Giles Kisby
GE Y1 Musculoskeletal
Musculoskeletal:
Spring Term:
LECTURES:
07/03/14: Bone Development and Metabolism: Duncan
Bassett
Los (from booklet):
Define bone structure.
Explain the difference between intramembranous and endochondral ossification.
Define the role of the osteoblast, osteoclasts and chondrocyte.
Recall the bone remodeling cycle in adult bone.
Define osteoporosis, list its common causes and outline treatment strategies that may be used.
Define Paget’s disease and the bone pathology seen in this disorder.
Los (from slides):
1. Contrasting endochondral and intramembranous ossification
2. Understand the role of chondrocyte, osteoblasts, osteoclasts and osteocytes
3. Describe the bone remodelling cycle
4. Contrast the affect of intermittent and continuous PTH on the skeleton
5. Define age related osteoporosis and list the common risk factors
6. Describe the causes of secondary osteoporosis
7. Describe DXA BMD analysis with particular reference to the T and Z scores
8. List the main medications used to treat osteoporosis and describe their action
9. Compare and contrast the uses of PTH and the bisphosphonates
10. Describe the skeletal consequences of long term glucocorticoid treatment
11. Describe the indications for treatment of Paget’s disease and the mechanism of
action of the therapy
Notes
1
Giles Kisby
-
GE Y1 Musculoskeletal
Skeletal Physiology
o Bone Structure
 Osteoid: is a protein mixture secreted by osteoblasts that forms the organic
matrix of bone. Bone is formed when osteoid mineralizes
 There are two types of osseous tissue that form bones:
 Cortical bone = compact bone:
 Forms the cortex, or outer shell, of most bones
 Osteon: refers to the functional unit of most compact bone
comprised of a central blood vessel [in a “Haversian canal”] and
concentric rings of new bone encircling the vessel
o Hydroxyapatite crystals [Ca10(PO4)6(OH)2] pack in
between Type 1 collagen fibrils within and between each
ring
o Each ring is from successive remodelling cycles
o Osteon structure limits fracture propagation
o Collagen fibres orientated in all various directions within
each ring
o Type I collagen molecule:
 Triple helical collagen molecule
 2x alpha 1 (COL1A1) and 1x alpha2 (COL1A2)
o 200 non-collagenous proteins are also present in bone
o Human bone is 60% mineralised: increased mineralisation
increases stiffness but reduces flexibility
o Cortical bone accounts for 80% of the total bone mass of an
adult skeleton
 The microscopic difference between compact and cancellous bone is
that compact bone consists of haversian sites and osteons, while
cancellous bones do not.
 Also, bone surrounds blood in the compact bone, while blood
surrounds bone in the cancellous bone
 Cancellous bone = trabecular bone = spongy bone:
 Filling the interior of the bone is the trabecular bone tissue (make
the overall organ lighter and allow room for blood vessels and
marro)
 Trabecular bone accounts for the remaining 20% of total bone mass
but has nearly ten times the surface area of compact bone. Its
porosity is 30–90%
 Compared to compact bone, cancellous bone has a higher surface
area to mass ratio because it is less dense
 The primary anatomical and functional unit of cancellous bone is the
trabecula.
 Cancellous bone is highly vascular and frequently contains red bone
marrow where haematopoiesis, occurs.
2
Giles Kisby
GE Y1 Musculoskeletal

o
Cancellous bone is typically found at the ends of long bones,
proximal to joints and within the interior of vertebrae.
Bone development:
 Long bones form by endochondral ossification
 Type II collagen is found in cartilage (tensile strength)
 Aggrecan (Aggrecan is the major proteoglycan in articular cartilage)
is negative so draws in water for compressive strength
 CHONDROCYTES ARE THE ONLY CELLS FOUND IN HEALTHY
CARTILAGE; undergo proliferation  differentiation  hypertrophy
(chondrocytes can expand 10x just before they die; helps extend
bone)  death as they migrate out from center of the bone; this
leaves a tunnel through which blood vessels can form; bone can
then be laid down from these centers to form cortical bone from
these centers (primary ossification center)
o Sox9: Master transcriptional regulator in chondrocyte
3
Giles Kisby
GE Y1 Musculoskeletal
o

FGF/FGFRs: Inhibit chondrocyte proliferation and
differentiation
o Indian hedgehog (Ihh): Promotes chondrocyte proliferation
and induces PTHrP
o PTHrP/PTHR1: Inhibit chondrocyte differentiation
 Secondary ossification center is at the epiphysis growth plate; the
growth plate is supported by trabecular bone and will fuse with the
‘head’ bone only when growth is complete
 Achondroplasia:
o Cause: Constitutively active FGF/FGFR3 signalling inhibits
chondrocyte proliferation and differentiation
 Gain of function mutation FGFR3
o Most common form of dwarfism
o Macrocephaly [head is abnormally large], frontal bossing,
midface hypoplasia, small chest, rhizomelia [shortened
limbs]
Craniofacial bones by intramembranous ossification
 Fontanelles form
 Mesenchymal cells differentiate into osteoblasts
 Bone (osteoblasts) is formed directly without a cartilage scaffold
o Osteoblasts, chondrocytes and adipocytes all derive from
mesenchymal cells
o Osteoblasts are formed from the mesenchymal cells in the
context of Runx2, Osterix and high B-Catenin
[other factors also have pos / neg roles: Wnt, BMPs and
FGFs
Systemic hormones: GH/IGF1, glucocorticoids, E2: Estradiol,
PTH and 1,25(OH)2D]
o Wnt signalling role:
 Promotes osteoblast differentiation, proliferation
and mineralisation
 On absence of Wnt
 GSK3/APC/Axin degradation complex
targets B-catenin for degradation by
phosphorylation
 On presence of Wnt: Wnt binds Frizzled with coreceptors LRP5/6 and inhibits GSK3
 Preventing B-catenin degradation
 B-catenin enters nucleus regulating target
genes (but is not a TF itself)
 Negative regulation of Wnt signalling [ie these neg
regulators are targets for new anabolic agents for
treatment of osteoporosis]:
4
Giles Kisby
GE Y1 Musculoskeletal


