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MSK 2 Flashcards

1
Q

what are the 3 key components of cartilage

A
  1. perichondrium
  2. chondrocytes
  3. extracellular matrix
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2
Q

describe the structure of cartilage perichondrium

A

outer fibrous connective tissue sheath

contains VASCULAR SUPPLY for the avascular cartilage

inner chondrogenic layer is essential for growth and maintenance–> grow and secrete matrix

absent on articular cartilage and fibrocartilage

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3
Q

on what type of cartilage is the perichondrium absent

A

absent on articular cartilage and fibrocartilage

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4
Q

what is the function of the perichondrium

A

contains vascular supply

inner layer is chondrogenic–important for growth and maintenance

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5
Q

what % of cartilage is chondrocytes

A

5%

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6
Q

what are chondrocytes

A

large rounded cells situated in the lacunae of matrix

cells are grouped in “isogenous nests”

mainly secretory–ultrastructure reflects protein and carbohydrate synthesis

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7
Q

what 3 important enzymes do chondrocytes produce and what do they do

A
  1. collagenase 1 (MMP1)–> targets type 2 collagen arcade
  2. stromelysin (MMP3)–> targets proteoglycans (proteoglycanase)
  3. collagenase 13 (MMP13)–> targets type 2 collagen arcade
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8
Q

what makes up 95% of cartilage

A

extracellular matrix

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9
Q

what is the ECM in cartilage made up of?

A

90% water

collagen (hyaline–type II; fibrocartilage–type I)

elastin (in elastic cartilage)

proteoglycans–> contain sulphated and non-sulphated glucosamine (GAGs)

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10
Q

why % of the dry weight of hyaline articular cartilage is proteoglycans

A

50%

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11
Q

what charge do proteoglycans hold

A

negative charge

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12
Q

what gives cartilage the deformability and ability to distribute load in a reversible sponge-like fashion?

A

proteoglycan aggregates and the water they attract

explanation:

  1. PG aggregates are bulky–> they are held in check by type 2 collagen arcade with is like a cage for the PGs
  2. most PG monomers can aggregate to HYALURONIC ACID to form these PG aggregates–> the monomers are called AGGRECAN–> these monomers have a hook that allow them to bind to the hyaluronic acid (called “hyaluronic acid binding protein”)
  3. these aggregates attract a high water content (due to GAGs negative charge) which allows for deformability due to the ability to have great flexes in water content
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13
Q

why is it significant that PG aggregates are stuck in a collagen network?

A

because this protects them from enzymatic degradation by metalloproteinases

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14
Q

what are GAGs

A

glucoaminoglycans–> attached to the protein core of proteoglycans

highly negatively charged, which makes the PG hydrophilic and attract water

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15
Q

name the 2 GAGs

A

chondroitin sulfate

keratan sulfate

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16
Q

describe the structure of chondroitin sulfate

A

larger of the GAGs and is located at the superior aspect of the core protein

composed mostly of GALACTOSAMINE DISACCHARIDES

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17
Q

describe the structure of keratan sulfate

A

shorter GAG chains at the proximal or amino terminal of the core protein

enriched GLUCOSAMINE–> supplyment efficacy poorly shown

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18
Q

what are proteoglycans made up of

A

consist of a core protein and GAGs

the core protein is the backbone of the PG subunit and GAGs are added to the protein core

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19
Q

which type of cartilage is the most widely distributed

A

hyaline

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20
Q

which type of cartilage is the rarest

A

elastic

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21
Q

which type of cartilage is a mix of both cartilage and dense connective tissue?

A

fibrocartilage

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22
Q

in what body structures would you find type II cartilage

A 
ribs
trachea
bronchi
joint surfaces
growth plates of bone
sutures of the skull
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23
Q

what type of collagen do you find in the ECM of hyaline cartilage

A

type II

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24
Q

describe the regenerative potential of hyaline cartilage

A

low regenerative potential because it has no venous or lymphatic drainage

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25
Q

describe the appearance of hyaline cartilage

A

glassy-slippery

bluish-white/translucent

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26
Q

what is the metabolic rate of hyaline cartilage

A

low

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27
Q

what is the function of hyaline cartilage during the fetal period

A

serves as a provisional skeleton

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28
Q

what is the function of hyaline cartilage after birth

A

epithyseal growth plates

articular surfaces

adult skeleton

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29
Q

where in the body would you expect to find elastic cartilage

A

epiglottis
eustachian tube
ear and external auditory meatus

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30
Q

what type of collagen would you find in the matrix of elastic cartilage

A

type II

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31
Q

describe the structure of elastic cartilage

A

bendable but firm

elastic fibres in matrix

little degenerative change

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32
Q

where in the body would you expect to find fibrocartilage

A

intervertebral disc

menisci

tendinous instertions

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33
Q

what type of collagen is found in the matrix of fibrocartilage

A

type I

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34
Q

describe the structure of fibrocartilage

A

firm with great tensile strength

collagen type I fibres are parallel with line of pull/stress

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35
Q

what provides the lubrication and nutrition for the chondrocytes in articular cartilage

