (collagen III) at the site of a healed skin injury which is then slowly replaced by collagen type 1. ▪Keloids occur most often in individuals of African descent and can be a difficult clinical problem to manage. ▪It causes skin disfiguring, and its excision is always followed by recurrence.  Case Scenario A 5-year-old boy is brought to the physician by his parents for evaluation of easy bruising. He has met all developmental milestones. Vital signs are within normal limits. He is at the 50th percentile for height and weight. Physical examination shows velvety, fragile skin that can be stretched further than normal and multiple ecchymoses. Joint range of motion is increased. A defect in which of the following is the most likely cause of this patient's condition? A. α-collagen triple helix formation B. α1-antitrypsin production C. Fibrillin-1 glycoprotein production D. Proline and lysine hydroxylation Any Questions?  References: 1.Basic Histology: Text & Atlas. Editor: Luiz Carlos Junqueira, MD, PhD; Jose Carneiro, MD, PhD. 14th Ed. 2. Wheatear’s functional histology: A text & color atlas.15th Ed.