Target Wnt: Wnt binding (WIF-1 , cereberus
and sFRP)
Target coreceptor: LRP5/6 degradation
(Sclerostin (SOST gene in nature) and
Dickkopf (Dkk))
Relavant info from endo:
•
PTH regulates calcium via PTHR1 in bone:
•
PTHR1 expressed in osteoblasts and osteocytes but NOT
osteoclasts
•
PTH has anabolic and catabolic actions:
•
PTH can stimulate bone resorption or formation
•
Intermittent PTH (net trabecular formation)
•
Continuous PTH (net cortical resorption)
•
PTH increases osteoclast differentiation indirectly by action
in osteoblasts
•
Increased expression of M-CSF/RANKL
•
Reduced expression of OPG
5
Giles Kisby
GE Y1 Musculoskeletal
•
PTH regulates maturation of preosteoblasts
•
Intermittent PTH increases Runx2
•
Continuous PTH represses Runx2
•
PTH also increases bone formation by paracrine
mechanisms:
•
Increased FGF release at osteocytes
•
Increased signalling for osteoblast lineage:
Increased IGF-1
Increasing Wnt signalling
Reduced inhibition of Wnt signalling: dec
dickkopf and Sclerostin, the product of the
SOST gene
o
Maintenance of adult bone
 Terminally differentiated osteoblasts act as Mechanosensors & regulators of
bone remodeling
 The bone remodelling cycle:
 Functions:
o Maintain homeostasis of Ca 2+ and PO4
o Repair damaged matrix and micro-fractures
o Adapt to mechanical stress and strain
 Cells involved:
o Osteocytes make up 90-95% of all adult bone cells
o Osteoblasts 5% of all adult bone cells
o Osteoclasts 1-2% of all adult bone cells
 Osteocytes regulate bone turnover
o
In response to bone loading state

During bone loading osteocytes inhibit
osteoclast resorption (via inc OPG and TGFB)

Unloading, hypoxia or apoptosis
initiates resorption (via inc RANKL)
o
In response to endocrine phosphate needs


Low phosphate:
 Osteocyte Sclerostin binds LRP5 ( dec Wnt
signaling and dec bone formation)
Vs
High phosphate:
 Osteocyte Matrix extracellular
phosphoglycoprotein (MEPE) inhibits
phosphate resorption
 Osteocyte Dmp1 and Phex decrease
leading to inc FGF23 for increase to
phosphate levels
6
Giles Kisby
GE Y1 Musculoskeletal

Osteoclasts
o Development:

Osteoclasts derive from the
myeloid lineage; therefore:


o
Osteoclasts are multinucleated cells
M-CSF regulates proliferation, survival and
differentiation of precursors
 RANKL is key osteoclastogenic cytokine sufficient for
differentiation
 OPG is a ‘decoy receptor’ (binds and blocks RANKL:
ie physiological inhibitor of RANKL/RANK signaling)
[RANK is on the osteoclast precursor]
 Denosumab acts like OPG therefore can be used as a
drug to reduce bone resorption via dec osteoclast
levels
 PTH, 1,25(OH)2D and pro-inflammatory cytokines
increase RANKL expression and suppress OPG
Function:
 Active osteoclasts are polarised cells: Attach to the
bone surface via integrin α5β3 (this forms the
sealing zone that degradatory components are
secreted into; nb lacunae = an unfilled space; a gap,
as created under site of osteoclast binding):
 Requires action of small GTPases (inhibited
by bisphosphonates)
 Secrete hydrogen and chloride ions that
dissolve bone mineral
 Matrix metalloproteinases (MMPs) and
Cathepsin K degrade the collagen matrix:
Cathepsin K inhibited by Cathepsin K
inhibitors
7
Giles Kisby
-
GE Y1 Musculoskeletal
Skeletal Pathology
o Osteoporosis
 Traits:







Increased bone resorption relative to formation
Low bone mass
Micro-architectural deterioration
Fragility fractures
Diagnosis of osteoporosis: Fragility fracture and decreased bone
mineral density (BMD)
Peak bone mass
 Achieved at 20 - 30 years of age
 major genetic component to peak bone mass
 Estrogens is critical in both male and females for peak bone mass
 Peak influenced by: Physical exercise, alcohol excess, smoking,
eating disorders, systemic illness
Increased progressive loss of bone mass occurs from 45 years of age;
Mechanism:
 Estrogens deficiency at the menopause
o More rapid loss in women due to estrogens deficiency at
menopause
o Increased expression of skeletal cytokines especially IL-6 inc
[“pro-inflammatory cytokines”]
o Reduced expression of OPG and thus increased
osteoclastogenesis
 Investigation
o Ca2+, Pi, ALP [high bone alkaline phosphatase in
osteoporosis], Cre [looking for potential liver problem giving
dec hydroxylase activity], PTH, 25-OH-vitD, DEXA, Urinary
8
Giles Kisby
GE Y1 Musculoskeletal