A

synovial fluid

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36
Q

what is the function of synovial fluid and how does it achieve this function

A

protects cartilage and other joint structures from stresses during loading

LUBRICIN is the main lubricating component

high water content within the cartilage (90% wet weight) is squeezed out of cartilage during joint loading and resorbed during unloading

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37
Q

what is the function of lubricin and what is it made up of

A

main lubricating component in synovial fluid

it is a GLYCOPROTEIN synthesized by SYNOVIOCYTES (ype B) and CHONDROCYTES

present on superficial surface of hyaline cartilage

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38
Q

what is the factor that limits articular cartilage repair

A

articular cartilage is avascular, aneural and alymphatic

healing is limited by lack of vascularity and lack of cells that can migrate to injured sites

cartilage lacks undifferentiated cells that can migrate, proliferate and participate in the repair response

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39
Q

how do injuries that extend deep into the tidemark region heal?

A

heal with fibrocartilage rather than hyaline cartilage as before (fibrocartilage has poorer orientation and has type 1 instead of type 2 collagen)

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40
Q

how are superficial lacerations characterized with regard to cartilage healing

A

these lacerations do not cross the tidemark

do not progress but also do not heal–> laceration for life

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41
Q

how are deep lacerations characterized with regard to articular cartilage healing

A

may heal with fibrocartilage

undifferentiated marrow mesenchymal cells differentiate to produce fibrocartilage however it does not have the normal structure, composition, or mechanical properties of articular cartilage and thus has poor durability

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42
Q

what are the only cells found in hyaline articular cartilage

A

chondrocytes

are the only cells in articular cartilage which produce/organize and maintain the ECM

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43
Q

what are chondrocytes derived from

A

from mesenchymal cells

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44
Q

what is the function of chondrocytes

A

only cells in articular cartilage that produce/organize and maintain ECM

occupy relatively small surface area and are dominated by their ECM of PG, Type II collagen and water

chondrocytes synthesize ALL of the matrix molecules and enzymes (i.e MMPs)

superficial chondrocytes are more active than deep ones

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45
Q

what are fibroblasts

A

principle cells of the tendon and are responsible for synthesis and secretion of GROUND SUBSTANCE and COLLAGEN FIBRES of the ECM

relatively few in numbers and are interconnected via gap functions for communication and coordination

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46
Q

describe the structure of fibroblasts

A

active fibroblasts exhibit long tapering and branched processes (adult tendon is less elaborate)

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47
Q

what are isogenous nests?

A

chondrocytes that are clustered into groups within the cartilage

as cells develop, they undergo one or two more divisions that give rise to the multicellular nests deep within the cartilage

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48
Q

why is differential staining of the cartilage matrix seen on histological examination?

A

due to high concentrations of SULFATED GLYCOSAMINOGLYCAN int he territorial matrix

(the lighter region outside of the territorial matrix contains a high content of type II collagen)

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49
Q

how does the cartilage receive nutrients and oxygen

A

nutrients and O2 must diffuse from blood vessels int he perichondrium since the cartilage is avascular

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50
Q

what are the two major dry weight components of articular cartilage matrix

A

type II collagen and proteoglycans

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51
Q

why are PGs hydrophilic and what is the consequence of this

A

because of GAGs

this is responsible for the high water content of cartilage

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52
Q

describe the process of collagen synthesis

A
  1. hydroxyproline, proline and glycine rich polypeptide sequence is translated at the RER
  2. subsequent modifications are made using vitamin C as a cofactor
  3. three alpha chains unite in a triple helix to form pro collagen–> this is packed by the Golgi and exported to the cell surface
  4. after release into the surrounding matrix, procollagen peptidase cleaves the molecule into tropocollagen subunits that self-assemble to form a collagen fibre which ultimately coalesces to form a collagen fibre bundle
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53
Q

describe the structure of type II collagen

A
  1. dry weight of hyaline articular cartilage is 50% type 2 collagen which is arranged like a set of confluent branches
  2. this arrangement gives the cartilage strength and structures and holds in the proteoglycans–> tensile strength is important to endure impact loading
  3. if collagen is broken down, hydrophilic PG aggregates are also broken down and escape into the synovial space (and are gone for good)
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54
Q

what are TIMPs

A

tissue inhibitors of metalloproteases–> counteract and block the MP enzyme

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55
Q

what cell releases MMPs

A

chondrocytes

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56
Q

what upregulates MMP release from chondrocytes

A

IL-1 (which is also produced by chondrocytes) and plasmin

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57
Q

how are osteoarthritis and MMPs related?

