Loco Med & Quiz PDF

Define Cartilage  A specialized form of connective tissue in which the extracellular matrix has a firm consistency that allows the tissue to bear mechanical stress without permanent distortion. Perichondrium  Dense connective tissue (that surrounds most of cartilage) which contains...

Define Cartilage  A specialized form of connective tissue in which the extracellular matrix has a firm consistency that allows the tissue to bear mechanical stress without permanent distortion. Perichondrium  Dense connective tissue (that surrounds most of cartilage) which contains rich blood supply for the nutrition of cartilage. Proteoglycans (of cartilage)  They are aggregates formed of Proteoglycans containing chondroitin-4-sulphate, chondroitin-6-sulphate and keratan sulphate (GAGs), linked to a protein core. COMPLETE 1. Cartilage tissue is derived from mesenchyme. 2. the cavities around chondrocytes are called lacunae. 3. Hyaline cartilage has collagen II → Basophilic. 4. Fibrocartilage matrix is acidophilic while hyaline and elastic’s are basophilic. 5. Elastic cartilage has collagen II + elastic fibers → Basophilic. 6. Fibrocartilage has collagen I → Acidophilic. 7. When chondroblasts become mature and imprisoned inside lacunae, they are called chondrocytes. 8. Collagen II fibrils form 40% of the dry weight of the matrix. Perfecto | 1 Ultra short questions 1. Mention the most important characters of cartilage  Avascular  No nerves  No lymphatic vessels 2. Enumerate functions of cartilage 1. Supports soft tissue (respiratory system). 2. Shock absorbing because it has a smooth surface and resilience. 3. Facilitates movements of joints. 4. Essential for development and growth of long bones. 3. What are the components of cartilage 1. Cells: 2. Extracellular matrix:  Chondroblast  Fibers  Chondrocyte  Ground substance 4. Enumerate types of cartilage - Hyaline cartilage 2. Elastic cartilage 3. Fibrocartilage 6. What are the components of ground substance of cartilage  Proteoglycans (chondroitin sulphate & keratan sulphate).  Hyaluronic acid.  Glycoprotein (Chondronectin). 7. "Cartilage is Avascular" Mention how cartilage gets its nutrition?  By diffusion from blood vessels in the surrounding connective tissue (perichondrium).  Synovial fluid in joint cavities (the articular cartilage is devoid of perichondrium). Perfecto | 2 9. Enumerate sites of hyaline cartilage 1. Fetal skeleton 3. Articular cartilage 4. Costal cartilage 2. Epiphyseal plate 5. Wall of large airways (nose, larynx, trachea, and bronchi) Mnemonics 10. Mention the structures of hyaline cartilage 1. Perichondrium 2. Cartilage cells:  Chondrocytes  Chondroblasts 3. Matrix:  Collagen type II fibrils  Proteoglycans & Glycoproteins 11. Describe Perichondrium and mention its layers  Dense connective tissue rich in blood vessels that covers hyaline cartilage (except at the articular cartilage of joints).  Perichondrium can be divided into: a) Outer fibrous layer of collagen type I fibers and fibroblasts, blood vessels. b) Inner cellular (chondrogenic) layer that contains chondroblasts. 13. Why collagen type ll fibrils can't be seen by LM  Because it has the same refractive index of the matrix. 14. Enumerate sites of elastic cartilage. 1. Ear pinna 2. External auditory canal 3. Eustachian tube 4. Epiglottis + Some cartilages of the larynx Perfecto | 3  15. How does elastic cartilage differ from hyaline cartilage  The matrix contains abundant network of elastic fibers (+ collagen II).  The elastic cartilage is yellow in color due to presence of elastic fibers (Elastin).  The elastic fibers make it less susceptible to degenerative damage. 16. Enumerate sites of Fibrocartilage. 1. Intervertebral discs 2. Symphysis pubis Remember  Fibrocartilage contains collagen There are other examples of fibrocartilage, some type I, while hyaline and elastic of which will be mentioned later: contain type II.  Menisci  Chondronectin (glycoprotein)  Glenoid labrum adheres chondrocytes to matrix  Acetabular labrum collagen 17. Describe the structure of Fibrocartilage It is a tissue intermediate between dense CT and hyaline cartilage.  Perichondrium: Not found  Ground substance: little in amount.  Matrix: Collagen I (acidophilic) between chondrocytes which are present in rows. 10. Describe the two ways of cartilage growth Interstitial growth:  Expansion of the cartilage from within by dividing the chondrocytes.  Increase in their number and synthesis of more collagen fibrils and ground substance. Increasing in Length Appositional growth:  Addition of new cartilage from outside by proliferation of chondroblasts at the surface of cartilage. Increasing in width. Perfecto | 4 11. Mention the site and components of intervertebral discs  Present between the bodies of two adjacent vertebrae and acts as a lubricant cushion.  Formed of 2 components: a) Annulus fibrosus: laminae of fibrocartilage surrounded externally by dense connective tissue. b) Nucleus pulposus: in the center of annulus fibrosus. It consists of few cells embedded in viscous fluid rich in hyaluronic acid and collagen type II. Compare Chondroblast Chondrocyte Shape Oval or spindle-shaped Oval to rounded (appear irregular because they shrink during preparation) LM Cytoplasm Basophilic Basophilic Nucleus Pale Deeply stained ,Central & Rounded Inner aspect of Deeper in the cartilage inside lacunae Location perichondrium In groups of up to 8 cells called isogenous groups (cell nests) Protein secreting cells: Protein synthesizing cells: Abundant RER Abundant RER Prominent Golgi EM Prominent Golgi Many mitochondria Many mitochondria The surface shows indentations and Extended chromatin protrusions increasing the surface area for exchange with the extracellular matrix. Synthesis of fibers and Function proteins of the matrix Synthesis of the matrix components Perfecto | 5  Hyaline cartilage Elastic cartilage Fibrocartilage Color Bluish white Yellow White Costal cartilage Ear pinna Articular surface External ear Intervertebral disc Sites Epiphyseal plate Eustachian tube Symphysis pubis Fetal skeleton Epiglottis Upper respiratory tract Present Perichondrium (except at articular cartilage) Present Absent Matrix Basophilic Basophilic Acidophilic Fibers Type II Type II + elastic fibers Type I Ground Substance Abundant More abundant Little Cells Chondroblast& Chondrocyte Chondroblast& Chondrocyte Chondrocyte ‫ بس زود أنه‬cartilage is Avascular structure ‫ اول حاجه المعلومه اللى كلنا عارفينها أن‬-. ‫ بتعدى فيه‬lymphatics ‫ وال‬nerves ‫كمان وال فيه‬ ‫ كان فيه اى نوع من ال‬cartilage ‫ ركزت قوى عن كل نوع من‬structure ‫ بعد كده أما دخلت فى‬- ‫ ونبهت عليها أن‬collagen )the most common type of cartilage( ‫ نعرف أنه‬.‫ مهم‬Hyaline ‫لما وصلنا ل‬ - articular surface ‫ هنا محاوط كله عدا‬perichondrium ‫واعرف ان‬ - ‫ ركز ع النوع‬type one collagen ‫ مهمه وان الطبقة الخارجيه فيها‬perichondrium ‫نعرف برضو طبقات ال‬ - - Chondroblast of hyaline cartilage is basophilic mainly due to abundant RER - Nucleus of chondroblast present in a peripheral position while Nucleus of Chondrocyte present in the center - Chondrocyte basophilia is less than Chondroblast basophilia cell nest ‫ وكمان ال‬lacunae ‫ركز على‬ - ‫ عنه‬hyaline more basophilic ‫ بس ال‬basophilic cytoplasm ‫ هو كمان‬elastic ‫واصال كمان قالت إن اه‬ - growth ‫فرقت بين نوعين ال‬ - ‫ عنها‬.‫ والمسئول‬width ‫ بزود‬appositional ‫ أما ال‬chondrocyte ‫ بزود طول والمسئول عنه ال‬interstitial ‫زود‬ - ‫ من فوق‬surface ‫ ألنها ع‬chondroblasts ‫ بس الدكتورة قالت إن‬cartilaginous ‫ وجزء‬bony ‫ جزء منها‬auditory tube ‫ أن ال‬ENT ‫كنا واخدين ف‬ - elastic cartilage ‫ االتنين فيهم‬internal &external perichondrium ‫ وركز أنه مش حوالينه‬inter vertebral disc ‫ قالت اشهر مثال‬fibrocartilage ‫اما وصلنا لل‬ - acidophilic cytoplasm ‫ فى التالته انواع وبرضو الوحيد اللى عنده‬type one ‫ركز برضو أنه الوحيد اللى بيحتوى على‬ anulus fibrosis ‫ ده موجود بس فى‬fibrocartilage ‫ أنه ال‬intervertebral disc ‫واألهم بقى فى تركيب‬ - ‫ &هيالورونيك اسيد لزوم انها‬viscous fluid‫ وشويه خاليا و‬fibers ‫ فيها‬matrix ‫ ما هو إال‬nucleus pulposus ‫اما‬ Perfecto - |6 ‫ يعنى‬cushion ‫تشتغل ك‬ Define Bone  A specialized supporting vascular type of connective tissue which is mesenchymal in origin and is one of the hardest tissues in the human body. Periosteum  Dense connective tissue that covers all bones externally. Sharpey’s fibers Endosteum bundles of collagen fibers which connect periosteum to bone  Thin membrane that lines all bones internally. Volkmann's canals  Communicating canals that connect Haversian canals with each other, with periosteum and with marrow cavities.  