MSK 2 Flashcards
what are the 3 key components of cartilage
- perichondrium
- chondrocytes
- extracellular matrix
describe the structure of cartilage perichondrium
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
on what type of cartilage is the perichondrium absent
absent on articular cartilage and fibrocartilage
what is the function of the perichondrium
contains vascular supply
inner layer is chondrogenic–important for growth and maintenance
what % of cartilage is chondrocytes
5%
what are chondrocytes
large rounded cells situated in the lacunae of matrix
cells are grouped in “isogenous nests”
mainly secretory–ultrastructure reflects protein and carbohydrate synthesis
what 3 important enzymes do chondrocytes produce and what do they do
- collagenase 1 (MMP1)–> targets type 2 collagen arcade
- stromelysin (MMP3)–> targets proteoglycans (proteoglycanase)
- collagenase 13 (MMP13)–> targets type 2 collagen arcade
what makes up 95% of cartilage
extracellular matrix
what is the ECM in cartilage made up of?
90% water
collagen (hyaline–type II; fibrocartilage–type I)
elastin (in elastic cartilage)
proteoglycans–> contain sulphated and non-sulphated glucosamine (GAGs)
why % of the dry weight of hyaline articular cartilage is proteoglycans
50%
what charge do proteoglycans hold
negative charge
what gives cartilage the deformability and ability to distribute load in a reversible sponge-like fashion?
proteoglycan aggregates and the water they attract
explanation:
- PG aggregates are bulky–> they are held in check by type 2 collagen arcade with is like a cage for the PGs
- 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”)
- 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
why is it significant that PG aggregates are stuck in a collagen network?
because this protects them from enzymatic degradation by metalloproteinases
what are GAGs
glucoaminoglycans–> attached to the protein core of proteoglycans
highly negatively charged, which makes the PG hydrophilic and attract water
name the 2 GAGs
chondroitin sulfate
keratan sulfate
describe the structure of chondroitin sulfate
larger of the GAGs and is located at the superior aspect of the core protein
composed mostly of GALACTOSAMINE DISACCHARIDES
describe the structure of keratan sulfate
shorter GAG chains at the proximal or amino terminal of the core protein
enriched GLUCOSAMINE–> supplyment efficacy poorly shown
what are proteoglycans made up of
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
which type of cartilage is the most widely distributed
hyaline
which type of cartilage is the rarest
elastic
which type of cartilage is a mix of both cartilage and dense connective tissue?
fibrocartilage
in what body structures would you find type II cartilage
ribs trachea bronchi joint surfaces growth plates of bone sutures of the skull
what type of collagen do you find in the ECM of hyaline cartilage
type II
describe the regenerative potential of hyaline cartilage
low regenerative potential because it has no venous or lymphatic drainage
describe the appearance of hyaline cartilage
glassy-slippery
bluish-white/translucent
what is the metabolic rate of hyaline cartilage
low
what is the function of hyaline cartilage during the fetal period
serves as a provisional skeleton
what is the function of hyaline cartilage after birth
epithyseal growth plates
articular surfaces
adult skeleton
where in the body would you expect to find elastic cartilage
epiglottis
eustachian tube
ear and external auditory meatus
what type of collagen would you find in the matrix of elastic cartilage
type II
describe the structure of elastic cartilage
bendable but firm
elastic fibres in matrix
little degenerative change
where in the body would you expect to find fibrocartilage
intervertebral disc
menisci
tendinous instertions
what type of collagen is found in the matrix of fibrocartilage
type I
describe the structure of fibrocartilage
firm with great tensile strength
collagen type I fibres are parallel with line of pull/stress
what provides the lubrication and nutrition for the chondrocytes in articular cartilage
synovial fluid
what is the function of synovial fluid and how does it achieve this function
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
what is the function of lubricin and what is it made up of
main lubricating component in synovial fluid
it is a GLYCOPROTEIN synthesized by SYNOVIOCYTES (ype B) and CHONDROCYTES
present on superficial surface of hyaline cartilage
what is the factor that limits articular cartilage repair
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
how do injuries that extend deep into the tidemark region heal?
heal with fibrocartilage rather than hyaline cartilage as before (fibrocartilage has poorer orientation and has type 1 instead of type 2 collagen)
how are superficial lacerations characterized with regard to cartilage healing
these lacerations do not cross the tidemark
do not progress but also do not heal–> laceration for life
how are deep lacerations characterized with regard to articular cartilage healing
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
what are the only cells found in hyaline articular cartilage
chondrocytes
are the only cells in articular cartilage which produce/organize and maintain the ECM
what are chondrocytes derived from
from mesenchymal cells
what is the function of chondrocytes
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
what are fibroblasts
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
describe the structure of fibroblasts
active fibroblasts exhibit long tapering and branched processes (adult tendon is less elaborate)
what are isogenous nests?