NTX [N-terminal telopeptide (NTx) molecules are mobilized
from bone by osteoclasts and subsequently excreted in the
urine]
o DEXA = Dual-energy X-ray absorptiometry: assesses BMD
(Bone mineral density)
 Results are interpreted according to the standard
deviation from the mean to give T and Z score:
 a) Sex matched peak bone mass (T-score)
[ie no. SD from those in 20s with a max
BMD]
 b) Sex and age matched BMD (Z-score) [ie
no. SD from those of same age as the
person]
 WHO diagnostic criteria:
 Osteoporosis
o T score ≤ - 2.5 lumbar spine, femoral
neck or total hip
 Osteopenia
o T score ≤ - 1.0 lumbar spine, femoral
neck or total hip
Treatment of age related osteoporosis
o Simple advice: inc weight bearing exercise, dec smoking and
alcohol
o Optimise vitamin D status: Calcium and vitamin D
supplementation
o Antiresorptive agents:
 Bisphosphonates (impaired sealing zone
attachment)
 Denosumab (monoclonal ab to RANKL) (OPG like
activity)
 Selective estrogens receptor modulators (inc OPG,
dec IL6)
o Anabolic agents
 Strontium ranelate (now limited use due to cardiac
risk)
 Teriparatide (PTH 1-34) (Intermittent PTH:
intermittent use activates osteoblasts more than
osteoclasts, which leads to an overall increase in
bone)
 continuous PTH - decrease Runx2
 Intermittent - increase runx2
9
Giles Kisby
GE Y1 Musculoskeletal

Secondary Osteoporosis
 Endocrine
o Thyrotoxicosis (increased bone turnover)
o Hyperprolactinemia (reduced gonadotrophins and sex
hormones Eg E2!!)
o Primary hyperparathyroidism (Increased resorption)
o Hypogonadism (increased resorption due to low E2 etc)
o Cushing’s Syndrome (impaired bone formation due to high
cortisol)
 Nutritional [but not severe enough to give osteomalacia]
o Vitamin D deficiency (impaired mineralisation)
o Coeliac disease (impaired mineralisation)
o Chronic liver disease [ie loss of liver vit d role]
 Iatrogenic
o High dose glucocorticoids (Glucocorticoid induced
osteoporosis)
o GnRH agonists (eg for prostate cancer: after about ten days,
a profound hypogonadal effect (i.e. decrease in FSH and LH)
is achieved through receptor downregulation by
internalization of receptors. Generally this induced and
reversible hypogonadism is the therapeutic goal.)
o Aromatase inhibitors (eg for Breast cancer)
o Thyroid hormone excess (Excessive replacement or Thyroid
cancer)
o Anticoagulants and Anticonvulsants [mech is unknown]
o Immunosuppression (inhibits calcineurin and NFAT to give
dec IL2 so dec im response but calcineurin-NFAT signaling
pathway helps to promote osteoblast differentiation)
o Thiazolidinediones (PPARϒ agonists; as on prev diagram this
is a inducer of the adipocyte lineage: dec
osteoblastogenesis, inc adipogenesis)
10
Giles Kisby
GE Y1 Musculoskeletal

o
Glucocorticoid induced osteoporosis in detail [Commonest iatrogenic cause
of osteoporosis]:
 As prev, inhibits osteoblast differentiation and encourages
osteoblast apoptosis:

Also: Decreased osteoclastogenesis but prolonged survival

Treatment
o Bisphosphonates
o Teriparatide
Paget’s Disease
 Traits:
 Localised disorder of bone remodelling)
 Osteoclast abnormality: Increased osteoclast numbers
 Osteoblast abnormality: Disorganised rapid bone formation
o Replacement by sclerotic bone
o Bone marrow cavity replaced by vascular fibrous
connective tissue
o Increase in bone size and bone deformity
 Increased markers of formation and resorption
o bALP: Bone alkaline phosphatase
o P1NP: Procollagen type I N-terminal propeptide
o uNTX: Urinary N-terminal telopeptide
 Aetiology
 Predominantly unknown
 Family history in 15%
 Declining in incidence: Reason for decline in frequency is unknown
 Clinical features
 Bone pain, joint pain, deformity, fracture
11
Giles Kisby
GE Y1 Musculoskeletal



 increased temperature [high metabolic activity]
 Deafness (due to cranial nerve compression)
 Abnormal x-ray
Complications
 Osteoarthritis due to deformity
 Cranial nerve palsy and spinal stenosis [abnormal narrowing
(stenosis) of the spinal canal]
 Hypercalcaemia if are also immobilised (immobility is associated
with hypercalcaemia in a variety of diseases, as here, but unknown
mech
 Fracture
 Osteosarcoma (very rare)
Diagnosis
 Raised alkaline phosphatase: ALP
 Abnormal x-ray (osteolysis, osteosclerosis and bone expansion)
 99Tc bone scan: is far more sensitive than plain X-ray; is taken up in
the areas of high turnover [Technetium-99m]
Treatment: Bone pain is the indication for treatment
 Ensure patients are vitamin D and calcium replete
 Simple analgesia (NSAIDs)
 Physio/hydrotherapy
 Bisphosphonates: reduce pain, do not prevent deformity or
deafness
 Zolendronic acid (Alk Phos normalises in 90%)
 Surgery for severe deformity or osteoarthritis
12
Giles Kisby
GE Y1 Musculoskeletal
07/03/14: Connective tissue and articulations: Matthew
Pickering
Los (from slides/booklet):
List the main components of the extracellular matrix
Recall the principal type of collagen in bone and articular cartilage
List the main collagen-cleaving enzymes (collagenases)
Explain what is meant by synarthrosis, diarthrosis, amphiarthrosis
Describe the structure of articular cartilage and synovium
List the key features of the heritable collagen disorders:
Osteogenesis imperfecta
Marfan’s syndrome
Ehlers-Danlos syndrome
Notes
-
Extracellular matrix [ie are initially just looking generally at ECM during this lec]
o ECM functions:
 Mechanical: tensile and compressive strength and elasticity
 Protection: buffering against extracellular change and retention of water
 Organisation: control of cell behaviour by binding of growth factors and
interaction with cell-surface receptors
o ECM contains:
 Proteins:
 Collagen
 Elastin
 Fibrillin
 Adhesin
 Proteoglycans:
 Are proteins bound to glycosaminoglycans (GAGs)
o
ECM contains:
 Proteins:
 Collagen
o 20-30% of body mass: is the most abundant protein in the
human body
o Types I, II, III, V and XI are the most abundant
o Bone = type I collagen
o Cartilage = type II collagen
13
Giles Kisby
GE Y1 Musculoskeletal
o
o
o
o
o
o
o
Triple helix: = tropocollagen
 3 polypeptide chains twisted into right handed
major helix
 Type 1 = 2x alpha 1 and 1x alpha2
 Type 2 = 3x alpha 1
 repeating triplet amino acid Glycine-X-Y
 300nm long and 1.5nm wide
During synthesis polypeptide chains are hydroxylated
 Enzymes: prolyl hydroxylase and lysine hydroxylase
 The enzymatic reactions need cofactors including
VITAMIN C
 In vitamin C deficiency (scurvy) collagen becomes
unstable
Degradation: Collagenases binds to triple helical collagen,
unwinds polypeptide chains and then cleaves -chains by
peptide hydrolysis
 Certain Matrix metalloproteinases [eg 1/8/13/
gelatinases/stromelysins] are collagenases
type 1 collagen
 2x alpha 1, 1x alpha 2
 bone, tendon, ligaments, skin, joint
capsule/synovium, cornea/sclera [= type 5]
type 2 collagen
 3x alpha1
 cartilage, intervertebral discs, vitreous humour [is
the clear gel that fills the space between the lens
and the retina of the eyeball] [= type 11]
type 3 collagen
 blood vessels
type 4 collagen
 basement membrane, lens capsule [ie is the
basement membrane of the lens]
14
Giles Kisby
GE Y1 Musculoskeletal