They are lined by endosteum and contains nerves and blood vessels. Ruffled border  Deep enfolding of the cell membrane of the surface of osteoclasts facing the bone. Clear zone (of osteoclasts)  A smooth ring-shaped area in osteoclasts surrounding the ruffled border. Its cytoplasm contains actin filaments which are arranged perpendicular to the cell membrane. Complete Function of clear zone 1. Bone is mesenchymal in origin. It holds osteoclasts to the bony surface 2. Matrix of bone is acidophilic. 3. Osteogenic cell, osteoblasts, osteocyte are bone forming cells, while osteoclasts are bone destructing cells. Perfecto | 7 4. Once osteoblasts are surrounded by matrix, they become inactive flattened cells with less basophilic cytoplasm called osteocytes. 5. Osteocytes represent the mature cell of bone. 6. Cytoplasmic processes of adjacent osteocytes contact with each other inside the canaliculi by gap junctions. 7. Osteoclasts are located in shallow depression in the matrix called Howship's lacunae. 8. Region of vesicles and vacuoles It is present in the cytoplasm just deep to the ruffled border (between basal zone and ruffled border). 9. Region of vesicles and vacuoles contain numerous endocytotic vesicles, lysosomes and large vacuoles. 10. The whole complex of concentric lamellae of bone surrounding a canal containing blood vessels, nerves and loose connective tissue is called Osteon or Haversian system. 11. Compact bone is covered externally by periosteum and lined internally by endosteum. 12. Basal zone of Osteoclasts contains the nuclei of the cell and other cell organelles. 13. Haversian canal is surrounded by 4 to 20 concentric lamellae of bone tissue. 14. Amorphous material surrounding each Haversian system and consists of mineralized matrix and few collagen fibers is called cementing substance. 15. Each Haversian system is formed by successive deposition of lamellae, starting from the periphery, so that younger systems have larger (wider) canals. 16. Nitric acid 5% is used as a decalcifying solution to examine bone. Ultra short questions 1. Enumerate bone cells 1. Osteogenic (osteoprogenitor) 2. Osteoblast 3. Osteocyte 4. Osteoclast Perfecto | 8 2. Mention components of intercellular calcified matrix  Inorganic component (50% of bone dry weight) (Ca+2 & phosphate)  Organic component (50% of bone dry weight): 1. Collagen fibers (type 1) Matrix is acidophilic 2. Ground substance ‫ وَالسََّلَمَةَ مِنْ كُل‬، َ‫ وَعَزائِمَ مَغْفِرَ ِتك‬،َ‫اَللّٰهُمَّ إنَّا نَسْأَُلكَ مُوْجِبَاتِ رَحْمَ ِتك‬ ِ‫َالنجَاةَ مِنَ النَّار‬ َّ ‫ و‬، ِ‫ وَالْفَوْزَ بِالْجَنَّة‬، ٍّ‫ وَالْغَنِيْمَةَ مِنْ كُل بِر‬، ٍ‫إِثْم‬ 3. Mention the origin of each bone cell Cell Origin Osteogenic cell Mesenchymal cell Osteoblast Osteogenic cell Osteocyte Osteoblast Osteoclast Fusion of blood monocytes 4. Mention the site of bone cells Osteogenic (osteoprogenitor) - On bone surfaces within periosteum and endosteum. Osteoblast - On the surface of bone, side by side resembling the epithelium. Osteocyte - Within the calcified bony matrix in a space called lacuna. Osteoclast - In shallow depression in the matrix called Howship's lacunae. - They are present on the surfaces where bone resorption occurs. Perfecto | 9 5. Describe the Histological features of osteogenic cells L/M: Spindle-shaped cells with pale-stained nuclei and basophilic cytoplasm. E/M: The cytoplasm contains many mitochondria and free ribosomes and polyribosomes. 6. Enumerate functions of osteogenic cells When stimulated, they give rise to: 1. Stem cells of bone and cartilage.  Osteoblasts: regions that are richly vascularized 2. Self – renewal, so they are considered as a (↑O2 tension) stock for future needs such as growth  Chondroblasts: regions with poor blood supply and repair of bone. (↓O2 tension) 7. Mention the LM picture of osteoblasts  Cuboidal or columnar, with deeply basophilic cytoplasm that show pale stained area called (-ve Golgi image) & rounded, pale, and eccentric nucleus.  They have cytoplasmic processes connecting them together.  Once osteoblasts are surrounded by matrix, they become inactive flattened cells with less basophilic cytoplasm called osteocytes.  Lacunae and canaliculi appear because the matrix is condensed around the cells and their processes. 8. Mention the EM picture of Osteoblasts  Have the characters of protein synthesizing cells [containing many rER, mitochondria, prominent Golgi near the nucleus and nucleus with mostly extended chromatin]. 9. Enumerate functions of Osteoblasts in bone formation  Synthesis of organic components of bone matrix (osteoid) which include type 1 collagen, proteoglycans, and glycoproteins.  They have high alkaline phosphatase enzyme activity which precipitates calcium salts in the matrix. Perfecto | 10 10. Describe the LM picture of osteocyte They are oval, flattened and smaller than osteoblasts with less basophilic cytoplasm, darker nucleus and low alkaline phosphatase activity. They lie inside lacunae between lamellae of matrix. There is one osteocyte in each lacuna that sends its processes to extend inside thin, cylindrical spaces called canaliculi between adjacent lacunae. 11. Describe the EM picture of osteocyte  Less active than osteoblast, osteocyte has less rER, Golgi and a nucleus with more condensed chromatin.  Cytoplasmic processes of adjacent osteocytes contact with each other inside the canaliculi by gap junctions. 12. Mention the function of osteocyte  Maintenance of bone matrix Remember  There is only one osteocyte in each lacuna.  There can be up to 8 chondrocytes in each lacuna. Perfecto | 11  Osteoclast is a giant cell 14. Describe the LM picture of osteoclast They are large, branched, and motile cells They are multinucleated (5-50 nuclei). They have acidophilic cytoplasm. The surface facing the bone is irregular (ruffled or striated border). 16. Mention the EM picture of Osteoclasts (Enumerate regions (zones) of osteoclasts) 1. Ruffled border (RB) 3. Region of vesicles and vacuoles (V) 2. Clear zone (CZ) 4. Basal zone 17. Mention the function of osteoclast  They secrete acid collagenase and other proteolytic enzymes that cause bone resorption. 18. Mention sites of compact bone 1. Diaphysis of long bones. 2. Covering any cancellous bone, e.g. the outer and inner plates of the skull and short bones. ‫سُبحانك اللهُمَّ وبحمدِك أشهدُ أنْ ال إلهَ إال أنت أستغف ُركَ وأتوبُ إليك‬ Perfecto | 12  Compact = Cortical 19. Describe the microscopic structure of compact bone  It consists of thin layers of bone lamellae. These lamellae are organized in the form of: a. The Haversian system b. Outer circumferential lamellae c. Inner circumferential lamellae. d. Interstitial lamellae 20. Mention the site of outer and inner circumferential lamellae  The outer circumferential lamellae: lie immediately beneath the periosteum, and parallel to it.  The inner circumferential lamellae (less): lie parallel to the endosteum around the marrow cavity. 21. Describe the interstitial lamella and what do they represent  Irregularly shaped groups of parallel lamellae located in between the Haversian systems.  Represent lamellae of old Haversian systems left during bone remodeling. 22. Describe the Haversian system  A long cylinder parallel to the long axis of the diaphysis.  Consists of a Haversian canal surrounded by 4-20 concentric lamellae of regularly arrange collagen fibers.  