Unit 2 LGS Flashcards
Identify the type of lesion and give an example
Atrophy - stretch marks, aged skin
Identify the type of lesion and give an example
Bulla - blisters
Identify the type of lesion and give an example
Cyst - cystic acne
Identify the type of lesion and give an example
Erosion - blister after rupture
Identify the type of lesion and give an example
Excoriation - scratch
Identify the type of lesion and give an example
Fissure - Cracks in dry skin, corners of mouth
Identify the type of lesion and give an example
Keloid - scarring
Identify the type of lesion and give an example
Lichenification - Chronic atopic dermatitis
Identify the type of lesion and give an example
Macule - freckle, flat nevi, petechiae
Identify the type of lesion and give an example
Nodule - dermatofibroma
Identify the type of lesion and give an example
Papule - Wart, elevated nevi
Identify the type of lesion and give an example
Patch - vitiligo, cafe au lait spots
Identify the type of lesion and give an example
Plaque - psoriasis, atopic dermatitis
Identify the type of lesion and give an example
Pustule - acne
Identify the type of lesion and give an example
Scale - dry skin, psoriasis, seborrheic dermatitis
Identify the type of lesion and give an example
Ulcer - stasis ulcer
Identify the type of lesion and give an example
Vesicle - Varicella, herpes zoster
Identify the type of lesion and give an example
Wheal - insect bite, allergic reaction
What is the cause of vitiligo?
Having a decreased amount or lack of melanocytes in an area of the epidermis
What is the classis presentation of herpes zoster?
Predict the histological findings.
Erythematous vesicles in a dermatomal pattern, typically unilaterally on one side of the trunk.
Acantholysis - separation of the skin in the stratum spinosum
A 4 year old presents with a quickly spreading rash all over. It’s pruritic and she has a fever. The rash shows papules, vesicles and crusts. What is the likley diagnosis?
Varicella
A patient presents with a velvety appearance in the fold of the neck. The pt’s hx is significant for diabetes. Predict the histological findings.
Acanthoses nigricans
Explain the pathophysiology of alopecia areota
Lymphocytes around the hair follicles lead to alopecia in one spot
A punch biopsy is used to
give full thickness sample to the subQ area
What are the functions of the skin?
Thermoregulation - sweat glands, fat
Containment of internal contents
Sensation - Merkel cells, free nerve endings, corpuscles
Vitamin D synthesis
Protective covering
What are two ways to confirm or rule out fungal involvement in a lesion?
Wood’s Lamp - fungi release bioctorins which fluoresce under UV light - doesn’t detect endothrix or non-fluorescent fungi
KOH test - KOH dissolves non-fungal cells, leaving fungi behind
Describe the type of glial cells and their function
Oligodendrocytes - “Schwann cells of the CNS” - form myelin sheaths around axons to provide insulation for AP
Astrocytes - form BBB - separates blood from extracellular fluid, allows nutrients to reach the brain while preventing pathogens from entering
Microglial cells - phagocytic cells - reactive to injury and mediate immune reactions
Define the structural components of a typical neuron
Dendrites - receive signals through synaptic cleft
Soma - cell body, houses nucleus and organelles
Axon hillock - absence of nissl bodies
Axon - contains dense bundles of microtubules and neurofilaments
Axon terminal - site of synapse
Oligodendrocytes/Schwann cells - myelinate axons
What’s the difference between a nerve and a nerve fiber?
A nerve fiber is a single neuron with a single axon and it’s myelin sheath
A nerve is a bundle of nerve fibers
Cell bodies are housed in the ____ matter while axons are housed in the _____ matter.
grey
white
What is the structural and functional unit of the nervous system, and it’s general function?
Neurons - electrochemical signaling to communicate sensory and motor information to and from the CNS, respectively
What is the function of epineurium, perineurium, and endoneurium?
Endoneurium covers individual nerve fibers
Perineurium covers fascicle of nerve fibers
Epineurium covers a nerve
Compare and contrast myelinated vs unmyelinated nerve fibers
Myelinated nerve fibers have abundant Schwann cells
Unmyelinated nerve fibers still have Schwann cells, but one SC engulf several nerve fibers
Which ions have a higher concentration inside the neuron than outside?
K+ ~145
(4-5 outside)
Which ions have a higher concentration outside the neuron than inside?
Na ~140 (~10 inside)
Cl ~100 (~3 inside)
Ca2+ ~8-10 (<1 inside)
HCO3 ~25-30 (7-10 inside)
Explain the ionic basis of a resting membrane potential
Difference in charge between the intracellular and extracellular space created by a chemical and electrical gradient, mostly dependent on K+
What would happen if a neuron was permeable to K+ only?
K+ would leave the cell quickly due to the concentration gradient pulling them outside of the cell –> sending RMP more negative.
As K+ leaves and the inside of the cell gets more negative, the electrical gradient reattracts positively charged K+ –> sending RMP more positive.
This would continue until an equilibrium is reached closer to the K+ resting potential
Explain why the rising phase of the action potential peaks at the value that it does, including critical factors that determine the actual value.
The peak of the rising phase is dependent on the concentration of Na+ ions inside and outside of the cell. When the sodium channels open, allowing Na+ ions to move down the concentration gradient into the cell, the resting membrane potential rises closer to the Na+ equilibrium potential. Once the RMP increases to approximately +30, potassium channels sodium channels begin closing and potassium channels open. With the opening of K+ channels, K+ leaves the cell decreasing the RMP once again toward the K+ equilibrium.
Describe the structure, function and significance of myelin in the process of AP conduction
Myelin sheaths prevent leakage of ions down the body of the axons which force AP forward
Nodes of Ranvier are necessary for depolarizing current to flow
How does hyper/hypokalemia effect APs
HyperK –> too much K+ outside of cell –> more positive RMP –> less stimuli needed to meet threshold
HypoK –> too little K+ outside of cells –> more negative RMP –> more work needed to meet threshold
How does hyper/hyponatremia affect APs?
HyperN –> too much Na+ in blood –> more positive RMP –> less stimuli needed to meet threshold
HypoN –> too little Na+ in blood –> more negative RMP –> not enough to create AP/ too much work –> reduced/no activity
If cells were made permeable to only one ion (K+ or Na+), when will the RMP voltage stop changing?
When the chemical force is equal to the electrical force.
Norepinephrine and Epinephrine bind to what class of receptors?
Adrenergic receptors
Acetylcholine binds to what class of receptors?
Cholinergic receptors
Describe the two Adrenergic receptors, where they are typically found, and what part of the nervous system uses them.
Alpha receptors - GPCR - generally found in smooth muscle - sympathetic nervous system
Beta receptors - GPCR - found in heart and lungs - sympathetic nervous system
Describe the two Cholinergic receptors, where they are typically found, and what part of the nervous system uses them.
