S&F exam 2 review.pdf

S&F Exam 2 Review Large group review #1 Before we get started Dr. C material - all you need to know is the info in the speaker notes of the ppt & be prepared to type in answers Anytime Dr. Talbot says “that would be a good test question” it will be a test question! For Biochem- focus on the word...

S&F Exam 2 Review Large group review #1 Before we get started Dr. C material - all you need to know is the info in the speaker notes of the ppt & be prepared to type in answers Anytime Dr. Talbot says “that would be a good test question” it will be a test question! For Biochem- focus on the words in red I am highlighting major important concepts, not everything so don’t only use this ppt If I mention anything that he told you that you won’t be tested on, please ignore the slide and go by what your teachers told you EMC Non-cellular component Functions: ○ Support ○ Strength (collagen) ○ Shock/weight absorption (proteoglycans & GAGs) ○ Adhesion/communication Produced by chondrocytes Glycoproteins and Proteoglycans GlycoPROTEINS ○ Mainly proteins, with glycans (sugars) added, less/short/branched carbohydrate ProteoGLYCANS ○ Mainly glycans, with proteins added, more/long/unbranched carbohydrate Glycoproteins & Oligosaccharides Sugars are COVALENTLY linked via 2 ways N-Linked ○ Sugar linked to asparagiNe (asN) ○ 2 Classes: complex or high mannose ○ Both contain the same pentasaccharide core O-Linked ○ Sugar linked to Serine (ser) or Threonine (Thr)  Glycoprotein synthesis N-link Glycoproteins: glycosylation begins in ER, completed in Golgi O-link Glycoproteins: glycosylation happens in Golgi Transported 3 ways: ○ To cell membrane ○ Secretory vesicles ○ lysosomes  GAGs & Proteoglycans Proteoglycans: consist of a core protein molecule attached covalently with glycosaminoglycan (GAGs) GAGs- negatively charged heteropolysaccharide chains Aggregate formation: Many proteoglycan monomers can associate with one molecule of hyaluronic acid to form proteoglycan aggregates (main component of cartilage’s ECM). Hyaluronic acid is different ○ A proteoglycan monomer associates with hyaluronic acid through ionic bonds Additional function: ○ Provide viscous, lubricating properties of mucous secretions (mucopolysaccharides) GAGs Six classes of GAGs Hyaluronic acid (no sulfate), do not form proteoglycan Chondroitin sulfate (MOST ABUNDANT) Heparin Keratan sulfate Heparan sulfate Dermatan sulfate Function Negative charge causes chains to repel each other=reduced friction GAGs absorb water like a sponge  Collagen Triple-stranded helical rod rich in glycine and proline residues Y : often hydroxyproline (unique to collagen) Three polypeptide chains are held together by interchain hydrogen bonds Important types: (Procollagen -> 1- skin, bone, tendons (OI) Tropocollagen) 2- cartilage 3- blood vessels (EDS) 4- Basement membrane 5- Corneal & Vascular endothelium (EDS) Collagen Synthesis In the RER ○ Pre-pro->pro ○ Hydroxylation of Proline/Lysine (Require Vitamin C) ○ Hydroxyproline helps stabilize the triple helical structure Triple Helix formation (Procollagen) -> ECM In the ECM ○ Procollagen -> Tropocollagen ○ Tropocollagen -> collagen fibrils ○ Cross-link formation (stabilized fibrils) by Lysyl Oxidase (Copper (Cu +) is required as a cofactor) to form mature collagen fiber Practice questions 1. Which GAG functions as an anticoagulant? 2. Which is the most abundant GAG? 3. What part of collogen synthesis required vitamin D? Answers 1. Heparin 2. Chondroitin sulfate 3. Hydroxylation Adipose tissue Mesenchymal cells / fibroblasts develop into lipoblasts (preadipocytes) that develop into white or brown Adipocytes White or unilocular. ○ single lipid droplet (thin ring of cytoplasm around empty vacuole) Signet ring cell ○ Membrane receptors for hormones ○ Convert androgens to estrogens ○ Leptin for appetite Brown or multilocular ○ multiple droplets ○ Produces heat ○ abundance of mitochondria that contains cytochrome oxidase Cartilage Specialized CT made of cells, fibers, & ground substance Gets strength from ECM Does not contain nerves, vessels, or lymphatics Cartilage * MUST KNOW *know the locations of the different types of cartilage & the differences Origin: mesenchymal cells Synthesis ○ 1. ChondroBLASTS produce ECM ○ 2. ChondroCYTES once they are enclosed by their own matrix ○ 3. Located in LACUNAE ○ PERIchondrium (surrounding mesenchyme) develops & has 2 layers of Dense IRCT Outer fibrous Inner chondrogenic = becomes chondroblasts Repair: ○ Chondrogenic cells of the perichondrium (appositional growth- adults) ○ Matrix composition of both Type I and Type II Cartilage cont. Joints Fibrous Joints: ○ Lack a joint cavity and held very close together by dense connective tissue ○ 1. Sutures- skull ○ 2. Syndesmosis- long bones of extremities (interosseous membrane) ○ 3. Gomphosis- teeth/ alveolar process Cartilaginous Joints: ○ Lack a joint cavity and held very close together by cartilage. ○ 