A

in OA, the degradative enzymes (MMPs) are way upregulated and out of control

cartilage in OA is hyperactive tissue with a lot of synthesis of PGs

however, degradation outweights synthesis and the scale is tipped towards catabolism

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58
Q

which MMPs break down type 2 collagen

A

MMP1 and MMP13

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59
Q

which MMPs break down proteoglycans

A

MMP3 (STROMELYSIN)

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60
Q

what is another name for MMP3

A

stromelysin

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61
Q

describe the state of the following factors in normal cartilage:

  1. water content
  2. PG aggregates
  3. collagen arcade
  4. metachromatic staining
  5. surface chondrocyte #
  6. MMP enzyme activity
  7. subchondral bone
  8. osteophytes
A
  1. well hydrated
  2. normal
  3. normal
  4. increased uptake
  5. intact, smooth, normal
  6. kept in check
  7. normal as a rule
  8. negative
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62
Q

describe the state of the following factors in OA cartilage:

  1. water content
  2. PG aggregates
  3. collagen arcade
  4. metachromatic staining
  5. surface chondrocyte #
  6. MMP enzyme activity
  7. subchondral bone
  8. osteophytes
A
  1. in early stages–> swelling pressure influx H2O; in late stages–> loss of H2O (dry)
  2. decreased
  3. decreased
  4. decreased/loss of uptake
  5. fibrillated, irregular chondrocyte; mitosis is ramped up (broad caps)
  6. upregulated and out of control
  7. sclerotic as a rule
  8. positive
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63
Q

describe the state of the following factor/structure in normal aging versus changes observed in OA:

fibrillation

A

normal aging: mild, non-progressive fibrillation

OA: severe progressive fibrillation

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64
Q

describe the state of the following factor/structure in normal aging versus changes observed in OA:

water content/drying

A

normal aging: less water content, drying or desiccation of cartilage

OA: initial swelling of collagen arcade in OA due to collagenase being up-regulated

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65
Q

describe the state of the following factor/structure in normal aging versus changes observed in OA:

tensile strength

A

normal aging: loss of tensile strength due to fragility of collagen network

OA: worse fragmentation of collagen arcade in OA due to collagenase being upregulated

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66
Q

describe the state of the following factor/structure in normal aging versus changes observed in OA:

proteoglycans

A

normal aging: decreased average size of PG monomers, decreased PG aggregates and decreased protein content

OA: decreased number of PGs, decreased PG aggregates due to CLEAVAGE of HABR, regression to fetal CS-4 instead of CS-6

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67
Q

describe the state of the following factor/structure in normal aging versus changes observed in OA:

chondrocyte phenotype shift

A

normal aging: hypocellular

OA: chondrocyte cloning in broad capsules; mitosis of chondrocytes; regression to fetal CS-4 instead of CS-6

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68
Q

what features are found in both normal aging and OA

A
  1. increased apoptosis
  2. ER stress
  3. many overlap in general (normal aging makes cartilage more vulnerable to changes of OA)
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69
Q

list the 6 types of joint

A
  1. synovial joint
  2. syndesmosis
  3. synchondrosis
  4. synostosis
  5. symphysis
  6. gomphosis
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70
Q

define synovial joint

A

most appendicular joints

covered by cartilage

connected by a capsule

SYNOVIAL FLUID

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71
Q

define syndesmosis

A

joint

two bones bound by fibrous tissue only

i.e skull sutures and ankle syndesmosis

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72
Q

define synchondrosis

A

joint

two bones bound by cartilage

i.e physis (between growth centres), C2 joint; can be pathologic

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73
Q

define synostosis

A

joint which become obliterated by a bony union

i.e pelvis + ileum + ischium + pubis; can be pathological

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74
Q

define symphysis

A

joint

opposing surfaces covered by cartilage, minimal movement, no synovium

i.e pubic symphysis, intervertebral discs

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75
Q

define gomphosis

A

joint

fibrous joint between tooth and socket

fibrous connection

blood vessels and nerves cross the joint

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76
Q

describe the structure of synovial joints

A
  1. two opposing bony segments covered by hyaline cartilage
  2. smooth, self lubricating joint with resilient articular cartilage–> this cushions and absorbs the force
  3. cavity contains joint fluid–> synovial fluid
  4. move movement and less stable than other types of joints
  5. bones attached peripherally by a fibrous tissue capsule which forms a closed cavity–> capsule and ligaments provide restraints to the movement of the joint
  6. all joints have nerve supply–> feedback loops for coordinated movement, which is important for reflexes
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77
Q

list the components of a synovial joint

A 
articular cartilage
synovium
synovial fluid
capsule and ligaments
supportive fibrocartilage
tendons
associated nerve and vessels
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78
Q

what is the synovium

A

lines entire joint cavity, except over the articular cartilage

two layers, inner and outer

inner–> thin syncytium–> contains cells specialized to clear waste material (type A) and cells specialized to synthesize hyaluronic acid (type B)

outer–> rich supply of blood vessels, lymph, and nerve fibres

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79
Q

what is the usual response to an injury to the synovium?