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
why is differential staining of the cartilage matrix seen on histological examination?
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)
how does the cartilage receive nutrients and oxygen
nutrients and O2 must diffuse from blood vessels int he perichondrium since the cartilage is avascular
what are the two major dry weight components of articular cartilage matrix
type II collagen and proteoglycans
why are PGs hydrophilic and what is the consequence of this
because of GAGs
this is responsible for the high water content of cartilage
describe the process of collagen synthesis
- hydroxyproline, proline and glycine rich polypeptide sequence is translated at the RER
- subsequent modifications are made using vitamin C as a cofactor
- three alpha chains unite in a triple helix to form pro collagen–> this is packed by the Golgi and exported to the cell surface
- 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
describe the structure of type II collagen
- dry weight of hyaline articular cartilage is 50% type 2 collagen which is arranged like a set of confluent branches
- this arrangement gives the cartilage strength and structures and holds in the proteoglycans–> tensile strength is important to endure impact loading
- if collagen is broken down, hydrophilic PG aggregates are also broken down and escape into the synovial space (and are gone for good)
what are TIMPs
tissue inhibitors of metalloproteases–> counteract and block the MP enzyme
what cell releases MMPs
chondrocytes
what upregulates MMP release from chondrocytes
IL-1 (which is also produced by chondrocytes) and plasmin
how are osteoarthritis and MMPs related?
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
which MMPs break down type 2 collagen
MMP1 and MMP13
which MMPs break down proteoglycans
MMP3 (STROMELYSIN)
what is another name for MMP3
stromelysin
describe the state of the following factors in normal cartilage:
- water content
- PG aggregates
- collagen arcade
- metachromatic staining
- surface chondrocyte #
- MMP enzyme activity
- subchondral bone
- osteophytes
- well hydrated
- normal
- normal
- increased uptake
- intact, smooth, normal
- kept in check
- normal as a rule
- negative
describe the state of the following factors in OA cartilage:
- water content
- PG aggregates
- collagen arcade
- metachromatic staining
- surface chondrocyte #
- MMP enzyme activity
- subchondral bone
- osteophytes
- in early stages–> swelling pressure influx H2O; in late stages–> loss of H2O (dry)
- decreased
- decreased
- decreased/loss of uptake
- fibrillated, irregular chondrocyte; mitosis is ramped up (broad caps)
- upregulated and out of control
- sclerotic as a rule
- positive
describe the state of the following factor/structure in normal aging versus changes observed in OA:
fibrillation
normal aging: mild, non-progressive fibrillation
OA: severe progressive fibrillation
describe the state of the following factor/structure in normal aging versus changes observed in OA:
water content/drying
normal aging: less water content, drying or desiccation of cartilage
OA: initial swelling of collagen arcade in OA due to collagenase being up-regulated
describe the state of the following factor/structure in normal aging versus changes observed in OA:
tensile strength
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
describe the state of the following factor/structure in normal aging versus changes observed in OA:
proteoglycans
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
describe the state of the following factor/structure in normal aging versus changes observed in OA:
chondrocyte phenotype shift
normal aging: hypocellular
OA: chondrocyte cloning in broad capsules; mitosis of chondrocytes; regression to fetal CS-4 instead of CS-6
what features are found in both normal aging and OA
- increased apoptosis
- ER stress
- many overlap in general (normal aging makes cartilage more vulnerable to changes of OA)
list the 6 types of joint
- synovial joint
- syndesmosis
- synchondrosis
- synostosis
- symphysis
- gomphosis
define synovial joint
most appendicular joints
covered by cartilage
connected by a capsule
SYNOVIAL FLUID
define syndesmosis
joint
two bones bound by fibrous tissue only
i.e skull sutures and ankle syndesmosis
define synchondrosis
joint
two bones bound by cartilage
i.e physis (between growth centres), C2 joint; can be pathologic
define synostosis
joint which become obliterated by a bony union
i.e pelvis + ileum + ischium + pubis; can be pathological
define symphysis
joint
opposing surfaces covered by cartilage, minimal movement, no synovium
i.e pubic symphysis, intervertebral discs
define gomphosis
joint
fibrous joint between tooth and socket
fibrous connection
blood vessels and nerves cross the joint
describe the structure of synovial joints
- two opposing bony segments covered by hyaline cartilage
- smooth, self lubricating joint with resilient articular cartilage–> this cushions and absorbs the force
- cavity contains joint fluid–> synovial fluid
- move movement and less stable than other types of joints
- bones attached peripherally by a fibrous tissue capsule which forms a closed cavity–> capsule and ligaments provide restraints to the movement of the joint
- all joints have nerve supply–> feedback loops for coordinated movement, which is important for reflexes
list the components of a synovial joint
articular cartilage synovium synovial fluid capsule and ligaments supportive fibrocartilage tendons associated nerve and vessels
what is the synovium
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
what is the usual response to an injury to the synovium?