Nicotinic receptors - Ligand gated channel - found in nerves and skeletal muscle - sympathetic and parasympathetic nervous system
Muscarinic receptors - GPCR - found in glands and smooth muscle - mostly parasympathetic nervous system (exception: sweat glands - sympathetic nervous system)
Describe the parasympathetic pathway to their effector organ
Presynaptic (long) neuron releases ACh –> Nicotinic receptor of postsynaptic (short) neuron which releases ACh –> Muscarinic receptor of effector organ
Describe the sympathetic pathway to sweat glands
Presynaptic (short) neuron releases ACh –> Nicotinic receptor of postsynaptic (long) neuron which releases ACh –> Muscarinic receptor of sweat gland
Describe the sympathetic pathway to the lungs or cardiac muscle
Presynaptic (short) neuron releases ACh –> Nicotinic receptor of postsynaptic (long) neuron which releases NE –> Beta receptors of the lungs or the heart
Describe the sympathetic pathway to effector organs via the Adrenal medulla
Presynaptic (short) neuron releases ACh –> Nicotinic receptor on chromaffin cells of the adrenal medulla which releases Epi, NE, or DA –> alpha or beta receptor of effector organs
Describe the pathway of a somatic neuron to skeletal muscle
Neuron releases ACh onto Nicotinic receptor of effector organ
How do alpha receptors regulate smooth muscle contractions?
SNS releases NE or Epi to alpha receptors –> Gaq activates PLC –> IP3 –> increase of SR Ca2+ –> increases cell Ca2+ –> increase of Ca2+-CM complex –> increase myosin light chain kinase activity –> Phosphorylates MLC –> contraction
How do beta receptors regulate smooth muscle contractions?
SNS releases NE or Epi to beta receptors –> Gas activates adenylyl cyclase –> cAMP –> inhibits myosin light chain kinase activity –> no phosphorylation of MLC –> relaxation
How does Nitric Oxide regulate smooth muscle contractions?
NO activates cGMP –> activates myosin light chain phosphatase –> breaks phosphorylation bond of MLC –> relaxation
Ascending paralysis is a hallmark clinical presentation for what disease?
Explain how it leads to neuropathy
Guillan Barre Syndrome - an immunologically mediated demyelinating peripheral neuropathy
T-cell mediated immune response leads to macrophage destruction of myelin sheaths
Explain how diabetes can lead to neuropathy
Hyperglycemia –> nonenzymatic glycosylation of proteins, lipids, nucleic acids –> formation of AGEs –> activates inflammatory signaling
Excess glucose -> depletes NADPH –> increase injury via ROS
Progressive symmetrical proximal to distal weakness which develops over months, along with reduced tendon reflexes are indicative of which disease
Explain how it leads to neuropathy
Chronic inflammatory demyelinating polyneuropathy
T cells and antibodies target molecules at Schwann cell-axon junction –> IgG and IgM found on myelin sheaths lead to recruitment of macrophages that strip myelin from axons –> over proliferation of SC –> onion bulb
What is Froment’s sign and what does it indicate?
Froment sign shows if a patient is able to hold a piece of paper between their fingers without flexing them.
Positive sign can be indicative of Cubital Tunnel syndrome which impinges the ulnar nerve
If someone says a patient has “Saturday night palsy”, what does that mean?
The patient had a compressed radial nerve for a prolonged period, causing weakness and inability to extend the thumb, along with sensory deficits
Location and function of Pacinian corpuscles
Deep dermis (subQ)
Deep transient pressure, high frequency vibration
Location and function of Ruffini corpuscles
Reticular layer of the dermis
Stretch, joint angle change, finger positioning
Location and function of Merkel cells
Papillary layer of dermis - base of epidermis
Light touch, texture, fine discrimination
Location and function of Meissner corpuscles
Papillary layer of dermis, projects into epidermis
Fine touch and pressure, low frequency vibration
Location and function of zonula occludens
(tight junction)
Located between epithelial cells circumferentially, close to apical side
Prevents paracellular movement, creates impermeable barrier
Location and function of zonula adherins
(adherins junction)
Located between epithelial cells circumferentially, basal to the zonula occludens
Create “belt-like” support between cells through E-cadherin connecting proteins
Location and function of desmosomes
(macula adherin)
Scattered on sides of epithelial cells
Connects keratinocytes to stratum spinosum with desmoglian, provides structure
Location and function of hemidesomsomes
Basal side of epithelial cell
Connects cell to basement membrane
Location and function of gap junctions
Sides of epithelial cells
facilitate electrochemical communication b/t cells
Which sensory receptors have large receptive fields?
Pacinian corpuscles
Ruffini corpcuscles
Which sensory receptors have slow adaptation?
Ruffini corpuscles
Merkel disks
Describe warm thermoreceptors
Small, unmyelinated
Increase AP frequency with increase skin temp (30C-45C)
Describe cold thermoreceptors
Two types: myelinated (Aδ) and unmyelinated (C) fibers
increase AP frequency with decrease skin temp (43C-25C)
Outline the four types of nociceptors and their sensitivities to tissue damage
Chemical: secretions associated with inflammation, substances released from ruptured cells, caustic agents (acid)
Thermal: extremes of temperature >45C, <20C (hot stove, dry ice)
Mechanical: extreme pressure (blunt trauma, crush injuries)
Polymodal: responds to at least 2 of the 3
What determines core temperature?
Heat gain + Body heat content - heat loss to environment
When core temp __________, the body responds with vasodilation.
increases
When core temp _________, the body responds with vasoconstriction
decreases
What is the role of PGE2 in inflammation/infection?
Infection causes release of inflammatory response (IL1, TNFa, IL6) and endogenous pyrogens to produce PGE2 –> stimulates hypothalamus to increase body temp to new “Tset”
What are the thermoregulatory responses during the onset of fever?
During the return to normothermia?
How do cytokines play a part in this?
When cytokines are released, the Tset increases which causes the body to conserve heat to raise it’s temp (shivering, vasoconstriction). Once concentration of pyrogens has decreased, the Tset decreases and body begins releasing heat to get back to Tcore (evaporation, vasodilation)
How does the core temp and set temp change with exercise? What is the body’s response to this?
The set temp does not change.
As muscles contract, the body generates heat which raises core temp. The body begins releasing heat through evaporation to get back to normothermia
Exercising in heat adds to heat gain. Exercising in humidity decreases ability to sweat which can be dangerous as the body cannot get back to core temp.
How do sympathetic responses of blood flow differ in apical skin vs nonapical skin?
The apical skin has glomus bodies connecting venules and arterioles to bypass capillaries which aid in reduction of heat loss when constricted in response to sympathetic NS signals
The nonapical skin lacks these AV anastomoses, and responds to both sympathetic and parasympathetic signals to vasoconstrict and vasodilate
What are the four key components included in an assessment of a pt’s capacity?
Communicating a choice
understanding
Appreciation
Rationalization/Reasoning
Describe the composition and neural control of sweat secretion by sweat glands
Eccrine (not apocrine) SG contribute to temp regulation
Sympathetic n releases ACh onto muscarinic receptor of secretory coiled cells –> activated phospholipase C –> stimulates PKC, increases Ca2+ –> triggers primary secretion –> absorption of Cl- in the duct –> attraction/absorption of Na+ in the duct –> osmotic gradient drives secretion of water into duct –> secretion flows along duct to skin –> reabsorption of NaCl out of duct –> limited reabsorption of water –> loss of solute-free water
What are the four proponents of ethical decision making?