1. Synchondrosis- ribs (hyaline) ○ 2. Symphysis- intervertebral disc/pubic symphysis (fibrocartilage) Synovial joints: ○ Articular cavity- no contact of bony surface) ○ Articular cartilage - hyaline cartilage without a perichondrium. ○ Capsule Fibrous layer Synovial membrane- synovial fluid (hyaluronic acid and Leukocytes) Muscle Tissue What is a motor unit? A lower motor neuron and the skeletal muscle fibers that it innervates  Connective Tissue of Skeletal Muscle Endomysium - Delicate connective tissue around individual fibers. Perimysium - Connective tissue that surround a group of fibers called a fascicle. Epimysium - Dense irregular connective tissue that surrounds the entire muscle. Skeletal Muscle Fiber Nucleus is peripherally located (different from cardiac and smooth muscle) Myofibrils containing actin and myosin Sarcoplasmic reticulum which expands into terminal cisterna next to T tubules Triad- the 2 terminal cisternae and T- tubule located at the junction of the A and I bands Myofibril Structure Z disk- defines the sarcomere which is what causes skeletal muscle contraction -I band- composed of ONLY actin (it is lighter than the A band which makes sense because there is only actin, NO myosin) -A band- contains BOTH myosin and actin (it is darker which makes sense since it contains both actin and myosin) -H band- essentially just the center of the A, contains ONLY myosin -M line- center line where myosin attaches Cardiac Muscle Epicardium- outer surface of the heart Myocardium- cardiac muscle held together by connective tissue. The inner portion contains specialized fibers and Purkinje fibers that are part of the impulse conduction system of the heart Endocardium- covers inner surface of heart Intercalated discs- located at the end of muscle fibers and provide attachment to neighboring cells Repair- damaged cardiac muscle is replaced by fibrous connective tissue NOT new cardiac muscle Smooth Muscle Found in places like gut, bile duct, urinary bladder, uterus, blood vessels, respiratory tract, and ureters Tension generated by contraction is transmitted through dense bodies to other cells allowing a group of cells to function like a unit Be able to compare and contrast types of muscle 1. Which types have centrally located nuclei? 2. Which type has diads? 3. Which type has traids? 4. Which type has dense bodies? Answers 1. Cardiac and smooth 2. Cardiac 3. Skeletal 4. Smooth Muscle Physiology Thick Filaments - Myosin - globular head/cross-bridges have 3 sites - ATPase site - Actin binding site - Light chain binding site (function not known) - Titin - connects myosin to z discs (anchors for thin filaments) Thin Filaments - Actin - forms filament that has binding sites for myosin - Tropomyosin - linear protein that covers the binding sites on actin so myosin cannot bind when muscle is resting - Troponin - complex consisting of 3 subunits (troponin T, I, C) - Troponin T binds to tropomyosin - Troponin I binds to actin and inhibits contraction - Troponin C binds to calcium and acts as the regulatory element of the troponin complex Contractile Cycle Myosin head binds actin Power stroke occurs, head moves (ADP and Pi released during this phase) Myosin binds new ATP, head releases actin ATP hydrolyzed, energy cocks the head back to starting position Calcium/Troponin Switch Ca controls if myosin can bind to actin by covering and uncovering the binding sites Action Potential causes release of Ca from where Sarcoplasmic Reticulum Ca binds troponin which shifts the position of the molecule and causes the uncovering of tropomyosin which uncovers binding sites on the actin Active myosin can then bind actin Excitation-contraction coupling - contraction - Muscle AP propagates along cell surface and reaches deeper via T-tubules - When T Tubule is depolarized, voltage gated Ca++ channels called DHPRs are activated - Opening of DHPRs allows Ca++ to enter sarcoplasm and it allows opening of Ca++ channels on SR membrane called Ryanodine receptors (RYR) Excitation-contraction coupling - relaxation 2 mechanisms: - Pump called sarcoplasmic and endoplasmic reticulum calcium ATPase (SERCA) - Uses 1 ATP to transport 2 Ca++ into SR lumen - Ca++ binding proteins (calsequestrin) inside the SR helps buffer Ca++ which allows a large amount of Ca++ to be stored inside the SR - Transporters on sarcolemma - Na/Ca exchanger - Plasma membrane Ca ATPase Overall the goal is to bring Ca++ back into the SR lumen ATP and creatine phosphate - ATP used for muscle contraction however amount is limited so cell needs to continuously synthesize ATP from other high energy molecules - First immediate fuel source: phosphagen system - Creatine phosphate (CP) also called phospcreatine (PCr) or phosphoryl creatine is used to produce ATP - Second fuel source: glycolysis - Third fuel source: oxidative phosphorylation Muscle Fiber Types Type I: red fibers, smaller, slower muscles, resistant to fatigue ○ postural