generally undergoes hyperplasia during joint inflammation–> leads to increased production of synovial fluid and joint effusion
describe the appearance of synovial fluid
viscous, pale yellow, clear fluid
what is synovial fluid made of
composed of dialyzed plasma with glycoprotein and hyaluronic acid (lubricin, proteinase, collagenase, prostaglandins)
low cell count
nourishes and lubricates joint surfaces
what is the normal amount of synovial fluid in the adult knee
about 5cc
lots of synovial fluid is indicative of pathological state
what types of joints are found in the vertebrae
anterior vertebral bodies are connected via symphyseal joints whereas posterior joints are synovial joints (because this is where the most motion is)
what is another name for the sesamoid bone
patella
what is the function of the sesamoid bones/patellas
increases the mechanical advantage of a tendon–> effect similar to a lever and bone is better in compression than tendon tissue
what is the innervation of the knee joint
femoral and obturator nerves
list the important ligaments of the knee joint we need to know
- fibular/lateral collateral ligament (LCL)
- tibial/medial collateral ligament (MCL)
- anterior cruciate ligament (ACL)
- posterior cruciate ligament (PCL)
- patella ligament
what does the lateral collateral ligament connect to
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
what is the function of the lateral collateral ligament
maintains side to side stability of the knee joint
resists lateral/VARUS movement of the knee
what does the medial collateral ligament connect to
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
what is the function of the medial collateral ligament
maintains side to side stability of the knee joint
resists medial/VALGUS movement of the knee
which ligament of the knee is attached to the medial meniscus via deep fibres
the MCL connects to the medial meniscus
what does the anterior cruciate ligament attach to
goes from the lateral condyle of the femur to the anterior part of the intercondylar area of the tibia
what is the function of the anterior cruciate ligament
maintains ANTERIOR stability of the knee joint–> resists anterior displacement of the tibia relative to the femur
provides support in rotation of the knee
what does the posterior cruciate ligament connect to
goes from the medial condyle of the femur to the posterior part of the intercondylar area of the tibia
what is the function of the posterior cruciate ligament
maintains POSTERIOR stability of the knee joint–> resists anterior displacement of the tibia relative to the femur
provides support in rotation of the knee
where does the patella ligament attach
from the patella to the tibial tuberosity
**3 bursae surround this tendon–> prepatellar, deep and superficial infrapatellar bursa
what are the menisci
crescent shaped FIBROCARTILAGINOUS structures with a triangular cross section
what are the menisci made of
composed mostly of TYPE I COLLAGEN fibres
what is the function of the menisci
disperse the weight of the body and reduce friction during movement
joint stabilization
load distribution
shock absorption
joint lubrication
what is the vascular supply for the menisci
mainly from the lateral and medial geniculate arteries
penetration is 20-30% in medial meniscus and 10-25% of lateral meniscus
how do the menisci connect to the knee joint
anteriorly via transverse intermeniscal ligament
peripherally via the coronary ligaments (tougher connection medial versus lateral)
what is the healing potential of the menisci
poor
unless the injury is peripheral and repairable
does the meniscus have a perichondrium
no
describe the shape and mobility of the medial meniscus
semicircular
peripheral margin is adherent to the deep part of the MCL
LESS MOBILE than the lateral meniscus and therefore more susceptible to injury
describe the shape and mobility of the lateral meniscus
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
what is osteoarthritis
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)
under what circumstances is articular cartilage damaged?