A

generally undergoes hyperplasia during joint inflammation–> leads to increased production of synovial fluid and joint effusion

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80
Q

describe the appearance of synovial fluid

A

viscous, pale yellow, clear fluid

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81
Q

what is synovial fluid made of

A

composed of dialyzed plasma with glycoprotein and hyaluronic acid (lubricin, proteinase, collagenase, prostaglandins)

low cell count

nourishes and lubricates joint surfaces

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82
Q

what is the normal amount of synovial fluid in the adult knee

A

about 5cc

lots of synovial fluid is indicative of pathological state

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83
Q

what types of joints are found in the vertebrae

A

anterior vertebral bodies are connected via symphyseal joints whereas posterior joints are synovial joints (because this is where the most motion is)

84
Q

what is another name for the sesamoid bone

A

patella

85
Q

what is the function of the sesamoid bones/patellas

A

increases the mechanical advantage of a tendon–> effect similar to a lever and bone is better in compression than tendon tissue

86
Q

what is the innervation of the knee joint

A

femoral and obturator nerves

87
Q

list the important ligaments of the knee joint we need to know

A
  1. fibular/lateral collateral ligament (LCL)
  2. tibial/medial collateral ligament (MCL)
  3. anterior cruciate ligament (ACL)
  4. posterior cruciate ligament (PCL)
  5. patella ligament
88
Q

what does the lateral collateral ligament connect to

A

goes from the lateral epicondyle of the FEMUR to the head of the FIBULA

**there is a bursa between the ligament and the joint capsule

89
Q

what is the function of the lateral collateral ligament

A

maintains side to side stability of the knee joint

resists lateral/VARUS movement of the knee

90
Q

what does the medial collateral ligament connect to

A

goes from the medial epicondyle of the FEMUR to the medial surface of the shaft of the TIBIA

**deep fibres are connected to the medial meniscus

91
Q

what is the function of the medial collateral ligament

A

maintains side to side stability of the knee joint

resists medial/VALGUS movement of the knee

92
Q

which ligament of the knee is attached to the medial meniscus via deep fibres

A

the MCL connects to the medial meniscus

93
Q

what does the anterior cruciate ligament attach to

A

goes from the lateral condyle of the femur to the anterior part of the intercondylar area of the tibia

94
Q

what is the function of the anterior cruciate ligament

A

maintains ANTERIOR stability of the knee joint–> resists anterior displacement of the tibia relative to the femur

provides support in rotation of the knee

95
Q

what does the posterior cruciate ligament connect to

A

goes from the medial condyle of the femur to the posterior part of the intercondylar area of the tibia

96
Q

what is the function of the posterior cruciate ligament

A

maintains POSTERIOR stability of the knee joint–> resists anterior displacement of the tibia relative to the femur

provides support in rotation of the knee

97
Q

where does the patella ligament attach

A

from the patella to the tibial tuberosity

**3 bursae surround this tendon–> prepatellar, deep and superficial infrapatellar bursa

98
Q

what are the menisci

A

crescent shaped FIBROCARTILAGINOUS structures with a triangular cross section

99
Q

what are the menisci made of

A

composed mostly of TYPE I COLLAGEN fibres

100
Q

what is the function of the menisci

A

disperse the weight of the body and reduce friction during movement

joint stabilization
load distribution
shock absorption
joint lubrication

101
Q

what is the vascular supply for the menisci

A

mainly from the lateral and medial geniculate arteries

penetration is 20-30% in medial meniscus and 10-25% of lateral meniscus

102
Q

how do the menisci connect to the knee joint

A

anteriorly via transverse intermeniscal ligament

peripherally via the coronary ligaments (tougher connection medial versus lateral)

103
Q

what is the healing potential of the menisci

A

poor

unless the injury is peripheral and repairable

104
Q

does the meniscus have a perichondrium

A

no

105
Q

describe the shape and mobility of the medial meniscus

A

semicircular

peripheral margin is adherent to the deep part of the MCL

LESS MOBILE than the lateral meniscus and therefore more susceptible to injury

106
Q

describe the shape and mobility of the lateral meniscus

A

almost circular

separated from the LCL by the tendon of the popliteus muscle and the capsule

more mobile than the medial meniscus and thus less susceptible to injury

107
Q

what is osteoarthritis

A

chronic disease in which degradation and loss of articular cartilage occur together with new bone formation at the joint surfaces and margins, leading to pain and deformity

classified as NONINFLAMMATORY ARTHRITIS

disease process results in a reduction in the proteoglycan content in cartilage leading to reduced resiliency and deterioration

the body is unable to repair articular cartilage and so the underlying bone responds by remodeling and forming bone spurs (osteophytes)

108
Q

under what circumstances is articular cartilage damaged?

A
  1. normal load on an abnormal joint–> change in mechanics due to injured structures
  2. abnormal load on a normal joint–> blunt trauma induces changes similar to those seen in OA
  3. normal load on normal cartilage with weakened subchondral bone–> avascular necrosis
  4. normal load on normal cartilage with stiffened subchondral bone–> Paget’s disease, high bone density
109
Q

what are the distinguishing features of osteoarthritis

A

limitation of motion and mechanical pain that is worsened by movement and alleviated by rest

110
Q

what is the most common joint disorder

A

OA

111
Q

what are the cardinal features of OA

A

disease evolves slowly

characterized by dterioration of articular cartilage and formation of bony spurs/osteophytes at CMC joints, 1st MTP joints (bunions), DIP joints (Heberden’s nodes) and PIP joints (Bouchard’s nodes)