stability Type II: white fibers, larger, gets fatigued easily: sprinting ○ Type IIa: fast oxidative ○ Type IIb: fast glycolytic Length Tension relationship (preload) - Isometric contraction - length stays the same, tension increases - Isotonic contraction - muscle moves an object, length changes, tension stays the same - Optimal length of actin and myosin overlapping allows the maximum force to be generated Force velocity relationship (afterload) - Velocity of muscle shortening is inversely proportional to the amount of load it needs to overcome - Load zero → muscle shortens with max velocity - At loads higher than muscle’s max load, muscle lengthens and contraction becomes eccentric as opposed to concentric contraction Hypertrophy and Hyperplasia growing → adding more sarcomere in series → increases length and they can shorten more and faster hypertrophy: increase # myofibrils in muscle cell Hyperplasia: increases # myofiber in each muscle hypertrophy and hyperplasia add sarcomeres in parallel but DOESN’t affect shortening length or velocity Summation and Recruitment Summation, temporal summation, frequency summation ○ increasing the FREQUENCY of motor unit stimulation Recruitment, spatial summation- increasing the NUMBER of contracting muscle fibers ○ smaller motor units recruited 1st and larger motor units when more force needed Mechanosensors Muscle spindles: ○ inside muscle and run parallel to regular muscle fibers ○ sense length & rate of stretching ○ stretching triggers AP ○ stretch reflex: knee-jerk ○ maintain muscle tone Golgi Tendon Organs ○ in tendons of muscles ○ sense tension & send info to brain ○ bisynaptic reflex arc: prevent injury by inhibiting contraction of muscle Denervation Nerve innervating muscle gets damaged → muscle becomes flaccid & paralyzed ACh from damage nerve released → fasciculations Fibrillation happens due to hypersensitivity to ACh Denervation causes atrophy Need to reinnervate w/in few months to reverse this ○ muscle replaced by adipose & fibrous tissue → permanent shortening and deformity (contracture) EMG Electromyography Pick up compound muscle action potential Not pathognomonic just supports diagnosis Examples to use: MS, neuropathies, myasthenias, myotonias, myopathies, muscular dystrophies Smooth Muscle 2 types - Multiunit - may contract independently of its neighbors due to the lack of electrical connection via gap junction - Each myocyte has its own neuron innervating it which makes it capable of finer control - Unitary - electrically coupled via gap junctions and contract together as a unit by diffusion of ions through those gap junctions - Coordinated but less specific muscle contraction Unique features: ○ actins anchored to dense bodies in cytoplasm & plasma membrane ○ caveolae in smooth muscle = T-tubules ○ innervated by neurons from ANS Phasic and Tonic Tonic - Under continual tension (anal and urinary sphincters) Phasic - Tension fluctuates (intestines during peristalsis) Smooth Muscle Ca2+ Sources Extracellular Ca comes through voltage-gated channels Sarcoplasmic Ca release by binding of Ca to RYR; Ca-induced Ca release 2nd messenger-mediated Ca release from SR by IP3 Smooth muscle contraction - Unlike skeletal muscle, smooth muscle is more dependent on extracellular Ca for its contraction → know the pathways - Regulatory site for contraction is on the myosin molecule - Instead of troponin, smooth muscle has calmodulin in cytoplasm - 4 Ca++ find to calmodulin forming Ca-calmodulin complex → binds to myosin light chain kinase (MLCK) → MLCK phosphorylates regulatory light chain on myosin → conformational change in myosin increasing its ATPase activity → crossbridge and contraction Relaxation requires myosin light chain phosphatase (MLCP) Practice Question Which of the following is a role for ATP in contractions of skeletal muscles? A: When ATP binds to a site on the myosin head, actin is released from its separate binding site on the myosin head. B: When ATP binds to a site on actin , myosin is released from its separate binding site on actin. C: The Na,K-ATPase enzyme in the membrane of the sarcoplasmic reticulum uses ATP energy to move Na + and K+. D: When creatine kinase splits ATP, its energy causes the myosin heads to move about 10 nanometers. E: The trigger for muscle contraction is release of ATP from mitochondria Answer A Practice Question Which of the following statements about muscles is true? A. Smooth muscles are very slow and only develop small tensions. B. Fast-twitch white skeletal muscle fibers have abundant mitochondria in order to have rapid twitch speeds. C. Slow-twitch red skeletal muscle fibers are more abundant in whole muscles used for posture. D. In multi-unit smooth muscles that are not innervated, contractile tension can be increased by recruitment and frequency summation. E. Fast-twitch white skeletal muscle fibers are the most efficient of all muscle fiber. Answer C Practice Question A piece