Each canal in lined by endosteum and contains blood vessels, nerves and loose C.T. 23. Describe the lamellae around Haversian canal  Fibers are parallel to each other and follow a helical course.  Direction of the helix is different for different lamellae, so that Fibers from adjacent lamellae intersect at approximately right angles.  Osteocytes are present inside lacunae between or within lamellae. Perfecto | 13 24. Is Haversian system constant (doesn’t change)?  No, there is continuous destruction and rebuilding of Haversian systems (remodeling) 25. Give a short note about Haversian canal  Haversian canal runs parallel to the long axis of the bone and is connected to each other, with periosteum and with endosteum by transverse or oblique canals known as Volkmann's canals (lined with endosteum and contain blood vessel, nerves and C.T). 26. Enumerate sites of Spongy bone 1. Flat banes (e.g. diploe of skull, scapulae, and iliac bones) Secondary bone can be 2. Irregular bones: (e.g. vertebrae) either compact or spongy 3. Epiphysis of long bones. 4. Shafts of the ribs. Perfecto | 14  Cancellous = Spongy =Trabecular 27. Describe the structure of cancellous bone  It is composed of branching and anatomizing bone trabeculae with multiple bone marrow cavities (containing blood vessels, fat cells and blood forming cells) in between them.  The bone trabeculae are formed of irregularly arranged bone lamellae with osteocytes inside lacunae in between.  The bone marrow cavities are lined by endosteum.  Haversian systems are absent in the thin trabeculae of cancellous bone.  Cancellous bone is surrounded and protected by a layer of compact bone covered by periosteum. ،ِ‫اللَّهُمَّ إِني أَعُوذُ ِبكَ مِنْ الْهَم وَالْحَزَن‬ َ‫ وَأَعُوذُ ِبك‬،ِ‫وَأَعُوذُ ِبكَ مِنْ الْعَجْزِ وَالْكَسَل‬ ِ‫ وَأَعُوذُ ِبكَ مِنْ غَلَبَة‬،ِ‫مِنْ الْجُبْنِ وَالْبُخْل‬ ِ‫ وَقَهْ ِر الرجَال‬،ِ‫الدَّيْن‬ ،‫ وَ ِرزْقًا طَيبًا‬،‫فعًا‬ ِ ‫اللَّهُمَّ إِني أَسْأَُلكَ ِعلْمًا نَا‬ ً‫وَعَمََلً مُتَقَبََّل‬ Perfecto | 15 Compare Osteoprogenitor Osteoblast Osteocyte Osteoclast Origin Mesenchymal cell Osteoprogenitor Osteoblast Blood monocytes Oval Large Branched Shape Spindle Cuboidal/Columnar Flattened Motile Oval, Rounded, Multinucleated LM Nucleus Dark Pale Pale & Eccentric (5-50 nuclei) Deep Basophilia & Cytoplasm Basophilic Negative Golgi Pale Basophilia Deep acidophilia image Less rER, Protein Golgi, 4 zones Many mitochondria synthesizing cell: nucleus with Abundant EM and free ribosomes Aundant rER, more lysosomes and and polyribosomes mitochondria, condensed Mitochondria prominent Golgi chromatin On the surface On the surface of of bone in On bone surfaces bone, side by side In lacunae depressions in Sites within periosteum resembling the within matrix the matrix and endosteum epithelium (Howship's lacunae) ‫سُبحانك اللهُمَّ وبحمدِك أشهدُ أنْ ال إلهَ إال أنت أستغف ُركَ وأتوبُ إليك‬ Perfecto | 16  Periosteum Endosteum Lines the bone marrow cavity and also The outer covering of bone the haversian system Structure  Outer fibrous layer  Osteogenic cells Dense connective tissue that contains bundles of collagen called  Osteoblast Sharpey’s fibers that binds periosteum to bone.  Inner cellular layer Osteogenic cells ----------------------------------------------- Compact Bone Cancellous Bone Shape Dense with no holes Spongy with many holes Shaft of long bone Diploe of flat bone Sites Inner and outer tables of flat bone Epiphysis of long bone Periosteum Present Absent Endosteum Lines the haversian canal Lines the marrow cavity - Regularly arranged lamellae - Irregularly arranged lamellae arrangment - Arranged in osteons - Arranged in trabeclae periosteum ‫ هو اللى متغطى ب‬compact bone ‫ وال‬compact bone ‫هنا هى متحاوطة ب‬ Perfecto | 17  Primary Bone Secondary Bone Names Woven/Immature Lamellar/mature First bone Sites In adults In development and repair Time of Temporary Permanent presence More Less Cells (osteocytes) (osteocytes) Collagen Irregular Regular Minerals More Less (Ca+2) (stronger) Proteoglycan & More Less Glycoprotein Unevenly stained with Staining Acidophilic area of basophilia ‫ال يؤمن أحدكم حتى أكون أحب إليه‬ ‫من والده وولده والناس أجمعين‬ Perfecto | 18  Bone development Define: intramembranous ossification Osteoblasts differentiate directly from embryonic mesenchymal membrane and begin secreting osteoid tissue endochondral ossification Replacement of pre-existing hyaline cartilage by bone ,resorption of cartilage Enumerate: Mention type of bone formation - Intramembranous ossification - Endochondral ossification Site of intramembranous ossification Flat bone as skull ,mandible ,maxilla & clavicle Describe mesenchymal tissue Star shaped pale cell widely separated by intercellular substance and connected with each other by their processes Stage of intramembranous ossification - Formation of ossification center in the fibrous connective tissue - Bone matrix is secreted within the fibrous membrane - Formation of woven bone and periosteum - Bone collar of compact bone forms and bone marrow appears Perfecto | 19 Site of endochondral ossification Short and long bone Stages of endochondral ossification - Hypertrophy and destruction of chondrocytes leaving lacunae separated by septa of calcified cartilage matrix - Invasion of osteogenic cells and blood capillaries the lacunar space - Osteogenic cells give rise to osteoblast which form bone matrix over the remnants of calcified cartilage Steps of osteogenesis is of long bone? - This process begin with embryonic models of skeletal elements that made hyaline cartilage - The bone collar develops beneath the perichondrium around middle of long bone causing degeneration of underlying cartilage - Invasion of degenerating cartilage by capillaries and osteoprogenitor cells to produce primary ossification center in diaphysis - Osteoid deposit by new osteoblast ,undergoes calcification into woven bone and is remodeled as compact bone - Around the time of birth secondary ossification centrrs begin to develop by a similar process in the epiphysis - Primary and secondary ossification center separated by epiphyseal plate that provides for continued bone elongation - Two ossification centers don't merge until the epiphyseal plate disappears when full stature is achieved Perfecto | 20  ‫ن ست‬ ‫ن ج كام حاحه كدا‬ - Begin by hyaline cartilage - Late of first trimester bone collar develops - Bone collar develops by intramembranous ossification - Primary ossification center in diaphysis - Around the time of birth secondary ossification center begin to develop - Secondary ossification center in epiphysis - During childhood primary and secondary ossification center separated by epiphyseal plate - Epiphyseal plate disappears when full stature Longitudinal growth of bone depend on presence of the epiphyseal plate of cartilage Steps of growth of epiphyseal plate - Resting zone: randomly oriented chondrocytes - Proliferative zone: chondrocytes proliferate and form columns parallel to long axis of bone - Hypertrophic zone: chondrocytes increase in size ,accumulate glycogen and lipids , separated by matrix septa - Calcification zone: lacunae appear as empty spaces , cartilage matrix become calcified , prevent diffusion of nutrients - Ossification zone: ✓ blood vessels and osteoprogenitor cells invade empty space ✓ Osteoblast lay down bone matrix over the septa of calcified cartilage matrix and trapped cells are transformed into osteocytes - Bone spicules: - central area of calcified cartilage matrix appear basophilic , superficial layer of primary bone tissue appear acidophilic Perfecto | 21 Define Connective tissue  One of the four main classes tissues (epithelial, connective, muscular, and nervous tissue). Elastin  A connective tissue protein with rubber-like properties. Elastic fibers  Fibers, composed of elastin and glycoprotein microfibrils (fibrillin), that can be stretched and recoil giving elasticity to C.T. Collagen  A structural protein found in C.T. and is the most abundant protein in the human body. Procollagen  A precursor of collagen that has a central region of triple helix flanked by the nonhelical amino- and carboxyl-terminal extensions called propeptides. Tropoelastin  linear polypeptide Composed of about 700 amino acids that are primarily small and nonpolar (Glycine, alanine, and valine). ----------------------------------------------- COMPLETE 1. The collagen superfamily of proteins includes more than 25 collagen types. 