112
Q

where are bunions found

A

due to OA spurs

1st MTP joints

113
Q

where are Heberden’s nodes found

A

from OA

DIP joints

114
Q

where are Bouchard’s nodes found

A

from OA

PIP joints

115
Q

what are the most commonly affected joints in OA

A 
knees
hips
DIPs 
carpometacarpal joint of the thumb
cervical and lumbosacral spine
116
Q

what is the pathophysiology of OA

A
  1. initiating factor is unknown but seems to arise in the cartilage itself
  2. mechanical loading and microtrauma to the cartilage damages the chondrocytes and leads to the release of enzymes and loss of normal synthesis by chondrocytes
  3. once the collagen arcade is disrupted, the released MMPs work to break down the collagen and proteoglycan polymer structure, causing proteoglycans to be released out of the collagen cage
  4. proteoglycans are initially cleaved at the binding site to hyaluronic acid, just distal to the HABR, thereby preventing reattachment of PGs to the hyaluronic acid
  5. PG fragments are released out of the cartilage and into the synovial fluid where they are further broken down
117
Q

which MMP breaks down proteoglycans

A

MMP-3/stromelysin

118
Q

which MMPs break down collagen

A

MMP1 and MMP13

119
Q

describe OA cartilage

A

brittle and fibrillated

120
Q

what are the hallmark changes of OA seen on radiograph

A
  1. subchondral cysts
  2. joint space narrowing
  3. osteophytes
  4. sclerosis
121
Q

what macroscopic changes are seen in OA

A
  • softening (chondromalacia)
  • fibrillation
  • erosions
122
Q

what histological changes are seen in OA

A
  • surface erosion/irregularities
  • deterioration of the tidemark
  • fissuring
  • cartilage destruction
  • eventual eburnated bone
123
Q

what is the tidemark

A

the transitional zone, appearing as a wavy line, between calcified and uncalcified cartilage

124
Q

what are the biochemical changes seen in OA

A
  1. loss of PG content and composition with increased water content
  2. PG is shorter chains with increased chondroitin/keratin sulfate ration
  3. PG largely unbound to hyaluronic acid because of proteolytic enzymes and decreased number of link proteins
  4. collagen content is maintained but poorly organized and orientation is severely disturbed likely due to increased collagenase
  5. proteolytic enzymes/MMPs increased (collagenase, gelatinase, stromelysin)
  6. cathepsin B and D increased (proteases)
  7. increased IL-1 and other cytokines
125
Q

list non-medical management options for OA

A
  1. physiotherapy for knee strengthening
  2. occupational therapy
  3. weight loss
  4. occupational therapy
  5. splints (unloading braces)
  6. switch to swimming, cycling
126
Q

what is the pharmacological management for OA

A
  1. first line tx: acetaminophen
    - if it fails, add in or replace it with an NSAID
  2. NSAIDS
    - must watch for side effects (i.e if COX 2 selective so risk for cardiac disease//if nonselective risk for nausea, GI bleed, dyspepsia)
  3. injection therapy (mainly for knee)
    A. corticosteroid injection
    -no more than 3/year in a given joint, may reduce cartilage’s ability to repair
    -works via decreasing protease activity and inflammation and thus decreasing pain
    -70% have 3 months of reduced pain
    B. viscosupplentation
    -injection of purified hyaluronic acid to restore synovial fluid viscosity
    -3 injections over course of a week to last 6 months
    -less than 50% see benefit
    -2% get violent allergic inflammatory synovitis
  4. naturopathic–> glucosamine sulphate (contains keratin sulphate; efficacy not proven)
127
Q

what is possible surgical management for OA

A
  1. arthroscopy–> can be of diagnostic value–> do lavage, rinsing or debridement of joint–> decreased symptoms in short term because wash away inflammatory mediators but no long term efficacy
  2. total joint replacement/arthroplasty–> at end stage of the disease when there is night pain–> 90% last 15 years
  3. osteotomy–> cut bone, add wedge, correct deformity (of varus or valgus)–> partial joint replacement
  4. unicompartment (partial) knee replacement–> only done if all the other compartments are good–> 80% last 10 years
128
Q

what does NSAID stand for

A

Nonsteroidal anti-inflammatory drugs

129
Q

what is the prototype NSAID

A

ibuprofen

130
Q

list the propionic acid derivative NSAIDS

A

NAPROXEN
fenoprofen
ketoprofen
flurbiprofen

131
Q

list the acetic acid derivative NSAIDs

A 
DICLOFENAC
ketorolac
sulindac
piroxicam
meloxicam
tolmetin
mefenamic acid
132
Q

list the cox-2 selective NSAIDs

A

CELECOXIB
refecoxib
valdecoxib

133
Q

what type of NSAID are the following drugs

  1. naproxen
  2. sulindac
  3. tolmetin
  4. celecoxib
  5. fenoprofen
  6. mefenamic acid
  7. flurbiprofen
  8. ketoprofen
  9. refecoxib
  10. ketorolac
  11. piroxicam
  12. valdecoxib
  13. meloxicam
  14. diclofenac
A
  1. propionic acid derivative
  2. acetic acid derivative
  3. acetic acid derivative
  4. cox-2 selective
  5. propionic acid derivative
  6. acetic acid derivative
  7. propionic acid derivative
  8. propionic acid derivative
  9. cox-2 selective
  10. acetic acid derivative
  11. acetic acid derivative
  12. cox-2 selective
  13. acetic acid derivative
  14. acetic acid derivative
134
Q

what is the function of the COX enzymes

A

COX is an enzyme that catalyzes the conversion of arachadonic acid to prostaglandin (PG)–> AA is converted to a variety of important PGs and thromboxane A2