of tissue is stretched, and so are the plasma membranes of its cells. This opens stretch- activated calcium ion channels, leading to calcium influx and a muscle contraction. This event is most likely to occur in A. multi-unit smooth muscle cells. B. unitary smooth muscle cells. C. slow-twitch skeletal muscle cells. D. fast-twitch skeletal muscle cells. E. cardiac annulus fibrosus cells. Answer B Integument Skin, hair, sebaceous, sweat glands, nails = integumentary system Skin = epidermis, dermis, hypodermis Thick = hairless ○ Palms, plantar foot Thin = hairy Functions: protective barrier, receptors for pain, temp, discriminative touch, crude touch, vibration, control body temp, synthesis of Vit D Epidermis Top to bottom ○ Stratum corneum ○ Stratum lucidum ○ Stratum granulosum ○ Stratum spinosum ○ Stratum basale (germinativum) Cells ○ Keratinocytes ○ Melanocytes ○ Merkel cells ○ Langerhan’s cells No blood vessels Stratum Corneum and Lucidum Corneum ○ New cells get pushed up here ○ Turnover time 25-50 days ○ Flattened dead cells w/out nuclei = filled w/ soft keratin Lucidum ○ Only in thick skin Stratum granulosum, spinosum, basale Granulosum: ○ Most superficial layer of NON-keratinized cells ○ Keratohyalin granules → overfill cells, rupture cells → release hydrophobic glycophospholipids (makes waterproof) Spinosum ○ Cells have cytoplasmic processes ○ Langerhan’s cells here Basale ○ Cuboidal cells ○ Mitotic layer ○ Melanocytes and merkel cells here Melanocytes Melanin pigment forming cells Long cytoplasmic processes to contact cells in basale and spinosum Melanocytes attached to basement membrane by hemidesmosomes Skin color = size and # of melanosomes Exposure to UVB light stimulates changes in melanin Melanin granules protect from UV radiation Langerhans Spider-like cells in stratum spinosum Lack desmosomes = able to move APC - uptake, process, and present antigens to T-lymphocytes Merkel Cells Connected to keratinocytes by desmosomes Most numerous in fingertips Mechanoreceptor cells - discriminative touch Dermis Dense irregular CT w/ collagen and elastic fibers Papillary & reticular layers ○ Papillary More superficial Contain dermal papillae → interdigitate w/ epidermis ○ Reticular Deep layer Orientation of collagen fibers → lines of skin tension (cleavage, Langer’s lines) → surgical incisions Vascular supply for epidermis/dermis Hypodermis Adipose tissue and loose CT Insulates, allow movement of skin, contain lower part of sweat glands and hair follicles, adipose cells Dense in scalp, palms, soles Thin Skin Also called non-acral skin Only referring to thickness of epidermis ○ Ie. Skin on back Epidermis: NO stratum lucidum Dermis: hair follicles w/ arrector pili, sebaceous glands, sweat glands; fewer & shallower dermal papillae Innervation of Skin Somatosensory nerve fibers ○ Pain, temp, discriminative/non-discriminative touch , pressure, vibration, conscious proprioception ○ Encapsulated = connective capsule ○ Not encapsulated = free nerve ending Autonomic nerve fibers ○ Carry motor info to smooth muscle in skin ○ Only postganglionic sympathetic fibers → innervate blood vessels, arrector pili, sweat glands Wounds Partial thickness wound Full thickness wound - Epidermis and dermis ONLY - Down to Subq layer - Heals primarily by re-epithelization - Heals through stages of wound healing Split thickness graft Full thickness graft - Epidermis + part of the dermis - Epidermis + ALL dermis - Advantages: can cover larger area, and - Advantages: more cosmetically appealing more likely to work and better skin color match. No secondary - Disadvantages: not as cosmetically wound care because donor site is sutured appealing, different skin color than area close applied - Disadvantages: Higher graft failure & more metabolic needs than STSG. - Wouldn’t use with pt’s that have trouble with wound healing Stages of wound healing Alphabetical order: H, I, P, R Only happens for FULL thickness wounds - Hemostasis: 0-3 hours after injury - Inflammation: 3 hours - 3 days - Proliferation: 3-21 days - Remodeling: 21 days- 2 years People with wound healing problems get stuck in the inflammation stage Spongiotic Dermatitis Spongiotic vesicles in the epidermis due to the rupture of desmosomes 1. Atopic dermatitis 2. Nummular eczema 3. ID reaction 4. Dyshidrotic eczema Bullous Pemphigoid and Pemphigus Vulgaris Autoimmune disorders - Bullous Pemphigoid: causes tense bullae - HEMIdesmosomes are attacked at the epidermal/dermal junction and fluid infiltrates - Pemphigus vulgaris: no tense bullae - Desmosomes are attacked in the epidermis but no fluid filled bullae are made Filaggrin Filaggrin plays an important role in the skin’s barrier function and helps with the retention of moisture in the skin. - Mutation in filaggrin = atopic dermatitis - Absent filaggrin = ichthyosis vulgaris - Extremely dry skin because you can’t retain water Anastomoses Pathways for blood to be directly connected between