2. The three polypeptide a chains are held together by hydrogen bonds between the chains. Perfecto | 22 3. in collagen synthesis, the hydroxylating enzymes (prolyl and lysyl hydoxylases) require Fe+2, while lysyl oxidase requires Cu+2 4. The polypeptide precursors of the collagen molecule are formed in fibroblasts, osteoblasts or chondroblasts. ----------------------------------------------- Ultra short questions 1. Mention function of connective tissue - It provides support, binds together, and protects tissues and organs of the body. 2. Enumerate main components of connective tissue 1. Ground substance 2. Cells 3. Fibrous proteins 3. Give short note about ground substance of CT  It is a clear, colorless, viscous fluid that fills the space between the cells and fibers.  It is composed of proteoglycans and cell adhesion proteins that allow the connective tissue to act as glue for the cells to attach to the matrix. 4. Enumerate the most common cells found Within CT 1. Fibroblast 2. Osteoblast 3. Chondroblast 5. Mention the role of fibroblasts in the formation of extracellular matrix  Secrete polysaccharides and proteins that combine with extra-cellular fluids to produce a viscous ground substance that, with embedded fibrous proteins, forms the extra-cellular matrix.  Secret fibrous proteins 6. Mention main types of fibers secreted by fibroblasts 1. Reticular fibers 2. Elastic fibers 3. Collagen fibers 7. Mention Structure of Reticular fibers.  Formed from the same protein subunits as collagen fibers (α chains).  But narrow and arrayed in a branching network and most abundant in the reticular tissues of soft organs. Perfecto | 23 8. Mention Structure of elastic fibers. - Composed of elastin and glycoprotein microfibrils Elastin is a rich in proline and lysine but contains only a Little hydroxyproline and hydroxylysine. 9. Mention the role of fibrillin in formation elastic fibers.  Fibrillin is secreted into the extracellular matrix by fibroblasts and becomes incorporated into the insoluble microfibirIs, which appear to provide a scaffold for deposition for elastin. 10. Give short note about formation of elastic fiber. 1. Elastic fibers are composed of elastin and glycoprotein microfibrils. 2. Elastin synthesized from a precursor tropoelastin 3. Tropoelastin is secreted by the cell into the extracellular space where it interacts with glycoprotein microfibrils, such as fibrillin. 4. Fibrillin Provide scaffold for deposition of elastin. 5. Some of the lysyl side chains of the tropoelastin polypeptides are oxidatively deaminated by oxidase forming allysine residues. 6. Three allysyl side chains + one unaltered lysyl side chain from the same or neighboring Polypeptides form a desmosine cross-link. 11. Mention the structure of collagen.  A typical collagen molecule is a long, rigid structure in which three polypeptides (referred to as ' α chains') are wound around one another in a rope-like triple helix. Perfecto | 24 12. Describe Amino acid sequence of Collagen.  Collagen is rich in proline and glycine, both of which are Importance of proline important in the formation of the triple-stranded helix.  The glycine residues are part of a repeating sequence, - Proline facilitates the Gly-X-Y-, where X is frequently proline and Y is often formation of the helix of each α chain because its ring hydroxyproline (or hydroxylysine). structure causes "kinks" in the  Thus, most of the α chain can be regarded as a poly- peptide chain. tripeptide whose sequence is (-Gly-Pro-Hyp-). 13. Mention role of glycine in the formation of collagen.  Glycine, the smallest amino acid, is found in every third position of the polypeptide chain.  It fits into the restricted spaces where the three chains of the helix come together. 14. How does collagen monomers aggregate to form long fibers.  Collagen has an elongated, triple-helical Structure that places many of its amino acid side chains on the surface of the triple-helical molecule.  This allows bond formation between the exposed R-groups of neighboring collagen monomers, resulting in their aggregation into long fibers. 15. Mention importance of hydroxyproline in formation triple helix.  Hydroxyproline is important in stabilizing Hydroxylation of proline and lysine the triple-helical structure of collagen residues occurs after their incorporation because into polypeptide chains, so it maximizes interchain hydrogen bond formation. hydroxylation is considered a post translational modification 16. How does the Glycosylation occur? and when?  The hydroxyl group of the hydroxylysine residues of coIIagen may be enzymatically glycosylated. Glycosylation with glucose or glucosyl-galactose are sequentially attached to the polypeptide chain.  Prior to triple-helix formation. Perfecto | 25 17. Enumerate steps of collagen synthesis. 1. Formation of pro-α chains 2. Hydroxylation 3. Glycosylation 4. Assembly and secretion 5. Extracellular cleavage of procollagen molecules 6. Formation of collagen fibrils 7. Assembly and cross-link formation to form collagen fibers 18. Mention functions of signal sequence at N-terminal ends of prepro a chain. 1. This sequence acts as a signal that targets the polypeptide being synthesized for secretion from the cell. 2. The signal sequence facilitates the binding of ribosomes to the rough endoplasmic reticulum (RER). 3. Directs the passage of the prepro-α chain into the lumen of the RER. 19. How does prepro α chain become pro α chain  By cleavage of signal sequence in RER. 20. Enumerate requirements for hydroxylation process 1. Molecular oxygen 2. Fe +2 3. Reducing agent vit C 21. How does scurvy disease affect hydroxylation  In scurvy, hydroxylating enzymes, prolyl hydroxylase and lysyl hydroxylase, are unable to function due to lack of vit c. 22. Describe formation of procollagen.  The formation of procollagen begins with formation of interchain disulfide bonds between the C-terminal extensions of the pro-α chains.  This brings the three α chains into an alignment favorable for helix formation. Perfecto | 26 23. How is pro collagen released into extracellular space?  The procollagen molecules move through the Golgi apparatus, where they are packaged in secretory vesicles.  The vesicles fuse with the cell membrane, causing the release of procollagen molecules into the extracellular space. 24. Describe formation of tropocollagen.  After release of the procollagen molecules, they are cleaved by N- and C procollagen peptidases, which remove the terminal propeptides, releasing triple-helical tropocollagen molecules. 25. Describe arrangement of collage fibrils.  They form an ordered, overlapping, parallel array, with adjacent collagen molecules arranged in a staggered pattern, each overlapping its neighbor by a length approximately three-quarters of a molecule. 26. Describe cross-link formation between collagen fibrils.  The Cu+2 containing extracellular enzyme (lysyl oxidase) oxidatively deaminates some of the lysyl and hydroxylysyl residues in collagen.  The reactive aldehydes that result (allysine and hydroxyallysine) can condense with lysyl or hydroxy - lysyl residues in neighboring collagen molecules to form covalent cross-links and, thus, mature collagen fibers. Perfecto | 27 Perfecto | 28 Define: Bone  A specialized connective tissue that consists of a matrix in which cells are dispersed. Bone Remodeling  It is a process that couples bone resorption and formation and take place in the bone multicellular units.  