135
Q

what are the differences between COX-1 and COX-2 production and function

A
  1. COX-1 is a constitutive enzyme–> levels remain constant and found throughout the body
    - plays a maintenance or protective role–> is responsible for production of mucus in stomach and for platelet aggregation
  2. COX-2 is an inducible enzyme–> levels of activity can increase in response to a stimulus
    - main stimuli is inflammatory mediators and thus it is associated with inflammation
136
Q

which COX enzyme is associated with production of mucus in stomach and platelet aggregation

A

COX 1

137
Q

which COX enzyme is associated with inflammation

A

COX 2

138
Q

what is the theory behind COX 2 selective inhibitors

A

to preserve gastric cytoprotective effects while maximizing the anti-inflammatory effects

139
Q

what is an unanticipated effect of COX2 selective inhibitors

A

pro-platelet effects–> issues with CV disease

140
Q

what is the role of Prostaglandin E2 (PGE2)

A 
fever
pain
vasodilation
inflammation
mucus production
141
Q

what is the role of prostaglandin I2 (PGI2)

A

platelet inhibition

vasodilation

142
Q

what is the role of thromboxane A2? which COX enzyme is responsible for its production?

A

platelet activation
vasoconstriction

COX1

143
Q

which COX enzyme is responsible for the production of prostacyclins

A

both COX 1 and 2

144
Q

what is the role of prostaglandins in the tissues and joints? what COX enzyme is responsible for this?

A

COX 2 produces prostaglandins that act in the tissues and joints to mediate pain, inflammation and fever

prostaglandins sensitize nocireceptors to inflammatory mediators and so when NSAIDs are able to effectively halt the production of these PGs, pain is reduced

145
Q

which COX enzyme produces PGs that act in the GI mucosa and kidneys

A

COX 1 produces both

COX 2 also produces PGs that act in the kidneys

**important for maintaining vasodilation/perfusion to the kidneys and for HCO3- and mucus production in the stomach preventing ulcers (thus with NSAID use, kidney perfusion can be reduced and GI ulcers can develop)

146
Q

pharmacokinetics of NSAIDs

A

most NSAIDs are well absorbed and food has little effect on bioavailability

undergo extensive HEPATIC metabolism

short to intermediate half lives

available as topical forms (diclofenac, suprofen)

147
Q

which NSAIDs are available in topical forms

A

diclofenac

suprofen

148
Q

indications for NSAID use

A

pain
inflammation
fever

149
Q

contraindications for NSAID use

A

ACTIVE PEPTIC ULCER

patients with impaired renal function

150
Q

side effects of non-selective COX inhibitor NSAIDs

A
  1. GI due to reduced mucus
  2. edema–> due to inhibition of ADH and salt and water retention
  3. acute renal failure–> glomerular afferent vasoconstriction is unopposed reducing renal blood flow and function
151
Q

side effects of selective COX 2 inhibitor NSAIDS

A

CV–> suspected to be due to disruption of platelet balance

152
Q

side effects of both selective and nonselective NSAIDs

A
  1. CNS–> confusion, dizziness, depression, hallucinations

2. dermatological–> rash, including severe rash (stevens-johnson syndrome), photosensitivity

153
Q

what is the prototype glucocorticoid

A

prednisone

154
Q

other than prednisone, what are some other glucocorticoid drugs

A 
CORTISONE
hydrocortisone
methylprednisone
dexamethasone
triamcinolone
155
Q

name the endogenous glucocorticoid

A

cortisol

156
Q

what is cortisol made from

A

synthesized from cholesterol

157
Q

describe the production of cortisol

A

the hypothalamus secretes corticotrophin-releasing hormone (CRH) which stimulates the anterior pituitary to release adenocorticotrophic hormone (ACTH) which acts on the adrenal glands to produce cortisol

158
Q

where does cortisol act and how

A

acts in the nucleus of the cell–> acts via glucocorticoid receptor elements to regulate DNA transcription

159
Q

name the class of drug that are systemic steroids

A

glucocorticoids

160
Q

what are the catabolic actions of steroids

A

increased serum glucose–> increased gluconeogenesis, increased lipolysis, decreased uptake of glucose, direct inhibition of insulin

mobilization of calcium from bones

increased breakdown of muscle

161
Q

what are the inflammatory actions of steroids

A
  1. increased blood neutrophil counts
  2. increased marrow release and decreased tissue margination
  3. decreased number of other WBCs
  4. reduced function of lymphocytes and macrophages
  5. reduced function of phospholipase A2 (and thus reduces mediators of inflammation, like prostaglandins and leukotrienes)
162
Q

pharmacokinetics of steroids/glucocorticoids

A

largely bound to corticosteroid-binding globulin–> also bound to albumin but with low affinity