Medical indications - hx, goals of treatment, probability of success
Patient preferences - pt’s decision being respected, living will
Quality of life - chances to return to normal life, comfort, deficits
Contextual features - religious, economic, financial factors
What are the five models of osteopathic care?
Biomechanical model - relationships within MSK
Respiratory-circulatory model - respiratory mechanics and vascular and lymphatic drainage
Neurological model - normalization of somatic and autonomic nervous tone
Metabolic energy model - minimizing energetic demands on the body and optimizing metabolic and physiologic processes
Behavioral model - improving health through effect of the mind and spirit
Differentiate between linear and non-linear systems
Linear is when events happen consecutively (multiple causes for multiple effects)
Non-linear is when one intervention can cause multiple effects in the body in multiple systems
Describe the structure and function of fascia
Network of irregular connective tissue (collagen, glycoproteins, proteoglycans, hyaluronic acid, water)
Interpenetrates and surrounds all muscles bones and organs creating a unique environment for the body to function
Explain the physics behind viscoelasticity
Viscosity changes when put under stress due to electric charge accumulation in tissue
Hydrated proteins go from fluid to gel-like substance
Why blunt force trauma hurts the body so much –> feels like hitting concrete
Differentiate between interoception and proprioception
Interoception - sense of what’s going on inside the body
- pain, weakness, instability, mental status, etc
Proprioception - sense of where the body is in space
Define pandiculation
Stretch after period of rest or inactivity
yawning and stretching –> myofascial reset process - “gearing up” enzymes in muscles, warming up body for activity
Outline the phases of wound healing
Hemostasis - vasoconstriction, platelet aggregation, leukocyte migration
Inflammatory phase - neutrophil influx, chemoattractant release, macrophages, phagocytosis
Proliferative phase - fibroblast proliferation, collagen synthesis, ECM reorganization, angiogenesis, granulation tissue formation
Remodeling/maturation phase - epithelialization, ECM remodeling, increase of tensile strength of wound
What products are released from dense and alpha granules?
alpha - vWF, IGF-1, PDGF, TGF-B, VEGF, chemokines
dense - ADP, ATP, Ca2+, serotonin
What growth factors are chondroinductive and what is their function?
BMP-2 signaling pathways are major source to design and develop chondroinductive peptides for cartilage tissue engineering
How does a whole muscle fiber contract synchronously when the signal occurs only at a small area of the muscle membrane?
The depolarization at the NMJ propagates an action potential down the muscle fiber
Explain the generation and roles of the end-plate potential and muscle action potential
AP of the nerve releases ACh into synaptic cleft –> attached to nicotinic, ligand-gated Na/K channels –> depolarization of end plate on sarcolemma –> generation of AP
The epiblast and hypoblast become…
Epiblast - endoderm, mesoderm, ectoderm
Hypoblast - endoderm
Explain the steps of neurulation
Neural plate forms as ectoderm thickens and flattens on posterior side
Edges of neural plate move towards each other to form neural tube
Edges of plate fuse together to form tube
Neural tube detaches from rest of ectoderm
Neurulation is complete when last neuropores close
Explain the process of gastrulation
A migration of blastocyst cells inward to establish the three germ layers via invagination. The inner cell mass folds in on itself forming an indentation. The cells continue to push inward, forming the endoderm. Cells that remain on the outer surface are the ectoderm. Additional cells migrate between the endo and ectoderm forming the mesoderm
Define molar pregnancy
Enucleated egg fertilized by two sperm - basically tumor of a trophoblast
Obv signs are significantly high hCG levels
Outline the different pathways of epiblast formation
Ectoderm –> epidermis, brain, spinal cord, neural crest
Mesoderm –> notochord
Mesoderm –> somite –> sclerotome, dermatome, myotome
Mesoderm –> internal organs, connective tissue
Endoderm –> epithelial lining, glands, digestive and resp tracts
What part of the blastocyst becomes the placenta?
Trophoblast
These embryonic tissues become what adult tissues:
Neural tube –>
Neural crest –>
Somites –>
Lateral mesoderm –>
Trunk vessels –>
Motor neurons
Sensory neurons
Myoblasts and endothelial cells
Bone, cartilage
Circulatory structures
How does thalidomide affect limb growth?
It reduces the amount of FGF8 produced –> decreases or causes abnormal limb growth
Explain the characteristics and gene defect involved in Hand-foot-genital syndrome
HOXA13
Fusion of carpal bone and small, short digits
Explain the characteristics and gene defect involved in Synpolydactyly
HOXD13
Webbing of digits 3/4 fingers, 4/5 toes
Partial or complete duplication
Explain the characteristics and gene defect involved in Holt-Oram syndrome
TBX5
Lack of left thumb, little growth of right thumb
Incomplete clavicle
Explain the characteristics and gene defect involved in Scott-Taor syndrome
TBX4
Small patellae, abnormal morphology
hypoplastic medial femoral condyles in knees
Explain the characteristics and gene defect involved in Club foot
PITX1-TBX4
Fore foot adducted, short foot, heel varus in plantarflexion, thin calves
Explain how the excitation-contraction coupling works
Depolarization of the motor end plate –> sends AP down T-tubule –> depolarization of T-tubule –> conformational change of DHP receptors –> binds to Ry receptors on nearby SR –> opening of pore in SR –> release of Ca2+ from SR into ICF –> Ca2+ binds to troponin C –> pulls tropomyosin away –> unbinds from actin to expose binding site –> myosin head binds to actin
Relate myotonia congenita to ECC
Myotonia congenita disorder doesn’t have the Cl- receptors in the T-tubles –> cannot repolarize –> delayed relaxation of muscles –> temporary rigor mortis after exertion
Relate malignant hyperthermia to ECC
AD inherited disorder with abnormal RyR
Depolarizing muscle relaxants or anesthetics –> RyR stays open –> uncontrolled release of Ca2+ –> sustained muscle contractions –> continuous ATP use (hypermetabolism) –> continuous generation of heat
Outline the cycle of cross-bridging
Actin and Myosin unbound, ADP and P : relaxed muscle
Binding A-M releases ADP and P
A-M : muscle contracts
ATP binding releases A-M
ATP hydrolysis
A+M, ADP and P : relaxed muscle
What is the benefit of using Pancuronium as a nondepolarizing medication?
Pancuronium is a lipophilic steroid - less soluble = stays near site of action longer = longer duration of action
Contrast the mechanisms of action of depolarizing and nondepolarizing neuromuscular blockers
In normal physiology, ACh binds to receptor to open channel and Na+ enters and remaining ACh is broken down by AChE
With depolarizing NM blockers, competitive inhibitors bind to receptor to prevent ACh from binding –> keeps channels open for continuous Na+ influx –> no repolarization preventing further AP –> muscle fatigues –> spastic paralysis ?
With nondepolarizing NM blockers, competitive inhibitor binds to open channel but blocks Na+ from influxing ?
What is the mechanism of the malignant hyperthermia rescue therapy drug?
Dantrolene - binds to RyR to inhibit further Ca2+ release
What is the reversal agent for nondepolarizing NM blockers?