The dynamic process of continuous destruction and building of haversian system. Bone mineralization  Incorporation of hydroxyapatite into the newly deposited osteiod and starts as a hole called nucleation sites between collagen fibrils, then run in parallel to the collagen fibril to fill the space between them. COMPLETE: 1. Bone contains about 25% organic matrix, 5% water and 70% inorganic mineral. 2. The most abundant type of bone proteins is Collagen I, the other type of colllagen that bone contains is Collagen V. 3. The organic component of ECM of bone is called Osteoid. 4. Osteoclasts contain lysosomal proteolytic enzymes as collagenase and acid phosphatase. 5. The most abundant non-collagenous type of bone protein Osteocalcin. 6. Osteocalcin is γ carboxylated on glutamic acid residues with the help of Vit K. Perfecto | 29 Ultra short questions: 1. Enumerate non-collagenous proteins in bone 1. Osteocalcin 2. Osteonectin 3. Proteoglycan 2. Enumerate the receptors present on osteoblasts  Chemoreceptors: 1. PTH 2. Calcitriol ( 1, 25(OH)2 D3 ) 3. Estrogen (thus menopause women are subject (liable) to osteoporosis) 4. Growth factors  Mechanoreceptors 3. what's found on the membrane of osteoclasts  Proton pump  Receptors of calcitonin 4. Mention the importance of remodeling Maintains the integrity of the skeleton. Permits bone to adapt to both physical and hormonal signals. Maintains calcium and phosphate homeostasis. 5. Mention phases of bone remodeling 1. Activation 2. Resorption 3. Reversal 4. Formation (of matrix and mineralization) 5. Termination 6. Mention inhibitors of the nucleation step of mineralization 1. Glycoproteins Some factors are important for mineralization as: 2. Proteoglycans Alkaline phosphatase and acid phosphoproteins Perfecto | 30 7. What happens in the activation phase Osteocytes:  Detect the initiating signal as mechanical strain or hormone.  Stimulate the differentiation & maturation of osteoclasts. 8. What happens in the resorption phase  Digestion of bone matrix and mineral.  Osteoclasts attached to bone surface and secret H + ions to acidify resorbing area increasing the solubility of hydroxyapatite, thus bone demineralization Perfecto | 31 Compare: Fibril-forming Network-forming Fibril-associated collagens collagens collagens Long, stiff, triple helices Fibrils linked to other Assembly into sheet or cross-linked in a staggered Components in the meshwork array extracellular matrix For example: For example: For example: Type IV (basement Type IX (cartilage) Type l (Bone, skin) membrane) Type ll (cartilage) Type VIl (beneath Type Xl (ligaments) Type llI (arteries) Squamous epithelium) Mnemonic ‫ وكمان دا رقم واحد واكرت نوع موجود فهيكون موجود يف اكرب عضو‬،‫ يبقى هو موجود يف العضم‬،one ‫ تحتوي على كلمة‬Bone ‫ كلمة‬:Type I skin ‫موجود اللي هو الجلد‬ ‫ او ببساطة نقول واحد عضم اتنني غضاريف‬، ‫ يبقى موجود يف الغضاريف‬cartwolage ‫ مكتوبة‬cartilage ‫ هنتخيل ان كلمة‬:Type II Blood vessels (arteries) ‫ نفتكر‬، B ‫ يشبه حرف ال‬3 ‫ الرقم‬:Type III basement membrane ‫ يعني هيكون موجود يف األرضية اللي عليها الخاليا واللي هي ال‬four for floor ‫ افتكر‬:Type IV Squamous epithelium ‫ و‬Seven ‫ افتكر‬:Type VII ‫الس ََلَمَة ِم ْن‬ َّ ‫ َو‬، ‫زائ َم َمْغ ِفَرِت َك‬ ِ ‫ َوَع‬، ‫اتَر ْحَمِت َك‬ ِ ‫سأُل َك ُم ْو ِجَب‬ َْ ‫َا ّٰلل ُه َّم َّإنا َن‬ ‫النِار‬ َّ ‫الن َج َاة ِمَن‬ َّ ‫ َو‬، ‫ َو ْالَف ْوَز ِب ْال َجَّنِة‬، ‫ َو ْالَغِنْيَمَة ِم ْن ُكِّل ٍِّبر‬، ‫ُكِّلِإْث ٍم‬ Perfecto | 32 Enumerate: What's the results of imbalance in regulation of bone formation & resorption?  imbalance in regulation of bone remodeling’s two sub-processes result in many metabolic bone as diseases : o osteoporosis o Paget's disease Paget's disease of bone VS Osteoprosis It is due to dysregulated It may be due to lower than normal boneremodeling, specifically excessive maximum bone mass and greater than bone breakdown and subsequent normal bone loss disorganized new bone formation. Mention biochemical factors regulating bone remodeling and repair? 1.Growth factors:(systemic & local ) 2.Hormones 3.Vitamins Mention some systemic growth factors 1. Transforming growth factor β (TGF- β) MCQ ‫الدكتورة اكدت عليها كالترا و‬ 2. platelet-derived growth factor (PDGF) 3. fibroblast growth factor (FGF) 4. insulin-like growth factors (IGF-1, 2) What's the role of systemic growth factors?  All commit pluripotent mesenchymal cells to the osteoblastic lineage,  stimulate migration and proliferation and promote their further differentiation into mature cells. Perfecto | 33 Classify some Local growth factors : MCQ ‫الدكتورة اكدت عليها كالترا و‬ Enhance osteoclast Inhibit osteoclast osteoclast  Local factors as BMF ( bone morphogenic factor ) & growth factor : stimulate osteoblast differentiation. Mention affecting hormones 1.Parathyroid hormone (PTH) 3.Sex hormones 5.Glucocorticoids 2.Calcitonin 4.Growth hormone 6.Thyroid hormone Mention effects of PTH ? ‫ فى كل واحد‬amino acids ‫خد بالك من وظيفة الهرمونات وعدد‬ 1.Kidney :  Increase ca reabsorption while inhibit p reabsorption  increases 1-α-hydroxylase activity, stimulating the renal synthesis of 1, 25(OH)2D3, 2.intestinal tract :  increasing calcium and phosphate absorption 3.enhances bone resorption (increase osteoclasts number and activity). 4.increases collagenase secretion from osteoclasts ( activity) Compare between PTH & calcitonin.  In contrast to PTH, calcitonin is an inhibitor of osteoclast activity.  Calcitonin is not secreted until plasma calcium levels reached approximately 9.5 mg/dl in humans. Perfecto | 34 How female sex hormones(estradiol) preserve bone ?  Oestrogens stimulate osteoclast apoptosis and decrease osteoclastic activity What's effect of menopause on bone ?  Osteoporosis. ‫اعرف السبب هنا عشان مهم كالترا‬ H In detail: Estrogen deficiency, after menopause or following ovariectomy is associated with a progressive loss of trabecular bone structure where bone formation cannot compensate for the increased resorption resulting in osteoporosis. How male sex hormones ( androgen) preserve bone ?  Androgens on one hand inhibit osteoclast activity, osteoblast apoptosis  On the other hand, it stimulates osteoblast proliferation and differentiation How Glucocorticoids decrease new bone formation ?  Inhibit osteoblast differentiation & function What's the effect of Thyroid hormone on bone ?  Stimulate osteoclast & activate bone remodeling How GH is required for attaining normal bone mass ?  This effect is mediated by local production of insulin like growth factor-1 (IGF-1) which stimulates proliferation of osteoblast progenitor cell. Mention vitamins affecting bone  vit A.K.D.C Which vitamin control activity, distribution, and coordination of osteoblast/osteoclast ?  Vit A Perfecto | 35 Function of vit k ?  essential for γ-carboxylation of osteocalcin  may also affect the transcription of genes required for the expression of osteoblastic markers  collagen assembly What's the important vit in collagen assembl?/ binding to hydroxyapatite ?  Vit K Role of vit C ?  collagen biosynthesis  vitamin C mediated osteoblast differentiation  antioxidant effects on osteoclastogenesis. How production of 1,25(OH)2D in the kidney is tightly controlled ?  stimulated by parathyroid hormone (PTH)  inhibited by calcium, phosphate, and fibroblast growth factor 23. What are target tissues for vit D ?  bone, intestine, and kidney Mention effects of vit D ( not PTH )  It enhances normal bone growth and osteoid mineralization.  It increases renal tubular reabsorption of calcium and phosphate.) both )  It increases calcium and phosphate absorption through the intestinal tract.  It stimulates bone resorption.  Stimulate osteoponin and osteocalcin, suppressing collagen production. Perfecto | 36 ‫‪Compelete:‬‬ ‫ ‬ ‫‪The control of bone remodeling is complex‬‬ ‫ ‬ ‫‪PTH is an 84-amino acid while Calcitonin is a 32-amino-acid & GH is a 191 amino-acid‬‬ ‫ ‬ ‫‪PTH is responsible for the short-term regulation of calcium homeostasis‬‬ ‫ ‬ ‫‪signals for PTH secretion is Extracellular calcium levels‬‬ ‫ ‬ ‫) ‪Calcitonin is secreted by C cells of the thyroid gland ( parafollicular‬‬ ‫ ‬ ‫‪osteocalcin is one of the most abundant noncollaganeous bone proteins‬‬ ‫ ‬ ‫‪1,25 (OH)2D is the principal form of vitamin D, responsible for most of its biologic‬‬ ‫‪actions.