163
Q

indication for glucocorticoid use

A

inflammatory states (and many others) –> one of the main indications is the inhibition of the inflammatory response

tend to be more potent anti-inflammatories than NSAIDs

164
Q

what is the primary anti-inflammatory mechanism of glucocorticoids

A

lipocortin-1

lipocortin-1 both suppresses phospholipase A2, thereby blocking eicosanoid production and preventing the arachadonic acid cascade and also inhibits various leukocyte inflammatory events –> inhibit inflammatory immune response

inhibit prostaglandin synthesis both at level of phospholipase A2 as well as at the level of coclooxygenase/PGE isomerase (COX 1 and 2) (this is a much more NSAID like effect)

165
Q

contraindications of glucocorticoid use

A

active serious infection

166
Q

side effects of glucocorticoid use

A
  1. hyperglycemia and steroid induced diabetes
  2. weight gain and severe swelling
  3. psychiatric
  4. gastric and duodenal bleeding
  5. infections
  6. skin effects
  7. eyes (cataracts and glaucoma)
  8. muscular
  9. adipose distribution
  10. cushings syndrome
  11. adrenal suppression
167
Q

when are NSAIDs and glucocorticoids commonly prescribed

A

in the setting of inflammatory conditions that result in pain (i.e rheumatoid arthritis)

168
Q

what is the function of tendons

A

to transfer load from muscle to bone to move the joint

connects MUSCLE TO BONE

exposed to TENsile (tendons are exposed to tensile) and compressive forces and serve to transmit forces that move the joint

169
Q

what makes up the majority of the dry weight of tendons

A

type I collagen makes up 86% of the dry weight of tendons

proteoglycans make up 1-5% of dry weight

170
Q

what is the most common proteoglycan found in tendons

A

decorin

aggrecan is also seen in tendons which are compressive

171
Q

describe the structure and composition of tendons

A

collagen fibres embedded in water and proteoglycan matrix

relatively acellular

hierarchical structure (collagen–> microfibrils–> subfibrils–> fibrils–> fascicles–> tendon)

172
Q

what is the dominant cell type in tendons

A

fibroblast dominant cell type–> spindle shaped longitudinally and star shaped in cross section

in line with muscle fibres

173
Q

describe the source of the blood supply for tendons

A

tendons are relatively avascular, with the blood supply coming from the covering known as the EPITENON, the insertion site and surrounding tissue

174
Q

what is the epitenon

A

the connective tissue layer that surrounds the entire tendon

each fascicle is ensheathed by an endotenon

175
Q

what is the tissue classification of tendons

A

dense regular connective tissue

176
Q

what is the function of the endotenon in the tendon

A

provides a conduit for vasculature and nerves supplying the tendon

177
Q

what is the function of the fibroblasts in tendons

A

responsible for the synthesis and secretion of ground substances and collagen fibres of the ECM

are relatively few in number and are interconnected via gap junctions allowing communication and coordination

178
Q

what is the function of a ligament? what does it connect”

A

connects BONE TO BONE

function to RESTRICT joint movement/stabilize joint

179
Q

how does the structure of ligaments compare to that of tendons

A

ligaments are also dense connective tissue

however, they are shorter and wider than tendons, have a lower percentage of collagen and a higher percentage of water and proteoglycans than tendons

180
Q

how does the collagen in ligaments compare to the collagen in tendons

A

in ligaments, the collagen is less organized yet it maintains the hierarchy of structure

181
Q

what is the type if collagen most commonly found in ligaments

A

type I collagen (70% dry weight of ligament)

182
Q

how does the cell type found in ligaments differ from that of tendons

A

the primary cell type is still fibroblasts but the fibroblasts in ligaments are more round

183
Q

why do injuries to the ACL or PCL ligaments have trouble healing?

A

they are intra-articular ligaments which means they pass THROUGH the joint

the synovial membrane provides a barrier between the intra-articular ligament and the synovial fluid

however, rupture of the ACL or PCL also causes rupture of the synovial membrane barrier, thus exposing the ACL and PCL to synovial fluid

synovial fluid cannot clot, therefore exposure decreases the inherent regenerative potential of the ligaments

184
Q

where are extraarticular ligaments found

A

they are part of the capsule (i.e the MCL and LCL

185
Q

describe the muscle-tendon junction

A

the interface is characterized by numerous FINGER-LIKE extensions of the sarcolemma (cell membrane of muscle cells) that INTERDIGITATE with adjacent COLLAGEN fibres of the tendon

the interdigitation increases contact area therefore allowing high tensile forces to be distributed across the junction

SARCOLEMMAL DENSITIES are present along the mucsle-tendon
junction and represent proteins that serve as anchors between muscle and tendon