Elastin
o Present at ligaments, vessels and skin
o Elastin is polymer of tropoelastin monomers [lysine
residues in adjacent monomers cross link by forming
desmosine]
o Elastin = Fibres that can stretch when hydrated and return
to original length after being stretched
o Mutations in elastin gene cause autosomal dominant cutis
laxa
 Cutis laxa is a group of disorders that share common
finding of lax, redundant skin.
 skin does not recoil when stretched: ‘appears to
have lost elasticity’
Fibrillin
o
o

Present at ligaments, vessels and skin
Is a glycoprotein that is essential for formation of elastic
fibres: elastin must be deposited around a fibrillin core
therefore loss gives similar phenotype to elastin deficiency
o Fibrillin-1 mutations → Marfan’s syndrome
o Fibrillin-2 mutations → Contractural arachnodactyly
Adhesin
o Is a group term: refers to cell-binding glycoproteins present
in matrix and basement membranes
o attach to cells via cell integrins
o Include:
 Fibronectin in connective tissue
 Laminin in basement membrane
 Chondroadherin in cartilage
 Osteoadherin in bone
15
Giles Kisby
GE Y1 Musculoskeletal

Proteoglycans:
 Are glycoproteins containing one or more sulphated
glycosaminoglycan (GAG) chains
 GAGs: are repeating polymers of disaccharides [N-acetyl
glucosamine is usually one of the two repeating sugars; the chain is
also usually sulfated]:
[eg Heparan sulphate, Chondroitin sulphate, Keratan sulphate,
Dermatan sulphate, Heparin]
 Proteoglycans may be:
o Intra-cellular
o Cell surface-associated
o Secreted into ECM
 Intracellular proteogylcan - Serglycin
 Cell surface associated - betaglycan,
syndecan
 Secreted into ECM - aggrecan, decorin,
fibromodulin, lumican, biglycan
 Examples:
o Aggrecan (in association with hyaluronan) is the major
proteoglycan in articular cartilage
 Also: aggrecan molecules associate with central
hyaluronic acid filament in cartilage
o
Hyalurinic acid (by itself) is the only non-sulphated GAG and
is major component of synovial fluid where it has an
important role in maintaining synovial fluid viscosity
Synchondrosis, syndesmosis, secondary cart/symphysis, synovial
-
CLASSIFICATION OF JOINTS
o Synarthrosis:
 suture lines of skulls where adjoining plates are separated by thin fibrous
tissue
o Amphiarthrosis:
 adjacent bones bound by flexible cartilage (‘fibro-cartilaginous joints’)
 e.g. pubic symphysis, sacro-iliac joints, intervertebral discs
o Diarthrosis:
 synovial joints and include:
 Ball and socket e.g. hip joint
 Hinge e.g. inter-phalangeal joint
 Saddle e.g. first carpo-metacarpal joint
 Plane e.g. patello-femoral joint
 Synovium [=Synovial membrane] contains: macrophage-like phagocytic cells
and fibroblast-like cells
16
Giles Kisby
GE Y1 Musculoskeletal
-
ARTICULAR CARTILAGE
o Components:
 Collagen II: 90% is type II: tensile strength
 Chondrocytes
 Proteoglycan monomers (aggrecan): compressive strength
 Is combo of chondroitin sulphate chains and keratan sulphate chains
(ie on the protein)
 non-covalently linked aggrecan molecules associate with central
hyaluronic acid filament
 Negatively charged chemical groups of GAGs attract water
o Is an avascular and aneural structure
o Weight-bearing properties of articular cartilage depend on intact collagen scaffold
and high aggrecan content
-
OSTEOGENESIS IMPERFECTA
o = ‘brittle bone disease’
o mostly due to autosomal dominant collagen type I mutations
o variable phenotypic severity [Types I (good) – IV (bad) describe the severity]
o Pathogenesis:
 Abnormal type I collagen results in bone fragility: osteopenia and fractures
 Diminished collagen in the sclera (of the eye) leads to increased
translucency and apparent blueness of the sclera
17
Giles Kisby
-
GE Y1 Musculoskeletal
EHLERS-DANLOS SYNDROMES Ehlers-danlos syndromes:
o Majority are autosomal dominant disorders
o Involve abnormalities in synthesis or enzymatic modification of collagen
o [characterised by joint, tissue/skin laxity and arterial wall abnormality/estensibility]
o Clinical features:
 Joint hypermobility
 Skin fragility (easy bruising)
 Hyper-extensibility in other organs e.g. Gorlin’s sign: hyperextensible tongue
 Arterial wall laxity → aneurysms
o EDS type IV “= arterial form”: autosomal dominant defect in type III collagen found
in blood vessels
 little skin and joint disease but arterial or bowel rupture
o Not all are autosomal dominant disorders: EDS type VI (oculo-scoliotic) which is
autosomal recessive
 in addition to skin and joint hyperextensibility, scoliosis and ocular globe
rupture occur.
18
Giles Kisby
-
GE Y1 Musculoskeletal
MARFAN’S SYNDROME
o Autosomal dominant condition due to mutation in fibrillin-1 gene
o characterised by ocular, skeletal, vascular, lung and skin abnormalities
o Pathogenesis:
 Defect is due to fibrillin which forms constituent of extracellular microfibrils
that form sub-structure for elastin
 Fibrillin important in elastic walls of arteries especially aorta, zonular fibres
of the eye, ligaments, skin and lung parenchyma
o Clinical features:
 Musculoskeletal
 tall stature, long thin extremities, arachnodactyly,
 dolichostenomelia (low ratio of upper to lower body segments)
 pectus excavatum [“hollowed chest”],
 scoliosis
 high arched palate
 Other
 ectopia lentis i.e. upward dislocation of the lens
 ascending aorta dissection (most common cause of death)
 mitral valve prolapse, aortic regurgitation
 cystic lung disease and spontaneous pneumothorax
o “Patients are often unusually tall, their aorta is prone to rupture/displacement and
they can have abnormalities of the skeleton and joints and lens. The product of
the affected gene is unable to play its normal role in stabilising the elastic fibres
that give connective tissue its strength and flexibility.”
19
Giles Kisby
-
GE Y1 Musculoskeletal
OTHER SYNDROMES
o Stickler syndrome
 type II collagen
 Autosomal dominant, ocular and joint disease
o Alport’s syndrome