‬‬ ‫‪ -‬اكد قوى على أن شغل ال ‪ parathormone‬على ‪ intestine‬بيبقى ‪ indirect‬هو فقط‬ ‫بيحفز‪ hydroxylation of vit D‬لل ‪ active form‬بتاعته‬ ‫‪ -‬الل بالمناسبه اسمها التالت ‪ calcitriol‬لفظ ‪ ol‬دى معناها ‪ 3OH‬و فيتامين ‪ D‬يكمل بقى‬ ‫تحفيز لل ‪ intestinal cells‬على أنها تزود ال‪absorption of Ca+2&Po-4‬‬ ‫‪Vit D -‬بيحفز ال ‪ bone resorption‬برضو ايوه لما يالقى ال ‪ Ca+2‬فى الدم قليل بيعمل‬ ‫كده‬ ‫َ َ‬ ‫وبح ْمده َع َد َد َخ ْلقه‪ ،‬ورضا َن ْفسه‪َ َ ،‬‬ ‫َ‬ ‫بحان هللا َ‬‫ُس‬ ‫داد ك ِلما ِته‬ ‫وزنة ع ْر ِشه‪ِ ،‬‬ ‫وم‬ ‫ِ‬ ‫ِ‬ ‫ِ ِ‬ ‫ِ‬ ‫ُ‬ ‫ْ َ َ‬ ‫ُ ْ‬ ‫َ ّٰ ُ َّ َّ َ ْ َ ُ َ ُ ْ َ َ ْ َ َ َ َ َ َ ْ َ َ َ َّ َ َ‬ ‫السَل َمة ِم ْن ك ِ ِّل ِإث ٍم ‪َ ،‬والغ ِن ْي َمة ِم ْن ك ِ ِّل ِب ٍِّر ‪،‬‬ ‫اترحم ِتك ‪ ،‬وع زا ِئم مغ ِفر ِتك ‪ ،‬و‬ ‫اللهم إنا نسألك مو ِجب ِ‬ ‫َّ‬ ‫َّ َ‬ ‫ْ َ َ ْ َّ‬ ‫َوالف ْوز ِبال َجن ِة ‪َ ،‬والن َجاة ِم َن الن ِار‬ ‫ْ ْ‬ ‫ْ‬ ‫َ ُ‬ ‫َْ‬ ‫ْ‬ ‫َ ُ‬ ‫ْ‬ ‫ْ‬ ‫َّ ِّ َ ُ‬ ‫الل ُه َّم ِإ ِني أ ُعوذ ِب َك ِم ْن ال َه ِ ِّم َوال َح َز ِن‪َ ،‬وأ ُعوذ ِب َك ِم ْن ال َع ْج ِز َوالك َس ِل‪َ ،‬وأ ُعوذ ِب َك ِم ْن ال ُج ْب ِن َوال ُبخ ِل‪،‬‬ ‫ََ ُ ُ‬ ‫وذ ب َك م ْن َغ َل َبة َّ‬ ‫الد ْين‪َ ،‬و َق ْهر ِّ‬ ‫الر َج ِال‬ ‫ِ ِ‬ ‫ِ‬ ‫ِ‬ ‫وأع ِ ِ‬ ‫َ ََْ ُ‬ ‫َ َ َ َّ ُ َ َ‬ ‫َ َ َ ْ َ َ َ ْ َ َ َ َّ ْ ُ َ َ ْ َ َ ُّ ْ َ ْ ْ‬ ‫الل ُه َّم َأ ْن َت َر ِّ‬ ‫َّ‬ ‫ّللا كان ‪َ ،‬و َما ل ْم َيشأ ل ْم َيك ْن ‪،‬‬ ‫ش ال َع ِظ ِيم ‪ ,‬ما شاء‬ ‫ِ‬ ‫ر‬ ‫ع‬ ‫ال‬ ‫ب‬ ‫ر‬ ‫ت‬ ‫ن‬ ‫أ‬‫و‬ ‫‪،‬‬ ‫ت‬ ‫ل‬ ‫ك‬ ‫و‬ ‫ت‬ ‫ك‬ ‫ي‬ ‫ل‬ ‫ع‬ ‫‪،‬‬ ‫ت‬ ‫ن‬ ‫أ‬ ‫ال‬ ‫إ‬ ‫ه‬‫ل‬ ‫إ‬ ‫ِ ِ ِ‬ ‫ال‬ ‫ي‬ ‫ب‬ ‫ْ‬ ‫َ ْ َ ُ َ َّ َّ َ َ َ ُ ِّ َ ْ َ ٌ َ َ َّ َّ َ َ َ َ ُ َ‬ ‫ْ‬ ‫َّ ْ‬ ‫َ َ ْ َ َ ُ َّ َ‬ ‫ّللا ق ْد أ َحاط ِبك ِ ِّل ش ْي ٍء ِعل ًما ‪،‬‬ ‫اَّلل ال َع ِل ِّ ِي ال َع ِظ ِيم ‪ ,‬أعلم أن ّللا على ك ِل ش ي ٍء ق ِدير ‪ ،‬وأن‬ ‫وال حول وال قوة ِإال ِب ِ‬ ‫َ‬ ‫اط ُم ْست ِق ٍيم‬ ‫َّ ِّ َ َ‬ ‫وذ ب َك م ْن َش ِّر َن ْفس ي ‪َ ،‬وم ْن َش ِّر ُك ِّل َد َّابة َأ ْن َت آخ ٌذ ب َن َ‬‫َّ َّ ِّ َ ُ ُ‬ ‫اصي ِت َها ‪ِ ،‬إن َر ِبي على ِص َر ٍ‬ ‫ِ ِ ِ‬ ‫ِ ِ ٍ‬ ‫ِ‬ ‫ِ ِ‬ ‫الل ُهم ِإ ِني أع ِ ِ‬ ‫‪Perfecto‬‬ ‫|‬ ‫‪37‬‬ Complete: 1. Calcium is the most abundant mineral in the body. 2. 99% of the body’s calcium is present in the bone combined with phosphate in the form of hydroxyapatite. 3. The optimum ratio of calcium to phosphorus which allows maximum absorption is 1:2 to 2:1 as present in milk. 4. Total blood calcium level 8.6-10.3 mg/dl. 5. The biologically active form is the ionized form. 6. The major calcium binding protein is albumin. 7. The second most abundant element is phosphorus. 8. Serum level of phosphorus is 3 - 4 mg/Dl in normal adults. Mention: Factors increase absorption: - Vitamin D3 (Calcitriol). - Parathyroid hormone. - Acidic PH in upper intestine. - Amino acids: lysine and arginine. Factors decrease absorption - Fatty acid form insoluble calcium salt. - High Phosphate precipitate it as calcium phosphate. Functions of calcium - Major constituent of bone and teeth. - Calcium mediates excitation and contraction of muscle fibers. - Second messenger for hormone action. - Secretion of hormones, digestive enzymes, and neurotransmitters. Hormonal factors regulating blood calcium level - Calcitriol. - Parathormone (PTH). - Calcitonin. Biochemical importance of phosphorus - Form bone & teeth. - Energy transfer. - Activation & inactivation of several enzymes. - Nucleotide structure as ATP. Factors regulating phosphorus level - Calcitriol  Increase absorption from intestine - PTH  Increase excretion of phosphorus. - Ca / P ratio in diet  It affects absorption and excretion of phosphorus. Perfecto | 38 Complete: 1. Deposition of calcium salts helped by alkaline phosphatase enzyme. 2. Reconstruction of bone is removal external and internal callus. 3. Type of cell responsible for reconstruction of bone is osteoclasts. Define: Callus  Group of capillaries, osteoblasts, osteomucin that non calcified bone. Rickets  Disease resulting in softening of bone from deficient deposition of calcium salts. Osteomalacia  Softening of bone in adult female due to increase demand to vitamin D. Osteiporosis  Metabolic skeletal disease defined as reduction of amount of bone tissue. Mention: Steps of bone repair - Formation of hematoma at site of fracture. - Newly formed capillaries and osteoblasts derived from peritoneum. - Osteoblasts lay down osteomucin. - Formation of callus. - Deposition of calcium salts. - Reconstruction of bone. - Gradually transformation of callus into lamellar bone. Cause of hematoma after fracture Perfecto | 39 Laceration of blood vessel. Origin of newly formed capillaries and osteoblasts Derived from peritoneum. Date of formation of the following Osteomucin →second week after fracture. Callus →third week after fracture. Deposition calcium salts →third week after fracture. Type of callus appear External, intermediate and internal callus. General factor affecting rate of healing of bone - Age →healing rapid in young than in old. - General conditions →chronic disease delay rate of healing. - Cortisone →delay rate of healing. - Cytotoxic and irradiation →delay rate of healing. - Vit C→help formation ground substance. - Zinc→necessary in collagen formation. Local factor affecting rate of healing of bone - Proper vascularization→promote healing. - Immobilization →promote healing. - Foreign bodies→inhibit healing. - Infection →inhibit healing. Types of disease affected bone - Rickets. - Osteomalasia. - Osteoporosis. - Paget's disease. Types of rickets - Infantile rickets - Adolescent rickets. - Renal rickets. Perfecto | 40 Pathology or bone change in rickets - Swelling at end of bones at epimetaphyseal junction. - Broadening and irregularity of epiphyseal line. - Deformities in shape. Deformities in shape of bone at rickets patients - Skull→delay closure of fontanels and deficient ossification→craniotabes. - Teeth→delay eruption, irregularity of edge, softening and decay. - Thorax→pigeon shaped with thick prominent Deformities in shape in rickets costochondral junction →rachitic rosary. patients also associated with - Vertebral column→scoliosis. splenomegally and abdominal - Pelvic→trifoil appearance due to pressure of heads distension. of femora in acetabula ,pushing them inwards. - Lower limb→outward bend femurs, knock knee, forward bent tibia →Bowles. Cause of osteomalacia in adult female Increase demand to vit D because of Osteomalacia common in poor classes. multiple pregnancy and lactation. Pathology of osteomalacia - Failure of calcification and deformity in vertebrae, pelvic "trifoil" and limbs. - Muscles are hypotonic and weak. Cause of osteoporosis Diminished osteoblastic activity and Bone resorption in osteoporosis may increased bone resorption. be generalized or localized. ُ ََْ َ َ َ ُ َّ َ َ َ ْ ْ َ ْ ُّ َ َ ْ َ َ ُ ْ َّ َ َ َ ْ َ َ َ ْ َ َ َ ِّ ‫الل ُه َّم َأ ْن َت َر‬ َّ ، ‫ َو َما ل ْم َيشأ ل ْم َيك ْن‬، ‫ّللا كان‬ ‫ ما شاء‬, ‫ش ال َع ِظ ِيم‬ ِ ‫ر‬‫ع‬ ‫ال‬ ‫ب‬ ‫ر‬ ‫ت‬ ‫ن‬ ‫أ‬‫و‬ ، ‫ت‬ ‫ل‬ ‫ك‬ ‫و‬ ‫ت‬ ‫ك‬ ‫ي‬ ‫ل‬ ‫ع‬ ، ‫ت‬ ‫ن‬ ‫أ‬ ‫ال‬ ‫إ‬ ‫ه‬‫ل‬ ‫إ‬ ِ ِ ِ ‫ال‬ ‫ي‬ ‫ب‬ ْ َ ُ َ َ َ َ َّ َّ َ َ ٌ َ ْ َ ِّ ُ َ َ َ َّ َّ َ ُ َ ْ َ ْ ْ َّ َ َّ ُ َ َ ْ َ َ ، ‫ّللا ق ْد أ َحاط ِبك ِ ِّل ش ْي ٍء ِعل ًما‬ ‫ وأن‬، ‫ أعلم أن ّللا على ك ِل ش ي ٍء ق ِدير‬, ‫اَّلل ال َع ِل ِّ ِي ال َع ِظ ِيم‬ ِ ‫وال حول وال قوة ِإال ِب‬ َ ‫اط ُم ْست ِق ٍيم‬ َ َ ِّ َّ َ ‫ َوم ْن َش ِّر ُك ِّل َد َّابة َأ ْن َت آخ ٌذ ب َن‬، ‫وذ ب َك م ْن َش ِّر َن ْفس ي‬ُ ُ َ ِّ َّ َّ ٍ ‫ ِإن َر ِبي على ِص َر‬، ‫اصي ِت َها‬ ِ ِ ِ ٍ ِ ِ ِ ِ ِ ِ ِ ‫الل ُهم ِإ ِني أع‬ Perfecto | 41  Calcium and phosphorus are the 2 major elements of bone. Enumerate: Enumerate primary and secondary regulators of bone mineral metabolism. Primary: Parathyroid hormone (PTH) vitamin D Secondary: Calcitonin Glucocorticoid Estrogens Enumerate 4 bone mineral disorders. Osteoporosis osteomalacia Rickets Paget's disease Mention mechanism of action of the following: Parathyroid hormone (PTH) PTH stimulates membrane receptors