186
Q

name some proteins found in sarcolemmal densities in muscle tendon interfaces

A

vinculin
alpha-actin
talin
integrins

187
Q

name two intraarticular tendons

A

biceps tendon

popliteus tendon

188
Q

what is a tendinopathy

A

primarily degenerative condition–> usually an absence of inflammatory cells in or around the lesion

results from a cycle of increased demand on a tendon with inadequate repair (inadequate collagen and matrix production and tenocyte death results in a further reduction in collagen and matrix and predisposition to further injury)

189
Q

what 4 processes does the term tendinopathy encompass

A
  1. tendinosis–> tendon degeneration without clinical or histological signs of inflammation
  2. partial rupture–> histopathology in partial rupture is similar to tendinosis
  3. paratenonitis–> inflammation of the PARATENON (aka DeQuervains tenosynovitis, intersection syndrome)
  4. paratenonitis with tendinosis
190
Q

what is tendinitis

A

implies inflammation but does not respond like an inflammation–> may not be hot or respond to anti-inflammatories

prevalence in rare and recovery from early presentation is several days to 2 weeks

likelihood of full recovery from chronic symptoms is 99%

anti-inflammatories are recommended as tx

191
Q

describe the structure of a normal tendon versus that of a symptomatic tendon

A
  1. normal
    - dense, clearly defined parallel collagen bundles
    - no evidence of fibroblastic proliferation
    - small arteries are oriented parallel to fibres
  2. symptomatic tendon
    - degeneration with disordered arrangement of collagen fibrils
    - increased vascularity
    - absence of inflammatory cells
192
Q

how would you manage a chronic tendonopathy

A
  1. collagen repair may require a longer healing period than traditionally expected
  2. tissue damage quite advanced by the time patient feels pain
  3. generally allow for 2-3 weeks of relative rest before initiation of strengthenin
  4. relative rest combined with biomechanical deloading (addressing predisposing factors, i.e excessive pronation and hill running)
193
Q

what are the two overall mechanisms of tendon injury

A

direct laceration or tensile overload

194
Q

what are the 3 phases of tendon healing

A
  1. hemostasis/inflammation–> after injury, the wound site experiences influx of inflammatory cells, platelets, fibrin clots (matter of days)
  2. matrix and cell proliferation–> fibroblasts proliferate, ECM, type III collagen/disorganized collagen (matter of weeks)
  3. remodelling/maturation–> matrix metalloproteinases degrade collagen matrix and replace type III with type I collagen and collagen is reorganized to be parallel to fibres of muscle load (matter of months to years)
195
Q

what are the long term effects of tendon injury

A

structural properties of repaired tendons may only attain 2/3 of normal

can have altered material properties as well

196
Q

what factors determine tendon healing outcomes

A 
biological environment
blood flow
exercise
age
in sheathed tendon it is important to prevent adhesions for a good outcome
197
Q

how do extra articular ligaments heal (i.e MCL)? how does this compare to intra-articular ligaments (i.e ACL)?

A

extra-articular ligaments heal with a fibrin clot

  • fibroblasts proliferate and secrete matrix–> early tissue is type III collagen
  • remodels to be more like normal ligament type–> contraction of healing tissue
  • entire process may take up to a year

intra-articular ligament are bathed in synovial fluid and thus do not have the same ability to heal as extra-articular ligaments–> synovial fluid does not clot

198
Q

how are ligament injuries classified?

A

grade 1–> mild sprain (stretches 1-4mm)

grade 2–> moderate sprain/partial tear (stretches 5-9 mm)

grade 3–> complete ligament tear (stretches > 10 mm)

**sometimes will occur as an “avulsion” with a bone fragment torn off with the ligament

199
Q

what is a sprain

A

injury involving the stretching or tearing of a ligament or joint capsule

200
Q

what is a strain

A

injury involving stretching or tearing of a musculo-tendinous joint

201
Q

what is a diarthrodial joint?

A

mobile joints which occur in all of the peripheral joints in limbs and in TMJ and apophyseal joints of the axial skeleton

surrounded by fibrous capsule and lined by synovium

where tendons and ligaments insert into bone–> entheses

202
Q

what are the zones of cartilage named? (list them)

A

Zone 1–> superficial/tangential

Zone 2–> middle/transition

Zone 3–> deep/radial

Zone 4–> calcified cartilage

203
Q

describe zone 1 (superficial/tangential) of cartilage

A

adjacent to the joint cavity

gliding

collagen is aligned parallel to the articular surface

disc shaped chondrocytes

sparse proteoglycans

high collagen and water concentration

204
Q

describe zone 2 (middle/transition) of cartilage

A

thicker, oblique collagen

round chondrocytes

marked proteoglycan content

most of the cartilage depth is zone 2

205
Q

describe zone 3 (deep/radial) of cartilage

A

collagen perpendicular to articular surface

round chondrocytes in columns

high proteoglycan content

206
Q

describe zone 4 (calcified cartilage) of cartilage

A

radially aligned collagen

round chondrocytes buried in calcified matrix

high concentration of calcium salts

low concentration of proteoglycans

hypertrophic chondrocytes in this layer produce collagen and alkaline phosphate to help mineralize the matrix–> borders are defined by the TIDEMARK as the upper border and CEMENT LINES as the lower line (formed during growth plate ossification)

MSK (5 decks)

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