AChE inhibitors (Edrophonium -shortest half life, Physostigimine - crosses BBB, Pyridostigmine - used to treat MG)
Sugammadex
Outline the pathogenesis of Duchenne MD
Loss of function mutation in dystrophin gene on X-chromosome
Dystrophin critical in contraction of muscle fibers
Outline pathogenesis of Myotonic dystrophy
Autosomal dominant multisystem disorder caused by CTG repeats in 3` noncoding region of DMPK gene
Outline pathogenesis of malignant hyperthermia
Autosomal dominant trait with variable penetrance coupled
Mutation in Ry receptors, sometimes DHP receptors
Define motor unit recruitment, and compare slow vs fast twitch motor units
Process in which number of active motor units increase
Weakest motor units always recruited first (Type I) –> progressively stronger units added as more force is added
Slow twitch motor units - small, innervated by easily excitable aMN
Fast twitch motor units - large, innervated by aMN that are more difficult to excite
Compare and contrast Type I, Type IIa and Type IIb muscle fibers
Type I: Slow oxidative (fatigue-resistant)
Type IIa: Fast oxidative (fatigueable)
Type IIb: Fast glycolytic (fatigueable)
Type I: high oxidative capacity, moderate glycolytic capacity
Type IIa: moderate oxidative capacity, high glycolytic capacity
Type IIb: low oxidative capacity, high glycolytic capacity
Type I and IIa: moderate diameter
Type IIb: large diameter
Type I: moderate SR Ca2+ pumping
Type IIa and IIb: high SR Ca2+ pumping
Explain the physiologic mechanism of a tetanic response
First stimulus causes a twitch
Another stimulus during the relative refractory period –> more Ca2+ –> further contraction
Force of contraction builds with each stimulus
Continuous, high frequency stimulus –> continuous muscle contraction
Describe how the forceful and repetitive muscular activity causes muscle hypertrophy
Repeated muscle contraction –> increased production IGF-1 –> activation PI3K –> increased AKT/mTOR pathway –> increased protein synthesis –> increased fiber size
Increased AKT/mTOR pathway –> inhibits FoxO-atrogene pathway –> decreased protein degradation –> increased fiber size
Repeated muscle contraction –> increased intracellular Ca2+, decreased [ATP] –> activation PGC-1a signaling –> increased slow fiber oxidative capacity
Explain how individuals infected by polio develop muscle weakness and atrophy
Viral replication in anterior horn cells (efferent cell bodies) and brainstem motor neuron cells –> destruction of somatic motor neurons to skeletal m fibers –> loss of stimulation –> disuse atrophy
Disuse atrophy –> decrease in size –> replaced by fibrous connective tissue –> denervation atrophy
Lack of stimulation to diaphragm –> respiratory paralysis
Compare the signs of UMN to LMN lesions
Upper motor neuron lesions
- Hyperreflexia (reflexes up)
- Hypertonicity (muscle tone up)
- Spasticity (contraction up)
- Disuse atrophy
- Babinski + (toes point up)
Lower motor neuron lesions
- Hyporeflexia (reflexes down)
- Hypotonicity (muscle tone down)
- Flaccid paralysis (muscle contraction down)
- Denervation atrophy
- Babinski - (toes point down)
Explain the difference between concentric, eccentric, and isometric contractions
Concentric and eccentric are isotonic - muscle tone is the same but length differs
- Concentric: contraction with muscle shortening
- Eccentric: contraction with muscle lengthening
Isometric contraction - Length is same but muscle tone differs - contraction without shortening or lengthening
During muscle contraction, which bands change and which stay the same?
I bands shrink as thick and thin filaments come together
A band does not change - area of thick filament and M line - where thin filaments overlap with thick
Explain Force-Velocity relationships of skeletal muscle
The more load increase, the less velocity of shortening
Once max load is reached, muscle begins to stretch
Max load is proportional to max rate of energy turnover
Contrast the basic mechanisms of C. Botulinum and C. Tetani
Botulinum blocks the release of ACh in the NMJ by cleaving SNARE proteins and binding to receptors –> no ACh –> no muscle activity
Tetani blocks the release of GABA and glycine which inhibit release of ACh –> nothing to inhibit release of ACh –> continuous ACh activity –> muscle spasms
Define fatigue in terms of biochemical mechanisms and its purpose
The inability of ATP turnover to keep paces with ATP usage –> reduction in ATP turnover, reduction in ability to produce force
Helps prevent ATP levels from dropping too low –> avoid rigor or irreversible muscle damage
Outline the two Phosphagen system reactions for skeletal muscle energy
Creatine Phosphate is a storage forms of ATP - holding Pi ready to easily phosphorylate ADP
Creatine Kinase
ADP + H + CrP –(CK)–> ATP + Cr
Adenylate Kinase
ADP + ADP –(AK)–> ATP + AMP
List the benefits of AMP as a biproduct of the phosphagen system
AMP stimulates Glycolysis
- increases PFK-1
- increases F2,6P
- stimulates AMPK –> inhibits glycogen synthesis, blocks FA metabolism, activates GLUT4, stimulates glycogenolysis
With what type of activity does the Phosphagen system dominate?
Short-term singular muscle contraction
Limited amount of repeated intense muscle contraction
Maximal muscular effort for 5-6s
-Weightlifting, start-stop events, sprinting, jumping events
What factors control the rate of Phosphagen system energy being regenerated/used?
[CrP] reduction
Severity of metabolic acidosis
Motor unit and fiber type used
What are the key enzymes and regulators of the Glycolytic energy system?
Enzymes: HK, PFK1, PK
Glucose + 2 NAD + 2 ATP –(HK)–> G6P –(PFK1)–> FBP –> 3-C Metabolites ——(PK)–> Pyruvate + 2 NADH + 4 ATP (2 net total)
HK regulator: G6P inhibits
PFK1 regulators: ATP, Citrate inhibit; AMP/ADP, F26B activate
Outline the five sources of Skeletal muscle Glycolysis
- Dietary glucose: GI –> liver –> blood –> tissue –> glycolysis
- Liver glycogenolysis: Glycogen –> liver glucose –> blood –> tissue –> glycolysis
- Cori Cycle (Lactic Gylcolysis): Tissue pyruvate –> tissue lactate –> blood lactate –> liver lactate –> liver glycogenolysis –> liver glucose –> blood glucose –> tissue –> glycolysis
- Cahill Cycle: Tissue AA oxidations –> convert a-KG to Glutamate –> convert Pyruvate to Alanine –> blood alanine –> liver alanine –> convert alanine back to Pyruvate –> liver gluconeogenesis –> blood glucose –> tissue –> glycolysis
- Muscle glycogenolysis: Glycolysis –> G6P –> muscle glycogenesis –> Glycogen stored in muscle –> muscle glycogenolysis –> finish glycolysis
At what point does Glycolysis take over as the dominant energy system?
10-15s after exercise begins
Outline the Lactic Glycolysis (Anaerobic respiration) system reaction
Pyruvate + NADH + H —(Lactate Dehydrogenase) —> Lactate + NAD
Why is Lactic Glycolysis important during intense exercise?