type IV collagen



o
autosomal recessive
Hereditary glomerulonephritis and deafness
“This inherited kidney disease is characterised by dysfunctional glomerular
filtering. The defective protein product of the affected gene cannot form its
normal sheet-like structure in the basal lamina where it normally provides
tensile strength. “
Dystrophic Epidermolysis bullosa

type VII collagen


Hereditary skin blisters
Dominant or recessive forms
20
Giles Kisby
GE Y1 Musculoskeletal
-
Junctional Epidermolysis Bullosa
o “Characterised by extensive mucocutaeous blistering and recurrent infections. The
protein product of the affected gene normally forms heterotrimeric molecules that
are crucial in forming the 2-dimensional structure of the basal lamina.”
o Laminin 5 or Type XVII collagen
-
Congenital Muscular Dystrophy
o Heterogenous group of neuromuscular disorders characterised by muscle weakness
and hypotonia. About half of these patients have mutations in a gene encoding of a
key component of the basal lamina of skeletal muscle.
o Laminin 2
21
Giles Kisby
GE Y1 Musculoskeletal
07/03/14: ARTICULAR PATHOLOGY: Matthew Pickering
Los (from slides/booklet):
-
Define what is meant by matrix metalloproteinase and give some examples of their
substrates
- Define what is meant by ADAMTS protease and understand that aggrecanases are important
in the turnover of proteoglycan in articular cartilage
- Recall that cathepsin K is important protease in bone matrix turnover
- Define two abnormalities seen in the synovium of patients with rheumatoid arthritis
- Explain the importance of the inflammatory cytokine, tumour necrosis factor-alpha (TNF-α)
in rheumatoid arthritis pathology
- Define two abnormalities seen in the cartilage and two abnormalities seen in the bone in the
osteoarthritic joint
From slides supplementary:
- Summarise the pathogenesis, clinical features and management of rheumatoid arthritis
- Explain the significance of a ‘rheumatoid factor’
- Explain the importance of anti-CCP antibodies in rheumatoid arthritis
Notes
-
Overview
o In brief:
 Connective tissue turnover is mediated by matrix proteinases through
complex regulatory networks
 Rheumatoid arthritis and osteoarthritis represent the two major articular
pathologies
 Rheumatoid is a disease of synovium whilst osteoarthritis is disease of
articular cartilage
o Connective tissue turnover and matrix proteinases
 Most of joint tissue is extra-cellular matrix and proteinases are key in
extracellular matrix (ECM) degradation
 Proteases are numerous and combine to form complex regulatory networks
o Articular pathology
 Rheumatoid arthritis
 Osteoarthritis
-
Connective tissue turnover
o Cartilage and bone destruction is mediated by ECM degradation
o Modulated by level of:
 Proteases
 MMP collagenases vs cartilage collagens
 ADAMTS aggrecanases vs cartilage proteoglycans
 Cathepsin K vs bone matrix [is in the acidic secretions of osteoclasts]
22
Giles Kisby
GE Y1 Musculoskeletal
o
o
o
o
 Protease inhibitors
 Matrix synthesis
Source of proteinases depends on pathological process:
 Osteoarthritis = chondrocyte (intrinsic)
 Rheumatoid arthritis = synovial cells (intrinsic), inflammatory cells
(extrinsic), chondrocytes
 Infection = inflammatory cells (extrinsic), bacterial proteases (exogenous)
MATRIX METALLOPROTEINASES
 Family of calcium-dependent zinc-containing endopeptidases
 Important functions include tissue remodelling and degradation of
extracellular matrix (ECM)
 ECM substrates include: [all the main ECM components:]
 Collagen and gelatin (=hydrolysed collagen)
 Elastin
 Proteoglycans and Matrix glycoproteins
 Regulated by hormones, growth factors and cytokines
 Synthesised in zymogen form by many cell types
 Inhibited by ‘tissue inhibitors of matrix metalloproteinases’ (TIMPs)
 Certain MMPs are COLLAGENASES:
 MMP-1, -8, -13 (= collagenase -1, -2, -3): cleave fibrillar collagen at a
single site to form fragments
 stromelysins and gelatinases degrade the collagen fragments [these
are also MMPs]
ADAMTS METALLOPROTEINASES
 ADAMTS = a disintegrin and metalloproteinase with thrombospondin motifs