- normal load on an abnormal joint–> change in mechanics due to injured structures
- abnormal load on a normal joint–> blunt trauma induces changes similar to those seen in OA
- normal load on normal cartilage with weakened subchondral bone–> avascular necrosis
- normal load on normal cartilage with stiffened subchondral bone–> Paget’s disease, high bone density
what are the distinguishing features of osteoarthritis
limitation of motion and mechanical pain that is worsened by movement and alleviated by rest
what is the most common joint disorder
OA
what are the cardinal features of OA
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)
where are bunions found
due to OA spurs
1st MTP joints
where are Heberden’s nodes found
from OA
DIP joints
where are Bouchard’s nodes found
from OA
PIP joints
what are the most commonly affected joints in OA
knees hips DIPs carpometacarpal joint of the thumb cervical and lumbosacral spine
what is the pathophysiology of OA
- initiating factor is unknown but seems to arise in the cartilage itself
- mechanical loading and microtrauma to the cartilage damages the chondrocytes and leads to the release of enzymes and loss of normal synthesis by chondrocytes
- 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
- 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
- PG fragments are released out of the cartilage and into the synovial fluid where they are further broken down
which MMP breaks down proteoglycans
MMP-3/stromelysin
which MMPs break down collagen
MMP1 and MMP13
describe OA cartilage
brittle and fibrillated
what are the hallmark changes of OA seen on radiograph
- subchondral cysts
- joint space narrowing
- osteophytes
- sclerosis
what macroscopic changes are seen in OA
- softening (chondromalacia)
- fibrillation
- erosions
what histological changes are seen in OA
- surface erosion/irregularities
- deterioration of the tidemark
- fissuring
- cartilage destruction
- eventual eburnated bone
what is the tidemark
the transitional zone, appearing as a wavy line, between calcified and uncalcified cartilage
what are the biochemical changes seen in OA
- loss of PG content and composition with increased water content
- PG is shorter chains with increased chondroitin/keratin sulfate ration
- PG largely unbound to hyaluronic acid because of proteolytic enzymes and decreased number of link proteins
- collagen content is maintained but poorly organized and orientation is severely disturbed likely due to increased collagenase
- proteolytic enzymes/MMPs increased (collagenase, gelatinase, stromelysin)
- cathepsin B and D increased (proteases)
- increased IL-1 and other cytokines
list non-medical management options for OA
- physiotherapy for knee strengthening
- occupational therapy
- weight loss
- occupational therapy
- splints (unloading braces)
- switch to swimming, cycling
what is the pharmacological management for OA
- first line tx: acetaminophen
- if it fails, add in or replace it with an NSAID - 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) - 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 - naturopathic–> glucosamine sulphate (contains keratin sulphate; efficacy not proven)
what is possible surgical management for OA
- 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
- total joint replacement/arthroplasty–> at end stage of the disease when there is night pain–> 90% last 15 years
- osteotomy–> cut bone, add wedge, correct deformity (of varus or valgus)–> partial joint replacement
- unicompartment (partial) knee replacement–> only done if all the other compartments are good–> 80% last 10 years
what does NSAID stand for
Nonsteroidal anti-inflammatory drugs
what is the prototype NSAID
ibuprofen
list the propionic acid derivative NSAIDS
NAPROXEN
fenoprofen
ketoprofen
flurbiprofen
list the acetic acid derivative NSAIDs
DICLOFENAC ketorolac sulindac piroxicam meloxicam tolmetin mefenamic acid
list the cox-2 selective NSAIDs
CELECOXIB
refecoxib
valdecoxib
what type of NSAID are the following drugs
- naproxen
- sulindac
- tolmetin
- celecoxib
- fenoprofen
- mefenamic acid
- flurbiprofen
- ketoprofen
- refecoxib
- ketorolac
- piroxicam
- valdecoxib
- meloxicam
- diclofenac
- propionic acid derivative
- acetic acid derivative
- acetic acid derivative
- cox-2 selective
- propionic acid derivative
- acetic acid derivative
- propionic acid derivative
- propionic acid derivative
- cox-2 selective
- acetic acid derivative
- acetic acid derivative
- cox-2 selective
- acetic acid derivative
- acetic acid derivative
what is the function of the COX enzymes
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
what are the differences between COX-1 and COX-2 production and function
- 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 - 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
which COX enzyme is associated with production of mucus in stomach and platelet aggregation
COX 1
which COX enzyme is associated with inflammation
COX 2
what is the theory behind COX 2 selective inhibitors
to preserve gastric cytoprotective effects while maximizing the anti-inflammatory effects
what is an unanticipated effect of COX2 selective inhibitors
pro-platelet effects–> issues with CV disease
what is the role of Prostaglandin E2 (PGE2)
fever pain vasodilation inflammation mucus production
what is the role of prostaglandin I2 (PGI2)
platelet inhibition
vasodilation
what is the role of thromboxane A2? which COX enzyme is responsible for its production?