Lactate - substrate of Cori Cycle –> replenishes muscle glucose
Pyruvate production exceeds mt uptake capacity
Prevents inhibition of Glycolysis
Regenerates NAD+
Slows metabolic acidosis by buffering H+
What are the possibilities and limitations of mitochondrial respiration?
Possibilities
Can power muscle contraction for as long as fuel is available to the muscle as long as exercise intensity is at a level the system can meet the demand
Limitations
Cannot meet energy demands of muscle at the beginning of (any) exercise
Cannot meet energy demands of muscle in very-high intensity
What are the fuels used by mitochondrial respiration?
Carbohydrates
Fatty acids
Ketone bodies
Amino acids
When does mitochondrial respiration take over as the dominant energy system?
~2-3 minutes after beginning of exercise in low, moderate, or high(ish) intensity exercise
Explain “hitting a wall” and “getting a second wind”
“Hitting a wall” is when there is a near total depletion of liver and muscle glycogen stores, meaning no fuel for glycolysis to make ATP
“Second wind” comes after this when the body switches to FA oxidation as the predominant ATP production system
What fuel source is used during higher-intensity, shorter duration activity?
Glucose - muscle glycogenolysis
What fuel source is used during lower-intensity, longer duration activity?
Fatty acids
How does insulin stimulate the body to use glucose/glycolysis as it’s primary fuel source?
- Increases [GLUT4] (↑ glucose uptake)
- Stimulates PFK-1 (↑ glycolysis)
- Promotes glycogen synthase (↑ glycogenesis)
- Promotes inhibition glycogen phosphorylase (↓ glycogenolysis)
- Stimulates protein synthesis (↓ AA oxidation)
- Inhibits FA uptake (↓ FA oxidation)
How does epinephrine control muscle energetics and the body’s fuel source?
↑ glycolysis - stimulates production of F26P –> stimulates PFK-1
↓ glycogenesis - inhibits glycogen synthase
↑ glycogenolysis - stimulates glycogen phosphorylase
↑ FA oxidation - stimulates FA uptake
How does Pompe Disease (GSD Type II) affect muscle energetics
Loss of a-1,4-glucosidase –> lysosomal enzyme responsible for glycogen degradation –> glycogen accumulation in lysosomes and cytosol
How does Cori Disease (GSD Type III) affect muscle energetics
Loss of glycogen debranching enzyme –> enzyme required for full removal of glycogen branches during glycogenolysis –> storage of structurally-abnormal glycogen
How does Andersen Disease (GSD Type IV) affect muscle energetics
Loss of glycogen branching enzyme –> enzyme required for synthesis of glycogen branches during glycogenolysis –> storage of structurally-abnormal, insoluble glycogen
How does McArdle Disease (GSD Type V) affect muscle energetics
Loss of myophosphorylase –> muscle isoform of glycogen phosphorylase - plays major role in breakdown of glycogen during glycogenolysis
How does Tarui Disease (GSD Type VII) affect muscle energetics
Loss of PFK-1 activity –> backflow of glycolysis from F6P to G6P –> shuttled to glycogenesis –> excess glycogen
How does Diabetes Mellitus affect muscle energetics
Insulin loss/sensitivity –> muscle unable to engage in insulin-dependent glucose uptake –> glycolysis and glycogenesis impaired –> excessive FA and KB delivered to muscle for primary fuel source
How does exercise help relieve hyperglycemia of diabetes?
Exercise-stimulated AMPK –> ↑ GLUT4 –> ↑ insulin-independent uptake of glucose into muscle
How does Primary Carnitine Deficiency affect muscle energetics?
AR inheritance - mutation of SLC22A5 gene
Loss of plasma membrane transporter for carnitine –> accumulation of fatty acyl-CoA in cytosol –> inability to do B-oxidation (FA oxidation) –> ↑ FA in blood –> hyperlipidemia
What are the major adaptive responses of Learning, Endurance Training, and Strength Training?
Learning: ↑ rate and accuracy of motor units (CNS)
Endurance: ↑ oxidative capacity in all involved motor units
Strength: Hypertrophy and enhanced glycolytic capacity of motor units
A lesion in nerve roots L2-L4 would result in the dysfunction of what nerve and DTR?
Femoral n, patellar DTR (dominant L4)
Obturator n, adductor DTR (dominant L3)
A lesion in nerve roots C5-C6 would result in the dysfunction of what nerve and DTR?
Musculocutaneous n, biceps DTR
A lesion in nerve roots C6-C7 would result in the dysfunction of what nerve and DTR?
Radial n, triceps DTR (dominant C7)
Radial n, Brachioradialis (dominant C6)
A lesion in nerve roots S1 would result in the dysfunction of what nerve and DTR?
Sciatic n, Achilles DTR
What dermatome and myotome contribute to the medial hamstring DTR?
L5, Tibial n
What dermatome and myotome contribute to the finger flexor DTR?
C8-T1, Ulnar n
Outline the normal pathway of a reflex arc
Lengthening of tendon (tap) –> stretch of muscle –> muscle spindle activation –> AP in Ia fiber –> aMN or interneuron –> activating aMN to affected muscle, inhibitory aMN to antagonist muscle –> contraction –> shortening of muscle –> unload of muscle spindle –> signal ends
How does the Golgi tendon pathway differ from the muscle spindle reflex pathway?
Golgi tendon pathway senses tension and sends inhibitory signals to agonist muscle, excitatory signals to antagonist muscle –> causing relaxation
Reflex pathway senses lengthening and sense excitatory signals to agonist muscle, inhibitory signals to antagonist muscle –> causing contraction
Describe the process of kinetic firing
The kinetic chain is a sequence of individual body segments and joints working together to accomplish a task
Compare closed vs open kinetic chains
Closed kinetic chains occur against resistance
–> when walking, the feet/legs are in closed kinetic chain because it’s in contact with a structure.
–> Closed has distal extremity stabilized, body moving around it
Open kinetic chains occur without resistance, not in contact with other structures
–> arms swinging freely when walking
–> open has proximal extremity stabilized, distal moving
Briefly describe BioTensegrity
Dysfunction of one joint affects the entire system
Which muscle is most likely to be inhibited by arthrogenic
muscle inhibition (AMI) of the knee? Why?
Vastus medialis (obliquus)
VMO is critical for stabilizing the knee joint
Explain how the principles of muscle energy technique takes
advantage of agonist and antagonist muscle groupings
Reciprocal inhibition - agonist muscle group (dysfunctional muscle) is relaxed and stretched further when antagonist muscle group is contracted
MET retrains neuromuscular firing patterns associated with SD
Increased __________ –> more prone to patellar dislocation and tracking issues
Q angle
What groupings give rise to neurokinetic chains?
Somites to myotomes, dermatomes and sclerotomes
Polymerized form of collagen type I and where is it mostly found?
Fibril
Bone, dermis, tendon, ligaments
Polymerized form of collagen type II and where is it mostly found?
Fibril
Cartilage, IV discs
Polymerized form of collagen type III and where is it mostly found?