arterioles and venules, without going through capillary beds Example: when it is really cold outside, blood can be shunted away from your fingers and toes Glomus bodies: AVA tumors, usually under nails Relaxed Skin Tension Lines **important AKA: Langer lines Located @ RETICULAR dermis Arranged PERPENDICULAR to the long axis How to make incisions: - Parallel to RTSL = best = wounds close with minimal tension - Perpendicular to RTSL = worst = wound can open under tension - Oblique to RTSL = second best option if you can’t do parallel Changes in skin with aging - Everything slows down, cracks, wrinkles. Think about why / where in the epidermis or dermis the changes are happening - Epidermis: slower epithelialization and wrinkling of skin - Think of how keratinocytes slow down and what are the effects of that - Melanocytes decrease and produce less melanin→ risk factor for what?? - Dermis: - Decreased collagen = atrophy of dermis - Degeneration of elastic fibers - Reduced sweat gland production (less sweating = dryer skin) - Reduced sensation - Reduced arterial perfusion - Subq: atrophies Skin Functions - Primary defense: intact s. corneum - Important in water retention of the skin (remember dry skin will crack!) - Once skin opens up = entry way for pathogens - Sebum - oil made by sebaceous glands - Provides acidic environment → toxic to bacteria - NOT found on palms and soles of feet - Normal skin fluora- microbes that live on your skin but don’t cause any harm - Diff organisms depending on the location of the body and skin temp, humidity, glandular distribution - Skin folds where moisture collects are big areas for normal and abnormal microbes to grow - Sebaceous glands provide food for microbes (think acne) Skin prep - Isopropyl alcohol - Fast but very drying - Povidone-iodine - Slower but more active at killing - Preference for open wounds - Can cause skin reactions → contact dermatitis - Chlorhexidine - Fast acting and active for several hours - Use with pt’s that have a betadine (iodine) allergy / shellfish allergy - Question: You have a patient that has a laceration on their arm and needs stitches, but recently discovered he is allergic to shrimp, which antiseptic would you use? Skin Immunity - In the epidermis: Langerhan’s - In the dermis: Macrophages & Mast cells - Part of the inflammatory response of wound healing - Mast cells release histamine → inflammation (wheal and flare reactions) - (come back to how APC help) Thermoregulation - Need to maintain core body temp around 98.6 → extremities get cold to make sure your organs are warm - Non-glabrous (hairy) skin: - apocrine and eccrine glands sweat to cool the body - Controlled by autonomic nervous system - Glabrous (hairless) skin: - Eccrine glands only- don’t sweat to cool, they just sweat for moisture - Controlled by sympathetic nervous system - Raynaud’s phenomenon - Dysfunction of the thermoregulation system - Autonomic nervous system neuropathy - When you’re cold → fingers get no blood flow Nerve sensation If you can’t feel it you can’t heal it - Nerve dysfunction of the skin can lead to: pruritus, dysesthesia, numbness Nails Nail anatomy is most important Think of the prefixes and suffixes rather than just memorizing Onycho = nail Lysis = breaking / separating Myco = fungus Etc. Be sure to look at the images when reviewing Non-encapsulated Merkel cells: discriminative touch Free nerve endings: pain, temp, itching, non-discriminative touch Hair follicle receptors: discriminative touch and vibration Encapsulated Meissner’s corpuscles = in dermal papillae → discriminative touch Pacinian corpuscle = in hypodermis → vibration Ruffini’s endings = deep in dermis → shearing stress  Vascular Supply Arteries in SubQ plexus give rise to: ○ Subpapillary plexus = upper dermis and epidermis; capillary loop in dermal papillae ○ Cutaneous plexus = hypodermis and deeper dermis Lymphatic vessels → below papillary layer of dermis Hairs Lanugo: fetus hair, thin, unpigmented Vellus: soft, short, colorless Terminal: hard, long, large, coarse, dark Hair follicle = shaft, bulb, CT sheaths Hair growth Anagen: growth phase, 2-7 years and 90% of hair is in this phase Catagen: regression, blood supply interrupted Telogen: resting phase, shedding Male pattern baldness ○ Follicles sensitive to DHT Arrector Pili and Sebaceous Glands Arrector pili ○ Smooth muscle ○ Attach @ angle ○ contraction = hair stands = goose bumps ○ Innervated: postganglionic sympathetic fibers Sebaceous ○ Secrete sebum onto hair follicle to waterproof & moisturize Sweat glands Eccrine ○ Everywhere EXCEPT axilla and perineum ○ Simple coiled tubular; secrete watery fluid ○ Spiral duct in epidermis, opens up on sweat pore ○ Merocrine process = product released Apocrine ○ Secrete milky odorless substance ○ Larger ○ Axilla, areola, perineum Nails Plate: free edge, body, lunula, root Bed: highly vascularized Matrix: surrounds nail root Folds: prox and lateral borders