platelet activation
vasoconstriction
COX1
which COX enzyme is responsible for the production of prostacyclins
both COX 1 and 2
what is the role of prostaglandins in the tissues and joints? what COX enzyme is responsible for this?
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
which COX enzyme produces PGs that act in the GI mucosa and kidneys
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)
pharmacokinetics of NSAIDs
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)
which NSAIDs are available in topical forms
diclofenac
suprofen
indications for NSAID use
pain
inflammation
fever
contraindications for NSAID use
ACTIVE PEPTIC ULCER
patients with impaired renal function
side effects of non-selective COX inhibitor NSAIDs
- GI due to reduced mucus
- edema–> due to inhibition of ADH and salt and water retention
- acute renal failure–> glomerular afferent vasoconstriction is unopposed reducing renal blood flow and function
side effects of selective COX 2 inhibitor NSAIDS
CV–> suspected to be due to disruption of platelet balance
side effects of both selective and nonselective NSAIDs
- CNS–> confusion, dizziness, depression, hallucinations
2. dermatological–> rash, including severe rash (stevens-johnson syndrome), photosensitivity
what is the prototype glucocorticoid
prednisone
other than prednisone, what are some other glucocorticoid drugs
CORTISONE hydrocortisone methylprednisone dexamethasone triamcinolone
name the endogenous glucocorticoid
cortisol
what is cortisol made from
synthesized from cholesterol
describe the production of cortisol
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
where does cortisol act and how
acts in the nucleus of the cell–> acts via glucocorticoid receptor elements to regulate DNA transcription
name the class of drug that are systemic steroids
glucocorticoids
what are the catabolic actions of steroids
increased serum glucose–> increased gluconeogenesis, increased lipolysis, decreased uptake of glucose, direct inhibition of insulin
mobilization of calcium from bones
increased breakdown of muscle
what are the inflammatory actions of steroids
- increased blood neutrophil counts
- increased marrow release and decreased tissue margination
- decreased number of other WBCs
- reduced function of lymphocytes and macrophages
- reduced function of phospholipase A2 (and thus reduces mediators of inflammation, like prostaglandins and leukotrienes)
pharmacokinetics of steroids/glucocorticoids
largely bound to corticosteroid-binding globulin–> also bound to albumin but with low affinity
indication for glucocorticoid use
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
what is the primary anti-inflammatory mechanism of glucocorticoids
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)
contraindications of glucocorticoid use
active serious infection
side effects of glucocorticoid use
- hyperglycemia and steroid induced diabetes
- weight gain and severe swelling
- psychiatric
- gastric and duodenal bleeding
- infections
- skin effects
- eyes (cataracts and glaucoma)
- muscular
- adipose distribution
- cushings syndrome
- adrenal suppression
when are NSAIDs and glucocorticoids commonly prescribed
in the setting of inflammatory conditions that result in pain (i.e rheumatoid arthritis)
what is the function of tendons
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
what makes up the majority of the dry weight of tendons
type I collagen makes up 86% of the dry weight of tendons
proteoglycans make up 1-5% of dry weight
what is the most common proteoglycan found in tendons
decorin
aggrecan is also seen in tendons which are compressive
describe the structure and composition of tendons
collagen fibres embedded in water and proteoglycan matrix
relatively acellular
hierarchical structure (collagen–> microfibrils–> subfibrils–> fibrils–> fascicles–> tendon)
what is the dominant cell type in tendons
fibroblast dominant cell type–> spindle shaped longitudinally and star shaped in cross section
in line with muscle fibres
describe the source of the blood supply for tendons
tendons are relatively avascular, with the blood supply coming from the covering known as the EPITENON, the insertion site and surrounding tissue
what is the epitenon
the connective tissue layer that surrounds the entire tendon
each fascicle is ensheathed by an endotenon
what is the tissue classification of tendons
dense regular connective tissue
what is the function of the endotenon in the tendon
provides a conduit for vasculature and nerves supplying the tendon
what is the function of the fibroblasts in tendons
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
what is the function of a ligament? what does it connect”
connects BONE TO BONE
function to RESTRICT joint movement/stabilize joint
how does the structure of ligaments compare to that of tendons
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
how does the collagen in ligaments compare to the collagen in tendons
in ligaments, the collagen is less organized yet it maintains the hierarchy of structure
what is the type if collagen most commonly found in ligaments
type I collagen (70% dry weight of ligament)
how does the cell type found in ligaments differ from that of tendons
the primary cell type is still fibroblasts but the fibroblasts in ligaments are more round
why do injuries to the ACL or PCL ligaments have trouble healing?