 Are a family with diverse functions but note ADAMTS-4 and 5 are
aggrecanases i.e. degrade aggrecan, the major human cartilage
proteoglycan
CATHEPSIN K
 Important in turnover of matrix of long bone
 Active against helical type I collagen
 Cysteine protease most active at acidic pH; are highly expressed by
osteoclasts; secretions of the osteoclast is acidic; Cathepsin K-deficient
osteoclasts cannot degrade bone protein matrix
 Human deficiency results in skeletal dysplasia (Pycnodysostosis)
23
Giles Kisby
-
GE Y1 Musculoskeletal
Articular pathology
o Rheumatoid arthritis
 Chronic autoimmune disease characterised by pain, stiffness and
symmetrical synovitis (inflammation of the synovial membrane) of synovial
(diarthrodial) joints
 PATHOGENESIS
 There is an excess of pro-inflammatory vs. anti-inflammatory
cytokines (‘cytokine imbalance’); immune cells recruited
 Neovascularization occurs
 The synovium becomes a proliferated mass of tissue (pannus)
 Treatment:
 Anti TNFα antibodies: TNFα is the dominant pro-inflammatory
cytokine so mAbs against this are used
o But use is linked to inc TB infection risk
 Interleukin-6 and interleukin-1 blockade: now available in clinic
 Anti-B cell antibodies: We can deplete B cells in rheumatoid arthritis
by parenteral (intravenous) administration of an antibody against a
B cell surface antigen (are vs CD20)
o But use linked to hepatitis B reactivation
 DENOSUMAB: monoclonal antibody against RANKL. RANKL
(“receptor activator of nfKB ligand”) is important in bone
destruction in rheumatoid arthritis:
o Produced by T cells and synovial fibroblasts in rheumatoid
arthritis
o Acts to stimulate osteoclast formation (osteoclastogenesis)
o Upregulated by: IL-1, TNF-a IL-17, PTH-rp
o Binds to RANK on osteoclast precursors; action antagonized
by OPG too
 ‘DMARDS’: disease- modifying anti-rheumatic drugs
o may induce remission (not cure) and prevent joint damage
o eg methotrexate, sulphasalazine [and its metabolite 5-ASA
nb given that ulcerative colitis produces arthritic symptoms,
the benefits may be a product of unrecognized ulcerative
colitis]
o all have significant adverse effects
 Glucocorticoid therapy (‘steroids’, ‘prednisolone’) but:
o preference is to avoid long-term use because of side-effects
o useful as short-term treatment options e.g. to control flare
of disease or inflammation of single joint
 Key features:
 Chronic arthritis
o Polyarthritis - swelling of the small joints of the hand and
wrists is common
o Symmetrical
24
Giles Kisby
GE Y1 Musculoskeletal
o
o




Early morning stiffness in and around joints
May lead to joint damage and destruction - ‘joint erosions’
on radiographs
o Swan-neck deformity [PIP hypext; DIP hypflex]
o Boutonnière (‘button-like’) deformity [PIP hypflex]
Extra-articular disease can occur
o Fever, weight loss [due to the immune complexes]
o Subcutaneous rheumatoid nodules [are associated with
Rheumatoid factor]
 central area of fibrinoid necrosis [fibrin-rich necrotic
material
 middle layer of macrophages and fibroblasts
 Outer layer of connective tissue
o Others rare e.g. vasculitis, episcleritis, Amyloidosis
Rheumatoid ‘factor’ may be detected in blood
o = IgM autoantibody against Fc portion of IgG [misnomer:
should really be called rheumatoid ‘antibody’ not ‘factor’]
 Will deposit elsewhere
Antibodies to citrullinated protein antigens (ACPA)
o Antibodies to citrullinated peptides are highly specific for
rheumatoid arthritis and also associated with smoking
 = Anti-cyclic citrullinated peptide antibody ‘anti-CCP
antibody’ [=ACPA]
o Citrullination of peptides is mediated by enzymes termed
Peptidyl arginine deiminases (PADs):
 perform Arg  Citrulline
 citrullinated peptides present in high concentrations
in neutrophils and monocytes
Primary site of pathology is in the synovium [the synovium becomes
a proliferated mass of tissue (pannus)]; synovium includes:
o Tenosynovium surrounding tendons
o Bursas
o Synovial joints
 Wrists
 Knees
 Ankles
 Metacarpophalangeal joints (MCP)
25
Giles Kisby
GE Y1 Musculoskeletal