linked to Gs protein that stimulates adenylate cyclase enzyme leading to increase cAMP. Vitamin D Calcitriol is lipophilic hormone passes passively intracellular and binds to cytoplasmic receptors forming a mobile complex that is then stimulates nuclear receptors which stimulate DNA transcription & new protein synthesis. Calcitonin It binds to membrane receptors. Bisphosphonate inhibit osteoclast activity leading to decrease in bone resorption. Perfecto 42 | Denosumab It is a monoclonal antibody against RANK ligand leads to inhibition of osteoclast activity and bone resorption. N.B Can be used for patients who don't tolerate bisphosphonate. Teriparatide It is a recombinant PTH. It is used by intermittent S.C. administration. It stimulates the production of new collagenous bone matrix (osteoanabolic therapy) thus the patients must receive enough vitamin D and calcium to mineralize the newly formed bones. Selective estrogen receptor modulators (SERMs) (Raloxifene) Acts as agonist on estrogen receptors in bone (stimulate osteoblasts & inhibit osteoclasts). Acts as antagonist on estrogen receptors in breast & endometrium. Perfecto 43| Mention Pharmacological effects of the flowing: Parathyroid hormone (PTH) PTH ↑Calcium level in blood through (hypercalcemic): ↑Active calcium absorption from intestine. ↑Calcium & decrease active reabsorption from kidney. ↑Active bone resorption. Vitamin D Vitamin D increases calcium level in blood through (hypercalcemic): ↑Active calcium absorption from intestine. ↑Active calcium reabsorption by kidney. ↑Active bone formation. Calcitonin Calcitonin is a hypocalcemic hormone through: decrease Bone resorption. decrease Active renal reabsorption of calcium & phosphate. Calcitonin possesses analgesic effects on bone pain & fractures. Mention Uses of the following: Parathyroid hormone (PTH) - Used by I.M. injection. - Acute tetany & hypocalcemia. Vitamin D It can be used orally or parentally in: - Osteoporosis. - Vitamin D deficiency (rickets in children & osteomalacia in adults). - treatment of hypocalcemia &tetany. Calcitonin - Hypercalcemia - Paget's disease of bone. - Post-menopausal osteoporosis. Perfecto 44 | Bisphosphonate Bisphosphonates are the first line therapy for osteoporosis due to established efficacy in preventing hip and vertebral fractures. Estrogen In hormonal replacement therapy to prevent post-menopausal osteoporosis. Mention preparation of the flowing: Vitamin D 1. Calcitriol (1, 25 (OH) Cholecalciferol). 2. Alfacalcidol (1 (OH) Cholecalciferol). 3. Ergocalciferol (Vitamin D2). 4. Dihydrotachysterol (Anti-tetanic 10, AT-10). Calcitonin 1. Human calcitonin: L.M. & S.C. 2. Salmon calcitonin: LM., S.C. & nasal spray. Bisphosphonate 1. Alendronate 2. Pamidronate 3. Risendronate 4. Zoledronate. Mention adverse effects of Bisphosphonate. 1. Nausea, vomiting and diarrhea. 2. Esophageal irritation, erosions, ulceration and bleeding. 3. Renal dysfunction. 4. Long term use increases the risk of atypical fracture of femur and osteonecrosis of jaw. Define and mention cause of Osteoporosis. Definition → Osteoporosis is a condition characterized by abnormal loss of bone. Cause → This condition occurs as a result of degrading the bone matrix by osteoclasts faster than its rebuilding by osteoblasts. Perfecto 45| Mention treatment of the osteoporosis. Non-pharmacological: Change lifestyle (stop smoking, alcohol and performing exercises). Pharmacological: Bisphosphonate Teriparatide Denosumab Estrogen and SERM Calcium and vitamin D should be added to all drug therapy regimens for osteoporosis. Mention Nature and source of vit D Steroid vitamin. Vitamin D2 is ergocalciferol Vitamin D3 is cholecalciferol. U.V. rays transfer the skin 7-dehydrocholesterol to Converted to 25- hydroxycholecalcifeol in the liver with the help of 25a-hydroxylase &then to 1, 25- dihydroxycholecalciferol (Calcitriol) by the action of 1a-hydroxylase in kidney. Mention the drugs that inhibit bone resorption 1. Bisphosphonates 3. Estrogen 5. Denosumab 2. Calcitonin 4. SERMs Mention the drugs that stimulate bone formation. 1. Teriparatide 2. Calcium 3. Calcitriol Perfecto 46 | Complete: 1. Pyogenic osteomyelitis is common in children especially in males. 2. Chronic non specific osteomyelitis occurs on top of acute haematogenous or traumatic osteomyelitis. 3. Adults are commonly affected by Chronic suppurative osteomyelitis. 4. Chronic suppurative osteomyelitis is characterized by multiple cloacae discharging pus. Mention 1. Types of Inflammatory bone lesions (Osteomyelitis) 1. Acute (< 2 weeks) 2. Chronic (> 2 weeks)  Suppurative  Specific  Non-suppurative  Non-specific 2. Predisposing factors of osteomyelitis 1. Rheumatoid Artheritis (Current or past injury) 2. Bone surgery 5. Cancer 8. Haemodialysis 3. Poor blood supply 6. Diabetes 4. Prosthesis 7. Drug injection/stroid 3. Causative organisms of osteomyelitis Bacteria Septic foci  Staphylococcus aureus (80%).  Tonsillitis  Staphylococcus albus.  Adenoids  GBS (Strept. Agalactia)  Suppurative otitis media  Pneumococci  Chronic sinusitis or abscess.  Aerobic Gram -ve bacilli  Anaerobic (Bacteroides) Fungi  Mycobacterium TB  Treponema pallidum  Candida albicans Perfecto | 47 4. Sites of acute pyogenic osteomyelitis 1. Upper femur The commonest site of 2. Lowe femur infection of pyogenic osteomyelitis is Metaphysis 3. Upper tibia 5. Why metaphysis is the commonest site of infection of pyogenic osteomyelitis 1. Most liable to trauma. 2. Its resistance is low (as it is the active growing part) 3. The most vascular site of bone + the blood flow is slow holding circulating organisms. 4. Organisms are deposited in the metaphyseal haematoma, which resulted from trauma. 6. The pathological features of pyogenic osteomyelitis  Lesion starts as a focus of suppuration in the metaphysis (commonly the femur & tibia)  Then, infection spreads to the medullary canal, cortex, and medulla....etc. 7. Fate of initial focus in pyogenic osteomyelitis 1. Absorption 2. Localization (Brodie's abscess) 3. Extension either horizontal or vertical 8. Mechanism of Traumatic osteomyelitis (Avascular necrosis) Bone: any Age: any  It occurs on top of trauma and compound fractures.  Organism reaches the bone directly (because of contamination) 9. Pathological features of traumatic osteomyelitis  The same as acute osteomyelitis except The lesion occurs in the diaphysis of long bone and skull bone. There is no formation of subperiosteal abscess due to adherent periosteum.  Formation of multiple cloacae discharging pus.  Chronic cases: may be complicated by secondary amyloidosis. Perfecto 48 | 10. Complications of Pyogenic osteomyelitis 1. Septicemia and toxemia Systemic spread 2. Systemic pyemia 3. Direct spread of infection to near-by tissues Local spread 4. Pathological fractures )‫مشاكل في العظم (كسور‬ 5. Chronic suppurative arthritis Chronicity 6. Chronic suppurative osteomyelitis: Alteration of growth due to affection of the epiphyseal plate. Secondary amyloidosis. Cancer 7. Squamous cell carcinoma may arise in the epithelialized sinus tract Compare: Horizontal extension VS Vertical extension Towards the surface of bone: Along the medullary canal: 1. Bone destruction 1. Septic thrombophlebitis 2. Subperiosteal abscess 2. Release of septic emboli into the 3. Bone necrosis (sequestrum) circulation → Systemic Pyaemia  New bone is laid down by the Vertical extension towards the epiphysis raised periosteum (Involucrum) and joint cavity is rare that surrounded the dead bone  as the epiphyseal cartilage is strong barrier against infection  This involucrum is perforated by  This can only occur in two multiple openings (Cloacae) that conditions: may open into the skin by multiple 1. In infants. sinuses discharging pus. 2. In congenital syphilis. N.B: In Horizontal extension, If the metaphysis is intra-articular, as in the hip joint, pus will infect the joint. Perfecto 49 | Complete: 1. Hematogenous osteomyelitis is primarily Monomicrobial 2. while osteomyelitis due