Fibril
Dermis, blood vessels, lymphatic tissue, liver, lung
Important for repair of tendons
Polymerized form of collagen type V?
Associated fibril with collagen Type I
Polymerized form of collagen type XII?
FACIT to collagen type I
Polymerized form of collagen type XI?
Associated fibril with collagen Type II
Polymerized form of collagen type IX?
FACIT to collagen type II
What is the function of FACITs?
Crosslink cartilages
What are the functions of proteoglycans in the ECM?
- Binds and releases water
- Lubricant for articular cartilages
- Allows for diffusion of nutrients in and waste out of the connective tissue
- Acts as barrier to bacteria
What is the principal collagen in tendon and ligaments?
Type I (two a1 chains and one a2 chain)
What collagens regulate the structure of a tendon?
Type V, XII, and XIV (the associated fibrils and FACITs)
What is a tenocyte?
Secretes and builds ECM found between collagen fibers
What type of collagen is produced in the proliferation phase of wound healing?
Collagen Type III
What is the primary proteoglycan associated with cartilage?
Aggrecan
Hyaline cartilage:
–>ECM
–>Type of cells
–>Organization of cells
–>Presence of perichondrium
–>Locations/functions
–Histology
ECM: Type II collagen, abundant aggrecan, proteoglycans, GAGs
Cells: chondroblasts, chondrocytes, fibroblasts
Organization: Isolated in lanucae or in small isogenous groups
Perichondrium: Yes - contains fibroblasts, stem cells, blood vessels, small nerves
Location/Function: Aids in sliding within joints; model for bone growth; provides structural support in airway
Histology: homogenous and glossy, very pink
Elastin cartilage:
–>ECM
–>Type of cells
–>Organization of cells
–>Presence of perichondrium
–>Locations/functions
–>Histology
ECM: Type II collagen, elastin fibers, aggrecan, proteoglycans, GAGs
Cells: chondroblasts, chondrocytes, fibroblasts
Organization: small isogenous groups in lanucae
Perichondrium: Yes - contains fibroblasts, stem cells, blood vessels, small nerves
Location/Function: Provides flexible shape and support to soft tissues (external ear, auditory tube, epiglottis)
Histology: similar to Hyaline but abundant in elastin fibers
Fibrocartilage:
–>ECM
–>Type of cells
–>Organization of cells
–>Presence of perichondrium
–>Locations/functions
–>Histology
ECM: Type I collagen, Type II collagen, aggrecan
Cells: chondrocytes, fibroblasts
Organization: Isolated in lanucae; sometimes in small groups in rows
Perichondrium: No
Location/Function: Provides cushioning, strength, resistance to tearing and compression within IC discs, meniscus, pubic symphysis
Histology: Varying combinations of hyaline cartilage in dense connective tissue
What type of cartilage is this?
Hyaline cartilage
What type of cartilage is this?
Elastic cartilage
Can see elastin fibers
What type of cartilage is this?
Fibrocartilage
Where are stem cells housed in articular cartilage?
Superficial zone
Characteristics of Articular Cartilage
- Avascular
- Four layers
- No perichondrium
Collagen types in articular cartilage
Type II, VI, IX, X, XI
Collagen function in articular cartilage
Type II - Major component of fibrils, tensile strength
Type VI - forms microfibrils, pericellular
Type IX - FACIT, proteoglycan and collagen, interactions between II and proteoglycans
Type X - Hypertrophic and calcified cartilage
Type XI - Nucleation control within collagen fibril
Proteoglycans in articular cartilage and their functions
Decorin - Controls size/shape of fibrils; binds collagen II and TGF-B; interterritorial
Biglycan - Pericellular; binds collagen VI and TGF-B
Aggrecan - Compressive stability
Versican - Low level throughout articular cartilage life
Perlecan - Pericellular
Differentiate between Regeneration and Scar Formation
Regeneration is the complete restoration to normal state by differentiated cells and stem cells
Scar formation is when there is severe damage and it is replaced with connective tissue (fibrosis)
What determines a tissues ability to repair itself?
Type of tissue (labile, stable, permanent)
ECM integrity
GF produced at injured site (macrophages, stromal cells, epithelial cells, etc)
Integrins
Continuously dividing tissue with a short life span and can regenerate readily
Labile Tissue
Hematopoietic stem cells in bone marroe
Quiescent cells that proliferate in response to injury with limited capacity to regenerate
Stable Tissue
Most solid organs (liver, kidney, pancreas) and endothelial cells, smooth muscle cells, fibroblasts
Terminally differentiated cells with very long life that heal by scar formation
Permanent tissue
Cardiac cells, Neurons, skeletal muscles (kind of)
How is liver regenerated?
Kupffer cells (liver macrophages) autocrine release TNF to act on itself –> secretes IL6 paracrine to hepatocytes to initiate G0 to G1 –> GF released from injured area bind to EGFR and MET of hepatocyte –> cell proliferation –> TGF-B initiates termination once sufficient number of cells and hepatocytes return to G0
Explain the timeline of first intention wound healing
First 24 hrs: neutrophil accumulation
24-48 hrs: epithelial cells close wound
Day 3: neutrophils replaced with macrophages to clear debri; granulation tissue invades
Day 5: Neovascularization peaks; fibroblasts migrate/proliferate into granulation tissue
Week 2: Decrease in leukocyte infiltrate, edema, vascularity of GT
Week 4: essentially normal epidermis by end of month 1
Healing by first intention leads to ______% wound strength by 3 months
70-80
Outline healing by second intention
Severe wound –> necrotic debri and fibrin deposits –> increased inflammation and injury –> increased granulation tissue; loss of dermal appendages –> scar by end of 1 month (acelluar connective tissue) –> wound contractions to 5-10% original size by myofibroblasts
Fibrosis in tissue space occupied by an inflammatory exudate is called
Organization
Outline the synthesis of collagen
Inside rER: Collagen mRNA translation –> SRP –> pre-procollagen synthesized –> hydroxylation w/ Vit C (adds OH to lysine/proline) –> glycosylation (adds sugar to mark for exocytosis) –> linkage of three chains via disulfide bonds –> procollagen triple helix
In extracellular space: Procollagen peptidase cleavage of N- and C-terminals –> tropocollagen –> spontaneous fibril assembly –> lysine-hydroxylysine cross linkages by Lysyl oxidase and copper –> collagen
What is the significance of Glycosylation in collagen formation?
It marks the procollagen for exocytosis from the cell to continue synthesis
What is the significance of Vitamin C in collagen formation?