 Proximal interphalangeal joints (PIP)
 Metatarsophalangeal joints (MTP)
Important genetic component
 Specific HLA-DRβ gene variants mapping to amino acids 70-74 of the
T cell DRβ-chains are strongly associated with rheumatoid arthritis =
the ‘shared epitope’
 nb in the ‘shared epitope’ hypothesis: a common region of the beta
chain on the T cells is thought to be integral to presenting autoimmunological peptides.
Important environmental component
 Smoking: contributes 25% of population-attributable risk and
interacts with ‘shared epitope’ to increase risk
Radiographic abnormalities
 Early
o Juxta-articular osteopenia
 Later
o Joint erosions at margins of the joint
 Later still
o Joint deformity and destruction
26
Giles Kisby
-
GE Y1 Musculoskeletal
Osteoarthritis
o Chronic slowly progressive disorder due to failure of articular cartilage that typically
affects joints of the hand (especially DIP, PIP), spine and weight-bearing hips and
knees
o Caused by: (see pic)
 Excessive loading on joints
 Abnormal cartilage
o
o
Cartilage changes in osteoarthritis
 reduced proteoglycan
 reduced collagen
 chondrocyte changes e.g. apoptosis
Bone changes in osteoarthritis
 Proliferation of superficial osteoblasts results in production of sclerotic bone
[pathologic thickening of the bone] e.g. subchondral sclerosis
27
Giles Kisby
GE Y1 Musculoskeletal


o
Focal superficial necrosis resulting from focal stress on sclerotic bone
New bone formation at the joint margins (termed osteophytes)
 Osteophytes at the PIPJ are called Bouchard's nodes
 Osteophytes a the DIPJ are called Heberden's nodes
Schlerosis, cysts, osteophytes, narrowing
28
Giles Kisby
GE Y1 Musculoskeletal
14/03/14: Energy pathways in muscle and the Metabolic
Myopthies: (Federico Roncaroli)
Los (from slides/booklet):
-
-
-
-
Recognise the bioenergetics of muscle contraction
Summarise the role of creatine phosphate, creatine kinase and myokinase as a short term
energy source
Summarise the role of anaerobic glycolysis i.e. the break-down of glucose to lactate and
pyruvate and conversion of ADP to ATP (mainly type II fibres that have few mitochondria and
many glycogen granules) as an intermediate-term energy source
Summarise the role of oxidative phosphorylation i.e. aerobic process that generates ATP
from fat, carbohydrate and protein (type I fibres are suited to this as thay have many
mitochondria and lipid droplets) as a long term energy source
Distinguish the different types of metabolic myopathy
Summarise the key types of primary metabolic myopathies i.e. (1) glycogen storage
disorders, (2) lipid disorders and (3) mitochondrial disorders (NB detailed knowledge of
individual syndromes is not required)
Summarise the common glycogen storage disorders: Myophosphorylase deficiency (also
termed: McArdle’s syndrome, glycogen storage disorder type V) (NB detailed knowledge of
individual syndromes is not required)
Notes [lec was v. poor]
-
-
-
Primary muscle disease
o Genetic
o Non genetic
Secondary muscle disease: muscle involvement in a systemic condition
o Autoimmune
o Cancer
o Infection
ESSENTIAL CONCEPTS
o Energy pathways are aimed to reconstitute ATP from ADP
 ATP is the immediate source of energy: binds myosin and allows sarcomeric
contraction and release of actin
o Acetyl-CoA is the essential molecule of all pathways
o Muscle fibres need energy for contraction
o Slow and fast twitch fibres have different metabolic requirements [ie low but long
term requirements vs high but short term requirements]
29
Giles Kisby
GE Y1 Musculoskeletal


Slow fibres use/have: (run marathons)
 low glycogen
 high lipids [They are the major source of energy for muscle after
long exercise when glycogen is exhausted; Their hydrolysis produces
Acetyl-CoA]
 more mitochondria
 oxidative phosphorylation:
o aerobic process that generates ATP from fat, carbohydrate
and protein
o long term energy source
Fast fibres use/have: (run 100m)
 High glycogen level [Synthesised from glucose by Glycogen
synthase]
 Few mitochondria
 anaerobic glycolysis,
o the break-down of glucose to lactate and pyruvate
o intermediate-term energy source


-
Creatine kinase reaction [
],
Adenylate kinase reaction [ADP ⇔ ATP + AMP]
o Nb Adenylate kinase = myokinase; don’t confuse with
Myophosphorylase
From wiki; not from the course:
[note that the twitch category reflects the properties of the diff myosin isoforms: one key
difference between slow and fast twitch fibres is the ability of myosin ATPase, to speed up
30
Giles Kisby
GE Y1 Musculoskeletal
the cross bridge action. There is a small structural difference between FT and ST myosin
ATPase, which is enough to cause a difference in cross bridging recycling rates]
-
METABOLIC MYOPATHIES
o Usually infantile and adult forms – Infants are usually more severely affected
o They usually present with
 muscle dysfunction induced by exercise
 rhabdomyolysis
 may become mildly symptomatic during childhood and emerge late in life
o heterogenous group of disorders characterised by anomalies of energy production: a
huge array of the enzymes of the diverse pathways may be the root cause of the
myopathy
-
Types of myopathy:
o Congenital
o Dystrophies [degeneration due to disease or malnutrition]
o Metabolic / mitochondrial
o Inflammatory
o Neurogenic
-
Key types of primary metabolic myopathies:
[(NB detailed knowledge of individual syndromes is not required)]
o (1) glycogen storage disorders,
 Myophosphorylase deficiency = McArdle’s syndrome
 Is a glycogen storage disorder type V
 Myophosphorylase is the muscle isoform of the enzyme glycogen
phosphorylase:
o Cytosolic enzyme
o Removes glucose residues from α-(1,4)-linkages within
glycogen molecules
o Product of reaction: Glucose-1-phosphate. (NOT Glucose)
 CLINICAL FEATURES
o Exclusively myopathic
o Presents with cramps and myoglobinuria following exercise
o No respiratory impairment (unlike other myopathies)
 Autosomal recessive PYGM gene mutation on ch11[“phosphorylase,
glycogen, muscle”]
 80 known types of mutation: No protein expression or unstable
protein (ie wholly dysfunctional)
31
Giles Kisby
GE Y1 Musculoskeletal