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
where are extraarticular ligaments found
they are part of the capsule (i.e the MCL and LCL
describe the muscle-tendon junction
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
name some proteins found in sarcolemmal densities in muscle tendon interfaces
vinculin
alpha-actin
talin
integrins
name two intraarticular tendons
biceps tendon
popliteus tendon
what is a tendinopathy
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)
what 4 processes does the term tendinopathy encompass
- tendinosis–> tendon degeneration without clinical or histological signs of inflammation
- partial rupture–> histopathology in partial rupture is similar to tendinosis
- paratenonitis–> inflammation of the PARATENON (aka DeQuervains tenosynovitis, intersection syndrome)
- paratenonitis with tendinosis
what is tendinitis
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
describe the structure of a normal tendon versus that of a symptomatic tendon
- normal
- dense, clearly defined parallel collagen bundles
- no evidence of fibroblastic proliferation
- small arteries are oriented parallel to fibres - symptomatic tendon
- degeneration with disordered arrangement of collagen fibrils
- increased vascularity
- absence of inflammatory cells
how would you manage a chronic tendonopathy
- collagen repair may require a longer healing period than traditionally expected
- tissue damage quite advanced by the time patient feels pain
- generally allow for 2-3 weeks of relative rest before initiation of strengthenin
- relative rest combined with biomechanical deloading (addressing predisposing factors, i.e excessive pronation and hill running)
what are the two overall mechanisms of tendon injury
direct laceration or tensile overload
what are the 3 phases of tendon healing
- hemostasis/inflammation–> after injury, the wound site experiences influx of inflammatory cells, platelets, fibrin clots (matter of days)
- matrix and cell proliferation–> fibroblasts proliferate, ECM, type III collagen/disorganized collagen (matter of weeks)
- 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)
what are the long term effects of tendon injury
structural properties of repaired tendons may only attain 2/3 of normal
can have altered material properties as well
what factors determine tendon healing outcomes
biological environment blood flow exercise age in sheathed tendon it is important to prevent adhesions for a good outcome
how do extra articular ligaments heal (i.e MCL)? how does this compare to intra-articular ligaments (i.e ACL)?
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
how are ligament injuries classified?
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
what is a sprain
injury involving the stretching or tearing of a ligament or joint capsule
what is a strain
injury involving stretching or tearing of a musculo-tendinous joint
what is a diarthrodial joint?
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
what are the zones of cartilage named? (list them)
Zone 1–> superficial/tangential
Zone 2–> middle/transition
Zone 3–> deep/radial
Zone 4–> calcified cartilage
describe zone 1 (superficial/tangential) of cartilage
adjacent to the joint cavity
gliding
collagen is aligned parallel to the articular surface
disc shaped chondrocytes
sparse proteoglycans
high collagen and water concentration
describe zone 2 (middle/transition) of cartilage
thicker, oblique collagen
round chondrocytes
marked proteoglycan content
most of the cartilage depth is zone 2
describe zone 3 (deep/radial) of cartilage
collagen perpendicular to articular surface
round chondrocytes in columns
high proteoglycan content
describe zone 4 (calcified cartilage) of cartilage
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)