of plate Grooves: furrows b/n folds and bed Eponychium: edge of skin fold, covers nail root Hyponychium: thick epidermal layer beneath free edge of nail plate Bone Histology Bone tissue = cells + mineralized ECM (inorganic and organic) Inorganic = calcium phosphate → hydroxyapatite crystals ○ 99% Ca = in bone ○ Rigidity Organic = type I collagen, proteoglycans, non-collagen organic material ○ Elasticity and resilience Classification of Bone Shape ○ long = shaft w/ 2 heads ○ Short = cuboidal ○ Flat = plate-like ○ Irregular ○ Sesamoid Structure ○ Macro: compact (cortical) vs spongy (cancellous, medullary) ○ Micro: lamellar vs woven Development ○ Intramembranous vs endochondral Macroscopic Compact = forms outer shell Spongy = forms medullary center Outside of bone covered by periosteum → dense irregular CT and osteogenic cells (non-articular regions) Articular regions → covered by hyaline cartilage Microscopic Lamellar (mature) ○ Regular collagen alignment ○ Healthy adult ○ Found in compact and spongy bone Woven (immature) ○ Irregular collagen alignment ○ Developing bone and pathologic conditions = healing fractures, osteogenic tumors, metastatic formation ○ Found in compact and spongy bone **Components of compact bone ** Lamellar cylindrical units, called osteons or Haversian systems ○ Osteon consists of: longitudinal canals w/ blood vessels/nerves @ center ○ Surrounded by concentric lamellae (4-15 layers) ○ Lamellae have osteocytes in their lacunae and their cytoplasmic processes go out (canaliculi) ○ Volkmann’s Canal = interconnecting Haversian canals → transversely Interstitial lamellae → between osteons Circumferential lamellae → beneath periosteum and endosteum of marrow cavity ○ Peri = collagen fibers, blood vessels, nerves (outer) and osteogenic cells (inner) ○ Endo = osteogenic cells Know this slide well Spongy Bone Details spicules/trabeculae patterns w/ interconnecting marrow spaces Bone matrix is lamellar and has osteons if it is sufficiently thick Nourished from diffusion from marrow cavity Osteoblast Cuboid, basophilic cytoplasm, abundant RER, golgi, free ribosomes, secretory vesicles → know this Secrete osteoid and controls mineralization What is osteoid? ○ Procollagen ○ Proteoglycans ○ Alkaline phosphatase ○ Osteocalcin ○ Osteonectin ○ Bone sialoprotein Stimulated by vitamin D, estrogen and GF (IGF-1) Osteoprogenitor Cells Innermost layer of peri and endosteum Comes from mesenchymal cells Differentiate to osteoblasts, chondroblasts, fibroblasts Will do mitosis Osteoblast and osteoprogenitor After osteoid is formed → osteoblasts secrete Ca into ECM = mineralization Osteoblasts stimulated by Vit. D, estrogen, GF Structures: ○ Osteoprogenitor = spindle-shaped, pale stain cytoplasm, sparse RER, poor golgi ○ Osteoblast = single layer cuboidal → columnar cells; lots of RER and golgi Osteocytes When osteoblasts get enclosed by matrix → osteocytes These are small, so reduced organelles They have cytoplasmic processes extending into canaliculi → communication w/ their osteocyte neighbor via gap junction → forms network Purpose = maintain bone matrix Osteoclasts Bone resorption Comes from bone marrow Macrophage go through mitosis and the new cells fuse → large multinucleated osteoclast Cytoplasm = acidophilic Osteoblast regulate osteoclast formation ○ Blast secretes M-CSF → bind monocyte → induce expression of RANK on monocyte (macrophage now) ○ Blast has RANKL → binds to RANK on macrophage → osteoclastogenesis ○ Osteoprotegerin blocks RANKL binding to RANK Osteoblast gets activated by PTH → then stimulates M-CSF and RANKL More Details From Previous Slide Osteoclasts inhibited by calcitonin Activation of osteoclasts ○ After sealing zone & ruffled borders appear ○ In shallow depression called subosteoclastic compartment or Howship’s lacuna ○ Cytoplasm = acidified vesicles that insert into ruffled border w/ H-ATPase pumps → make environment acidic → demineralization occurs Cathepsin K → go from ruffled border to lacuna and breaks down organic matrix Degradation products get endocytosed and broken down more into AA, mono-disaccharides, Ca → released to capillaries Intramembranous Bone Formation Bone develop from mesenchyme Fetal life and into childhood The steps: ○ Mesenchymal cell condense in vascularized membrane-like structure → differentiate into osteoprogenitor cells → then to osteoblasts → secrete osteoid → mineralized matrix → gets enclosed by bone → osteocyte Where does occur? → Flat bones of skull Ossification centers fuse → trabeculae networks (immature bone) → remodel immature bone into lamellar bone by osteoclast resorption and osteoblast deposition Endochondral Bone Formation Long bones, short bones, irregular bones Mesenchyme → chondroblast → hyaline cartilage model → replaced by bone Fetal until adulthood Long bones ○ Ossification mid-shaft w/ hypertrophy of chondrocytes → 3rd fetal months ○ Hypertrophic chondrocytes secrete VEGF → VEGF induce perichondrium