Required for hydroxylation
Lack of Vitamin C –> poor wound healing –> scurvy
Osteogenesis Imperfecta pathogenesis and clinical features
AD mutation COL1A1/COL1A2 mutation –> decreased bonding between a-chains –> failed triple helix –> “brittle bone disease”
Growth delay, skeletal abnormalities, recurrent fractures, opalescent teeth
Ehlers-Danlos pathogenesis and clinical features
AD mutation COL5A1/COL5A2 –> ↓ procollagen peptidase –> ↓ tropocollagen synthesis –> ↓ fibril assembly
Defect in lysine-hydroxylysine crosslinking –> unstable collagen fibrils
Hypermobility
Tissue fragility, atrophic scars, poor wound healing
MV prolapse, easy cruising, varicosis, prominent eyes
Marfan Syndrome pathogenesis and clinical features
AD mutation of FNB-1 –> defective fibrillin (glycoprotein that forms protective sheath around elastin) –> defective elastin fibers
Tall stature, long extremities, hypermobility, arachnodactyly, hyperextensive skin, visual impairments, aortic disease, MV prolapse
Differentiate between interstitial growth and appositional growth in cartilage
Interstitial growth - mitosis of existing chondroblasts in lacunae
Appositional growth - formation of new chondroblasts peripherally from progenitor cells in perichondrium
Describe the structure of a typical proteoglycan
Core protein - made of serine residues - attachment points for GAGs
GAGs - negatively charged sugars that attract positive ions and water
Tetrasaccharide linkage - carbon chain binding GAG to core protein
Describe the embryological origin of tendons and ligaments
Progenitor cells (tenocytes) originate from ventral and lateral ectoderms
Syndetome - embryonic structural origin of tendons from somite
What is the key regulator in formation of tendons and ligaments?
Transcription factor SCX (scleraxis)
Describe the cell line of origin, morphological features and primary function of osteoblasts
Cell line of origin: Mesenchymal cells –> osteoprogenitors
Morphological features: cuboidal cells
Primary function: secretes organic extracellular matrix components and attracts inorganic ECM to build bone; lines the bone
Describe the cell line of origin, morphological features and primary function of osteocytes
Cell line of origin: Mesenchyme –> osteoprogenitors –> osteoblasts
Morphological features: cytoplasmic projections
Primary function: communication and mechanosensory
Describe the cell line of origin, morphological features and primary function of osteoclasts
Cell line of origin: monocytes
Morphological features: large, multinucleated, “macrophage-like”; integrins protein surround “feet” and suction to seal resorption hollow
Primary function: secrete hydrolytic enzymes and acid to digest matrix and resorb bone through phagocytosis and release into blood
Describe the cell line of origin, morphological features and primary function of bone-lining cells
Cell line of origin: osteoblasts ?
Morphological features: thin cells along periosteum and endosteum
Primary function: facilitate movement of calcium into and out of bone
Explain the function of alkaline phosphatase in bone remodeling
Osteoblasts secrete AP to attract inorganic ECM components from the diet such as calcium and phosphatase
Elevated levels of AP –> elevated osteoblastic activity
Explain the relationship between the Haversian canal, Volkmann’s canal, and the osteon
The Osteon is defined as a Haversian canal and it’s surrounding lamellae layers running lengthwise in the cortex of bone
The Haversian canal houses the capillaries and nerves
The Volkmann’s canal connects adjacent osteons to each other via the Haversian canals, and the osteons to the periosteum
Site of primary ossification
Diaphysis
Site of secondary ossification
Epiphysis
Contrast woven bone from lamellar bone
Woven bone is immature bone with poorly arranged collagen fibers and is generally very weak. It is the beginnings of all bone and gets remodeled into lamellar bone.
Lamellar bone has collagen fibers arranged in parallel sheets. It’s very strong and differentiates into two different types: Trabecular and Cortical
Differentiate Trabecular bone from Cortical bone
Trabecular - spongy bone - branching irregular network
–> occupies the center volume of long bones and houses bone marrow in trabeculae spaces
Cortical bone - compact bone - forms the edges of long bones
Explain the difference between the nutrient foramen and canaliculi
The nutrient foramen houses the nutrient artery that supplies the bone - typically entering through the diaphysis
The canaliculi house the osteocyte cytoplasmic projections which allow for intracellular communication and mechanosensory
Dysfunction of what transcription factor would disrupt intramembranous ossification?
RUNX2
MSC cell condensation –> RUNX2 –> osteoblasts
Dysfunction of what transcription factor would disrupt endochondral ossification?
SOX9
MSC cell condensation –> SOX9 –> chondrocytes –> osteoblasts
PTH has a (direct/ indirect) affect on osteoblasts, and a (direct/indirect) effect on osteoclasts
Direct on osteoblasts
Indirect on osteoclasts
Binds osteoblast –> increase RANKL –> stimulates osteoclasts
Calcitonin has a (direct/ indirect) affect on osteoblasts, and a (direct/indirect) effect on osteoclasts
Indirect on osteoblasts
Direct on osteoclasts
Biggest players of height in fetal, infantile, childhood, and puberty
Fetal: mother’s health
Infantile: nutrition, genetics
Childhood: growth hormone, thyroid development
Puberty: Estrogen
How do you measure bone age?
Xray of the left hand/wrist - measuring growth plate
What two factors stop the proliferation of chondrocytes in endochondral ossification?
Estrogen and Fibroblast growth factor receptor 3
What transcription factors regulate the hypertrophy of chondrocytes in EO?
SOX9 inhibits hypertrophy –> keeps cell alive
RUNX2 promotes hypertrophy –> apoptosis
Describe the relationship between PTHrP, IHH, and SOX9 in EO?
Parathyroid hormone-related peptide is secreted onto proliferating chondrocytes. PTHrP stimulates proliferation by secreting SOX9 which delays hypertrophy –> chondrocytes replicate and are pushed further from PTHrP and SOX9 –> begin to hypertrophy until meeting IHH which then stimulates more proliferation
Differentiate the characteristics of cortical and trabecular bone remodeling
Spongy bone - osteoclasts break down trabeculae –> osteoprogenitors differentiate into osteoblasts –> osteoblasts secrete osteoid
Compact bone - osteoclasts tunnel through bone –> blood vessels and nerves occupy tunnel –> blood provides osteoprogenitors –> osteoblasts line tunnel –> secrete osteoid from periphery inward –> osteocytes trapped in layers of lamellae
Explain steps of intramembranous ossification
- Mesenchymal cells aggregate in area where bone will form
- Differentiate into osteoprogenitors and osteoblasts
- Osteoblasts secrete osteoid –> osteoblasts become separated but remain attached through cytoplasmic processes
- Osteoid mineralizes; osteoblasts completely surrounded by matrix –> osteocytes
- Tissue vascularization brings in osteoclasts for remodeling bone
Explain steps of endochondral ossification
Hyaline cartilage template surrounded by perichondrium except at articulating surfaces –> perichondrium becomes periosteum –> bone collar forms impeding nutrient diffusion to cartilage –> chondrocytes undergo hypoxia, become hypertrophic, calcify, and undergo apoptosis –> apoptosis releases angiogenic factors –> recruits blood vessels –> blood delivers osteoclasts –> osteoclasts removed calcified cartilage matrix –> osteoprogenitors come and become osteoblasts –> osteoblasts secrete osteoid –> forms primary center of ossification in diaphysis –> bone collar extends –> osteoclasts and osteoblasts continue –> woven bone formed –> remodeling –> bone follows cartilage
List and describe the 5 growth plate zones
Zone of Reserve Cartilage - “clueless cartilage” - most distant from primary ossification - rich in Type II collagen
Zone of Proliferation - Site of chondrocyte mitosis - regulated by GH, IGFs, IHH, BMPS
Zone of Hypertrophy - Chondrocyte swelling - inhibited by IHH and PTHrP - cells release ECM Type X collagen
Zone of Calcification - Chondrocytes begin apoptotic pathway –> release AP and ATPase –> cleave calcium, phosphate from environment –> form calcium-P aggregates –> calcification
Zone of Ossification - Removal of calcified cartilage and remodeling of woven bone - closure accelerated by estrogen
Explain how each GF plays a part in bone growth: SOX9, GH, IHH, PTHrP, IGF-1, FBFR3, RUNX2
SOX9 - inhibits hypertrophy
RUNX2 - stimulates hypertrophy
GH - pro-proliferative (regulates longitudinal growth)
IHH - inhibits hypertrophy, stimulates proliferation
PTHrP - inhibits hypertrophy; maintains chondrocytes in proliferative state (Gs activation –> cAMP –> PKA –> P of SOX9)
IGF-1 - mediator of GH, stimulates hypertrophy
FBFR3 - expressed by proliferating/early hypertrophic chondrocytes to inhibit further proliferation by inhibiting IHH
Describe the regulation of parathyroid secretion and its role in calcium homeostasis including the role of Vitamin D, Phosphate and Magnesium
Release of PTH is controlled by a feedback system.