to contiguous spread is usually Monomicrobial or polymicrobia 3. Osteomyelitis occurs acute usually in Limbs (arms & legs ) in children 4. Osteomyelitis in adult predisposed patient is Chronic & occurs in pelvic & spine 5. Collagen binding adhesin allow staph aureus to attach to bone cartilage 6. Fibronectin binding adhesin allow staph aureus to attach to surgically implanted devices Define : Osteomyelitis  It's an inflammation of the bone caused by an infectious agent, it has a heterogeneous pathophysiology ,and is one of the most difficult infections to cure Enumerate: 1. Classify osteomyelitis according to time of evolution Acute osteomyelitis Chronic osteomyelitis 2. Enumerate sources of infection of osteomyelitis 1. Hematological( most common) 2. Continuous infectious focus 3. Direct spread into the bone due to trauma or surgery 3. Enumerate the causative organisms of osteomyelitis 1. Staph aureus ( most common) 2. Coagulase negative staph 3. Beta hemolytic streptococcus ( strept. Agalactia ) 4. Aerobic gram negative bacilli as pseudomonas 5. Anaerobic SPP 6. Fungi as candida albicans 7. Mycobacterium TB Perfecto 50 | 4. Enumerate the predisposing factors of osteomyelitis 1. Diabetes 2. Hemodialysis 3. Injected blood use / steroids 4. Poor blood supply 5. Bone surgery , prosthesis 6. A current or past injury as rheumatoid arthritis 5. Mention the pathogenesis of staph aureus osteomyelitis Staph aureus can adhere to the bone How?? ✓ It has expressing receptors , as adhesin ,for some components of the bone matrix as laminin, collagen, fibronectin ✓ Biofilm formation allowing its ▪ adherence to the bone ▪ increasing its antibiotic resistance ▪ Ability to survive intracellular Staph aureus can survive intracellular after being internalized by cultured osteoblasts 6. Enumerate the complications of osteomyelitis 1. Septicemia & toxemia 3. Pathological fractures 2. Systemic pyemia 4. Chronic suppurative arthritis 5. Direct spread of infection to nearby tissues 8. Mention 3 hematological tests used for osteomyelitis diagnosis 1. CBC 2. CRP 3. ESR 9. Mention the microbiological diagnosis of osteomyelitis Samples may be from blood, bone spacemen/ biopsy or needle aspiration Samples are subjected to  Microscopic examination using stains as gram or ziehl- nelsen stain  Culture on an appropriate culture media  Antibiotic sensitivity test 10. Mention the radiological diagnosis of osteomyelitis 1. MRI 2. X-ray 3. bone scanning Perfecto 51 | 11. Mention the symptoms of osteomyelitis 1. Bone pain 2. Constitutional symptoms as fever, malaise , chills, excessive sweating 3. Bore redness ,warmth & swelling 12. Mention the signs of osteomyelitis -Bone tenderness , swelling & redness 13. Mention treatment of osteomyelitis  Initiate intravenous antibiotics  Empiric therapy should always include coverage for staph aureus & consideration of CA-MRSA ( vancomycin, nafcillin & cephalexin )  May receive more than 1 antibiotic at time  Antibiotics taken at least for 4-6 weeks or more Surgical management:  removal of the infectious indus  Implantation of antibiotic beads or bumps or other modalities َ َ َ َ ،‫ ورضا َن ْفسه‬،‫وبح ْمده َع َد َد َخ ْلقه‬ َ َ ‫بحان هللا‬‫ُس‬ ‫داد ك ِلما ِته‬ ِ ،‫وزنة ع ْر ِشه‬ ‫وم‬ ِ ِ ِ ِ ِ ُ َ َ ْ ْ ُ َ َ َّ َ َ َ ْ َ َ َ َ َ َ ْ َ َ ْ ُ َ ُ َ ْ َ َّ َّ ُ ّٰ َ ، ‫ َوالغ ِن ْي َمة ِم ْن ك ِ ِّل ِب ٍِّر‬، ‫السَل َمة ِم ْن ك ِ ِّل ِإث ٍم‬ ‫ و‬، ‫ وع زا ِئم مغ ِفر ِتك‬، ‫اترحم ِتك‬ ِ ‫اللهم إنا نسألك مو ِجب‬ َّ َ َّ َّ ْ َ َ ْ ‫ َوالن َجاة ِم َن الن ِار‬، ‫َوالف ْوز ِبال َجن ِة‬ ْ ْ ْ ُ َ َْ ْ ُ َ ْ ْ ُ َ ِّ َّ ،‫ َوأ ُعوذ ِب َك ِم ْن ال ُج ْب ِن َوال ُبخ ِل‬،‫ َوأ ُعوذ ِب َك ِم ْن ال َع ْج ِز َوالك َس ِل‬،‫الل ُه َّم ِإ ِني أ ُعوذ ِب َك ِم ْن ال َه ِ ِّم َوال َح َز ِن‬ ِّ ْ َ َ ْ َّ َ َ َ ْ َ ُ ُ َ َ ‫الر َج ِال‬ ِ ‫ وقه ِر‬،‫وأعوذ ِبك ِمن غلب ِة الدي ِن‬ ُ ََْ َ َ َ ُ َّ َ َ َ ْ ْ َ ْ ُّ َ َ ْ َ َ ُ ْ َّ َ َ َ ْ َ َ َ ْ َ َ َ ِّ ‫الل ُه َّم َأ ْن َت َر‬ َّ ، ‫ َو َما ل ْم َيشأ ل ْم َيك ْن‬، ‫ّللا كان‬ ‫ ما شاء‬, ‫ش ال َع ِظ ِيم‬ ِ ‫ر‬‫ع‬ ‫ال‬ ‫ب‬ ‫ر‬ ‫ت‬ ‫ن‬ ‫أ‬‫و‬ ، ‫ت‬ ‫ل‬ ‫ك‬ ‫و‬ ‫ت‬ ‫ك‬ ‫ي‬‫ل‬ ‫ع‬ ، ‫ت‬ ‫ن‬ ‫أ‬ ‫ال‬‫إ‬ ‫ه‬‫ل‬ ‫إ‬ ِ ِ ِ ‫ال‬ ‫ي‬ ‫ب‬ ْ َ ُ َ َ َ َ َّ َّ َ َ ٌ َ ْ َ ِّ ُ َ َ َ َّ َّ َ ُ َ ْ َ ْ ْ َّ َ َّ ُ َ َ ْ َ َ ، ‫ّللا ق ْد أ َحاط ِبك ِ ِّل ش ْي ٍء ِعل ًما‬ ‫ وأن‬، ‫ أعلم أن ّللا على ك ِل ش ي ٍء ق ِدير‬, ‫اَّلل ال َع ِل ِّ ِي ال َع ِظ ِيم‬ ِ ‫وال حول وال قوة ِإال ِب‬ َ َ َ ِّ َ َّ َ َ َ ٌ َ ْ َ َّ َ ِّ ُ ِّ َ ْ َ ْ َ ِّ َ ْ َ ُ ُ َ ِّ َّ ُ َّ ‫اط ُم ْست ِق ٍيم‬ٍ ِ ‫ر‬َ ‫ص‬ ‫ى‬‫ل‬ ‫ع‬ ‫ي‬ ‫ب‬ ‫ر‬ ‫ن‬ ‫إ‬ ، ‫ا‬ ِ ِ ِ ِ ِ ِ‫ه‬ ‫ت‬ ‫ي‬ ‫اص‬‫ن‬‫ب‬ ‫ذ‬ ‫آخ‬ ‫ت‬ ‫ن‬ ‫أ‬ ‫ة‬ ‫اب‬ ‫د‬ ٍ ِ ِ ‫ل‬ ‫ك‬ ‫ر‬‫ش‬ ‫ن‬ ‫م‬ ِ ‫و‬ ، ‫ي‬ ‫س‬ ِ ‫اللهم ِإ ِني أعوذ ِبك ِمن ش ِر ن‬ ‫ف‬ Perfecto 52|  Osteoma Osteochondroma cancellous osteoma,exostosis Osteoid osteoma Osteoblastoma compact or ivory osteoma middle age, and adults and is more Incidence usually affects the common in males membranous bone as that of the skull. arises in any bone - from the epiphyseal cartilage commonly the cortex of of a growing long bone. Site long bones as femur and - It is the commonest benign tibia; usually painful tumour of bone affecting children and adolescents - solitary less than 1 cm. round to oval - Cartilage-capped - Subperiosteal osteoma is masses of outgrowth that is encircled by reactive hemorrhagic non-capsulated attached to the bone so that the X-ray gritty tan Grossly hard, bosselated, underlying skeleton by film of the tumour tissue. round to oval sessile a bony stalk. appears as a radiolucent tumors. - It stops growing at the small lesion (nidus) adult age when closure surrounded by dense of the epiphysis occurs. sclerosing margins. there is a center of - randomly osteoid and poorly interconnecting formed of concentrically mineralized woven bone trabeculae of woven irregular bone Microscopically arranged compact surrounded by dense bone prominently trabeculae lamellae of bone calcified bone. rimmed by osteoblasts. separated by containing few - The stroma surrounding vascular irregularly arranged the tumor bone consists connective tissue Haversian system. of loose connective and covered by tissue that contains cartilaginous cap. dilated capillaries. Perfecto 53 |  Osteoblastoma - benign bone tumor differs from osteoid osteoma in that it more frequently involves the spine; - the pain is dull, achy, and it does not induce a marked bony reaction Giant Cell Tumour of Bone (Osteoclastoma) Incidences More commonly in male between 20 and 40 years begins in the epiphysis (the commonest sites are the ends of long bones; Site lower end of femur, upper end of tibia or fibula, lower end of radius, upper end of humerus) Consistency firm mass size increased in size gradually and develops areas of necrosis and haemorrhage Necrosis (the tumor is osteolytic) results in the formation of multiple cystic cavities filled with blood. The tumour causes expansion of the bone but usually a thin shell of new cut section bone formed by the periosteum surrounds the tumour causing the egg- shell crackling sensation The tumour shows a soft friable reddish brown surface with areas of haemorrhage and cystic degeneration. X-ray Soap and bubble appearance Small mononuclear stromal cells with dark nuclei and 1. The tumour varying degrees of atypia, cells: these cells constitute the neoplastic component of the tumour. Microscopically: Numerous and contain 10-100 nucle. two types of cells They are of osteoclastic type. are present Osteocladts are homogenously distributed in the tumor 2. Giant cells : Areas of haemorrhage, necrosis, haemosiderin and osteoid may be seen. It may be complicated by pathological fracture. Perfecto 54|  Osteogenic sarcoma (osteosarcoma) Males are more commonly affected than females especially in teen Sex: Incidence ages Common between 10-20 years in the primary type and over 50 years Age: in the secondary type. Origin Arises from bone forming cells (osteoblasts). Primary osteosarcoma: idiopathic Predisposing Occurs in older age group factors Secondary It most commonly develops on top