to be vascularized ○ Hypertrophic chondrocytes make alkaline phosphatase → calcification ○ Hypertrophic chondrocytes apoptosis → form large cavities ○ Blood vessels grow & bring osteoprogenitor cells and precursors to hematopoietic cells Long Bones Osteoprogenitor and hematopoietic cells get to core of calcified cartilage Osteoprogenitor → osteoblasts → lay osteoid Osteoclast resorb cartilage/calcified bone → gets replaced by new bone Region = Primary ossification center and ossification will move to both epiphyses Secondary ossification: ○ Late fetal development - early teens ○ Hyaline cartilage remains @ articular surfaces and there is no bone collar Short and Irregular Bones Short ○ Carpal and tarsal bones ○ Usually have 1 primary center of ossification Irregular ○ Vertebrae, os coxae, scapula ○ Single or many primary and secondary centers of ossification Epiphyseal Plate Located in metaphysis, responsible for growth in LENGTH of bone Spongy bone gets converted to compact bone Long bone growth stops w/ closure of epiphyseal plates (bone replaces cartilage) Length Steps ○ Zones of resting cartilage → chondrocytes randomly dispersed ○ Zone of proliferating cartilage→ rapid mitosis and get into columns ○ Zone of maturation → chondrocytes enlarge ○ Zone of calcifying → calcify matrix and die ○ Zone of ossification → blasts lay osteoid, clasts resorb calcified cartilage; trabecular bone formed Mnemonic: "real people have career options" Long Bone Width Growth Vascular Supply Long bones ○ Nutrient, epiphyseal, metaphyseal, and periosteal arteries Short bones ○ Nutrient arteries Flat bones ○ Nutrient and periosteal arteries Irregular bones ○ Nutrient and periosteal arteries Bone Remodeling Needed for: ○ Normal maintenance of bone and repairing fractures Bone is dynamic = mechanical adaptation ○ Density will increase or decrease depending on the external load ○ Capacity to adapt to changes in load Process ○ Osteoclast excavates tunnel and osteoblast fills it in Estrogen Osteoblast is under estrogen control ○ Decrease apoptosis & RANKL activity Osteoclast under estrogen control ○ Increase apoptosis & decrease RANK induced activity Deficiency ○ Decrease BLAST activity and increase CLAST activity Osteoporosis ○ Blasts cannot fully repair resorptive defect → loss of bone mass Possibly reversible w/ estrogen therapy, Vit. D, Ca, weight-bearing Nutritional Deficiencies Vit. D → needed for Ca and phosphorus absorption; stimulates osteoblast ○ Deficiency defect in mineralization of osteoid → adults Defect in mineralization of cartilage in growth plates = rickets in children Vit. C → needed for collagen production ○ Deficiency Reduced formation of bone matrix and bone development Delayed wound healing (Scurvy) Fracture Repair Hemorrhage in area 1. Procallus formation → clotting and granulation tissue 2. Soft callus formation → osteoprogenitor cells become chondroblasts, so granulation becomes hyaline cartilage (binds fractured bone together) 3. Bony callus formation → chondrocytes in hyaline cartilage hypertrophy and release VEGF (replaced w/ primary bone) 4. Compact bone replaces spongy bone (remodeling) Fracture Repair Cont. Clot: blood vessels cross fracture and get broken → hematoma (6-8 hrs after injury) Callus: internal and external calluses (48 hrs after injury) Remodeling: dead portions of bone resorbed and trabeculae replaced by compact bone Diarthrodial Joints Moveable Articular cartilage ○ Hyaline has no perichondrium Articular cavity → articulating bony surfaces not intact Capsule → fibrous layer; synovial membrane layer ○ Synovial cells secrete synovial fluid Calcium Metabolism - Where is calcium required: - Where is calcium found in the body : - Muscles contractions - Intracellular: sequestered in the mitochondria or ER - Bone formation - Blood and ECF: at least half is bound to protein. Normal - Nerve conduction concentration is always near the saturation point of 350mg - Hormone release - Bone: ~99% of the body calcium is in bone in the form of - Blood coagulation hydroxyapatite crystals. 1% freely exchanges with the ECF - Intracellular signaling and serves as the reservoir for when you need calcium - Regulation of many enzymes Vitamin D **important Vitamin D is essential for calcium absorption. No vitamin D = no calcium even if you drink 10 gallons of milk ACTIVE Vit D = 1,25 dihydroxycholecalciferol ( 1,25 diOH D3) DIETARY Vit D = ergocalciferol (D2, from plants) and cholecalciferol (D3, from animal tissue) UV light is essential to make cholecalciferol (D3) which then is converted to active Vit D Vitamin D cont. - 2 hydroxylation reactions necessary to make ACTIVE vitamin D - @ Liver : cholecalciferol (D3) + OH at C25 → 25-hydroxycholecalciferol (25-OH D3) - @ kidney: 25-OH D3 + OH at C1 → 1,25-hydroxycholecalciferol via kidney alpha 1 hydroxylase - Active vit D = calcitriol - PTH stimulates kidney alpha 1 hydroxylase - If no PTH = no kidney alpha 1 hydroxylase = no final reaction to make calcitriol = no calcium absorption - Too much vitamin D = extra hydroxylation at C24 = 1,24,25 D3 or 24,25 D3 = inactive vitamin D Relationship of Vitamin D and Calcium 1. Calcitriol enters intestine cell → binds to receptor → goes into the nucleus → stimulates synthesis of calbindin → calbindin transports calcium from intestinal into bloodstream a. Calcitriol acts similar to steroid hormones b/c it goes into the nucleus and stimulates transcription of other proteins 2. Calcitriol stimulates osteoclasts at bone → bone resorption releases calcium and PO4 into the bloodstream 3. Calcitriol causes renal retention at kidneys → calcium remains in bloodstream instead of being excreted a. Controversial topic PTH and calcium Secreted by chief cells at the parathyroid gland (chiepht cells) 1. PTH stimulates kidney hydroxylase → forms active vit D → calcium can be absorbed 2. PTH stimulates bone resorption → calcium released into the blood 3. PTH causes renal retention of calcium → calcium remains in blood stream Regulation of PTH PTH and calcium are inversely proportional : more Ca2+ = less PTH (think of the functions of PTH as listed above) CaR/CaSR recognizes high serum calcium levels and signals to decrease PTH stimulation Calcitonin Lowers calcium levels Release from parafollicular / C cells from the thyroid gland (C cells = CalCitonin) 1. @ intestine: calcitonin inhibits absorption of calcium 2. @ bone: calcitonin inhibits osteoclasts → no bone resorption → no calcium released into blood 3. @ Kidney: calcitonin inhibits renal retention of Ca2+ → calcium is excreted Calcium homeostasis Key takeaway: - At any given point, you only need ~ 1000mg of Ca2+ in the blood - Your kidneys will release 200, which is replaced by 200 that you eat in diet - Calcium goes in and out of bone, anion complexes, and proteins to maintain the 1000mg H+ and Ca2+ compete for binding spots on albumin Acidemia = Hypercalcemia because the extra H+ take up more spots on the albumin → more free calcium in the blood → HYPERcalcium Alkalemia = Hypocalcemia because the less H+ leaves more open spots on albumin for Ca to bind → less free calcium in the blood → HYPOcalcemia HYPERcalcemia disorders Most common CAUSE of hypercalcemia = hyperparathyroidism (hyper PTH) ○ Think of why this makes sense ○ Hyper PTH = excess PTH which plays a role in releasing calcium into the bloodstream = hypercalcemia Signs and symptoms of hypercalcemia ○ Think of where calcium is found and how releasing too much into the bloodstream can be problematic ○ Bone = leeches bones and makes them weak = brittle bones ○ Kidneys = causes excess renal retention = kidney stones HYPOcalcemia disorders Most common causes = decreased PTH or active vitamin D Think of where calcium is needed and why having less can be problematic ○ Muscles especially - Remember the location and function of the main components of bone - Where do the vessels run through? → canal - Which cells are on the outer layer? → osteoblasts - Which cells maintain bone and communicate with each other? → osteocytes - How do they communicate? → canaliculi Osteoblasts What they do : 1. Osteoblasts secrete type 1 collagen, osteocalcin, etc → ○ Produce TYPE 1 collagen for the ECM form osteoid → scaffold for deposition of mineral ○ Produce osteocalcin 2. ALP breaks down PPi → promotes calcium and phosphate ○ Make RANKL and Osteoprotegrin (OPG) precipitation → hydroxyapatite crystals are formed ○ High ALP activity a. PPi normally prevents the precipitation so you need to ○ Deposit Ca++ and P- into the bone break it down This is how you build strong bone ○ The TARGET of PTH and vitamin D 3. OB’s make RANKL → binds to RANK on osteoclasts → OC PTH → increases OPG (which can lead to over are activated activated osteoblasts) 4. OB’s make OPG → competes with RANKL for RANK → Vit D → osteoblasts differentiation OC are inactivated Osteoclasts What they do: ○ Breakdown bone ○ Express RANK → therefore stimulated by OB’s ○ Inhibited by calcitonin → think about how calcitonin decreases calcium levels, and active osteoclasts are releasing calcium ○ Release acid via carbonic anhydrase into howship’s lacuna Notes to review  Calcium Homeostasis 3 hormones that regulate blood calcium levels ○ Vitamin D (Calcitriol)- goal is to INCREASE the amount of calcium in the blood (helps stimulate calcium absorption from our gut) ○ 2. PTH- goal is to INCREASE the amount of calcium in the blood (stimulates osteoclasts so they CAN break down bone and release calcium) ○ 3. Calcitonin- goal is to DECREASE the amount of calcium in the blood (inhibits osteoclasts so they CAN’T break down bone and release calcium)  Bone Physiology Osteoblasts: make new bone ○ Produce RANKL and OPG ○ The target of PTH and vitamin D Osteoclasts: resorption of bone ○ Have the receptor RANK ○ Inhibited by calcitonin Kahoot https://create.kahoot.it/share/sf-exam-3-kahoot/590c79a8-27d2-4b7a-a18a-e8a250e621d8