High calcium –> ↓ PTH secretion; low calcium –> ↑ PTH secretion
Vitamin D [1,25(OH)2D] - ↑ Vitamin D –> reduces PTH gene expression and transcription
Phosphate - ↑ serum phosphate –> ↑ PTH release
Magnesium - ↑ or ↓↓ magnesium –> ↓ PTH –> possible hypocalcemia
Explain the pathway of Parathyroid Ca2+ Sensing Receptor
GCPR receptor –> activates PI-PLC –> Ca2+ mobilization –> PKC activation –> Phospholipase A2 –> Arachidonic acid –> Leukotrienes –> Degradation of preformed PTH, decreased release of PTH
Explain how PTH promotes bone resorption
PTH is released –> binds to osteoblast PTHR1 –> increases RANKL expression –> osteoclast precursor RANK binds to RANKL –> activates osteoclast gene transcription –> differentiation into osteoclast –> increase of osteoclast activity
Label the regulators of the hematopoietic monocyte/osteoclast lineage
- MCSF (Macrophage colony stimulating factor) - contributes to differentiation, migration, survival; does not differentiate from macrophage
- RANKL - expressed by osteoblasts and osteocytes to commit cells to osteoclasts
- Osteoclast attaches to bone via integrins; cell reorganization begins
- OPG (Osteoprogesterin) - soluble decoy receptor - prevents RANKL from binding to RANK receptor
Describe the role of osteoprogesterin
Secreted by osteoblasts and osteocytes –> Competitively binds to RANK to stop formation of osteoclasts
Label the regulators and secretions of the mesenchymal/osteoblast lineage
- RUNX2 - transcription factor that helps commit to osteoblast
- Osterix - cellular production of Type I cartilage
-No osterix –> cells driven to cartilage - WTN pathway (LRP5) - paracrine or autocrine signaling
- Sclerostin - inhibits WNT LRP5 pathway - inhibits further differentiation/proliferation - induces osteoblast apoptosis - only secreted by osteocytes
- ECM production
- RANKL expression (OB life starts with release of RANKL to stimulate osteoclasts and break down bone)
- OPG secretion (as OB matures, it secretes OPG to stop osteoclastic activity and begin building)
Characterize the effect of estrogen on osteoblasts
- Increased OPG production - greater survival of OB
- Decreased Sclerostin production - more bone production
- Decreased RANKL production - greater survival of OB
- Increased osteoclast apoptosis
How do estrogen and glucocorticoids effect OPG?
Estrogen increases OPG production
Glucocorticoids decreases OPG production –> Increased apoptosis in osteocytes and osteoblasts, decreased in osteoclasts –> decreased bone formation, increased resorption
Short term –> GCC initially cause a rapid decrease in apoptosis and induce survival of osteoclasts. This leads to a small burst in resorption.
Long term –> GCC cause decreases in Ob proliferation. Cells that survive begin to produce increased levels of RANKL and less OPG. Bone formation goes down due to fewer cells, resorption goes up for the same reason plus increased RANKL production –> Osteoporosis
Explain how bisphosphonates effect bone growth
BP interrupt the production of signaling proteins and the maintenance of the ruffled border of osteoclasts –> inhibited bone resorption
BP attach to hydroxyapatite binding sites on bony surfaces (semi-permanent) –> osteoclast resorbs BP impregnated bone and cannot form ruffled border to adhere to bony surface, or produce protons necessary for continued resorption
BP also reduce osteoclasts activity by decreasing osteoclast progenitor development, promoting osteoclast apoptosis
BP also prevents osteocyte and osteoblast apoptosis
Describe how a RANKL antagonist (Denosumab) inhibits osteoclast proliferation, differentiation, and resorption.
Denosumab binds to RANKL to preventing binding to RANK –> prevents osteoclast differentiation/proliferations –> prevents bone resorption
Explain how Intermittent Teriparatide affects bone remodeling
Increased OB proliferation/survival - lay down ~30% more bone
Increased osteocyte survival
Increased bone formation
Delayed, increased RANKL expression –> increased resorption
Pulsative waves allow mature OB to live longer forming bone while pumping out OPG before any great amount of RANKL expression by new OB –> ~ 3 month bone formation head start –> PTH eventually kickstarts resorption –> OC begin to resorb
What is the purpose of the salvage pathway and why is it easily used?
Saves bases for reuse when not needed for nucleotides
Major source of lymphocytes
Energetically favorable
What are the four stages of bone healing in a fracture?
Stage 1 - Inflammation
- hematoma formation
- platelets signal fibroblast & inflammatory cells
Stage 2 - Soft callus
- MSC recruited Fibrin-rich granular tissue form
- VEGF creates new vessels
Stage 3 - Hard Callus
- External hard callus formed
- Low O2 –> chondrocyte differentiation
- Woven bone formed
Stage 4 - Remodeling
- Bone remodels
- Lamellar bone is formed
Differentiate between a segmental fracture, avulsion fracture, and comminuted fracture
Segmental - Bone broken in two places creating free-floating segment
Avulsion - fragment of bone pulled away from by attachment of ligament of tendon
Comminuted - bone shattered into multiple fragments
- complicated treatment, slower healing
Differentiate between an impacted fracture and compression fracture
Impacted - one fragment driven into another causing compression
- usually from one great force
Compression - Bone crushed or collapsed from loss of integrity
- vertebra, common in osteoporosis
Define greenstick fracture
Not completely fractured through with one side of the bone fractures and other side bending
Outline the Salter-Harris classification of fractures
Type 1 - Straight across the growth plate
Type 2 - Above the growth plate
Type 3 - beLow the growth plate Type 4 - Through the growth plate (above and below)
Type 5 - ERasure of growth plate (crushed)
SALTER
Define fascial creep
deformation of fascia at sufficient tensile prolonged stretch
Describes how it deforms over pressure and stress, and feeling under our hands when we manipulate it