o
o
Acid maltase deficiency = Pompe’s disease = alpha-glucosidase deficiency
 Is a glycogen storage disorder type II
 Defect of acid 1-4 alpha glucosidase [GAA gene; “glucosidase, alpha;
acid”]
o Lysosomal enzyme
o Hydrolyses linear α1-4 glucosidic linkages on
carbohydrates
o Catalytic site: Asp-518
 Clinical features
o Children:
 Muscle weakness and respiratory impairment;
especially severe in infants
 Common cardiac involvement
o Widespread accumulation of glycogen (eg positive in white
blood cells) [excessive accumulation of glycogen within
lysosome-derived vacuoles in nearly all types of cells.
Excessive quantities of free extralysosomal glycogen also
have been described]
o Increase in acid phosphatase activity at lysosomes
o Focal expression of MHC class I antigen (misdiagnosed as
possible myositis)
o The enzyme may retain some functionality; exact symptoms
depend of type of mutation
 Subtle changes in adults
 Is classed as an autosomal recessive mutation to
acid alpha-glucosidase GAA gene
(2) lipid disorders
 Result from defects of:
 transport
 or endogenous triglycerides catabolism
 or beta-oxidation
 Various clinical presentation: progressive myopathy with muscle weakness
or recurrent episodes of rhabdomyolysis causing intolerance to exercise
 PATHOLOGICAL FEATURES
 Accumulation of lipid droplets
 Fibre necrosis in some patients presenting with rhabdomyolysis
 e.g. carnitine deficiency syndrome
(3) mitochondrial disorders
 Presumably oxidative phos is defective etc
 Eg Impairment of respiratory chain eznymes
32
Giles Kisby
-
GE Y1 Musculoskeletal
Diagnosis techniques:
o Examination [weakness, wasting (gait, winging, ptosis), pain]
o Biopsy [BUT: if good may still be a myopathy, if bad may still be in normal range]
o MRI
o Genetic analyses
o Blood tests
o EMG [electromyography], NCV [nerve conduction veloicity] (these are for analysing
nerve problems eg MG diagnosis)
o Blood: CK (not raised in all myopathies; only if muscle cell membranes are
damaged), lactate, inflam markers
- Neuropathy results in distal weaknes of muscle e.g.
gripping
- Muscle problem results in proximal weakness- e.g.
shoulders, problems standing
33
Giles Kisby
GE Y1 Musculoskeletal
14/03/14: Molecular basis of muscle contraction (Valentina
Caorsi)
Los (from slides/booklet):
Recall the actin-myosin cross-bridging cycle.
Recall the organisation of individual myocyte and motor unit.
Explain the processes involved in depolarisation and intracellular calcium flux.
Distinguish the structure of the thin and thick filaments in muscle.
Notes
-
The contractile Unit: the Sarcomere
o Many in parallel per cell
o When end to end will form a myofibril; myofibrils continuous between myocytes
positioned end to end
o A band = all myosin
o I band = actin ONLY
o actin is the major component of thin filaments
 troponin and tropomyosin etc will also contribute to the light filaments
 actin filaments made by polymerisation of G-actin
 Thin filament length: 1.1 µm:
 Ie shorter than thick filaments
 Length regulated by nebulin and tropomodulin
o myosin forms the thick filaments
 are single molecules but the tails of many diff myosins can interlink as in
muscle
 myosin molecules are composed of a head, neck (= essential light chain +
regulatory light chain), and tail domain
 Titin is a large elastic and extensible protein that links the thick filaments to
the Z-line, thus ensuring that the thick filaments remain centred in the
sarcomere.
 Thick filaments length: 1.6µm
 Ie longer than thin filaments
34
Giles Kisby
GE Y1 Musculoskeletal
35
Giles Kisby
GE Y1 Musculoskeletal
-
Cross-bridges Cycle detail:
o See below:
o thin filament moves toward the centre of the sarcomere
o Step size is small: sliding produced by one cycle is only about 1% of the sarcomere
length
-
Motor Unit
o Is the Motor Neuron + all the muscle fibres it innervates
o 1 motor unit has muscle fibres of all the same type [ie slow vs fast; is because type is
determined by signalling from the nerve]]
 Ie fast vs slow etc is not just determined by glycogen reserves etc but also
determined by the isoforms of myosin present; these will all be of the same
type within a motor unit
o Muscles of a motor unit will contract simultaneously (all or none fashion)
o number of muscle fibres 1 motor unit innervates can vary
 smaller motor units present in the eye for sensitive movements
o Number of motor units that are in a muscle can vary
 More present at sensitive muscles eg eye muscles
o When a muscle grows only the number of actins and mosins etc within individual
sarcomeres/myofibrils increases; the number of sarcomeres/myofibrils stays the
same as does the number of motor units
36
Giles Kisby
-
-
GE Y1 Musculoskeletal
Latent period:
- Intention to move  Movement:
o Intention to move 
o Activity in cerebral cortex basal ganglia, cerebellum
o Motor cortex firing
o Impulses in descending motor pathways
o Motoneuron Excitation
o Impulse propagation to axon terminal
o Neuromuscular transmission
o Impulse propagation along muscle fiber plasmalemma
o Impulse into T-tubules
o voltage-gated DHPRs mechanically linked to RyR of SR inducing Ca2+ release
o Troponin binds Ca2+; tropomyosin moves out myosin binding sites on actin
o Cross-bridges engagement
o  Movement
Contraction:
o Cross bridge cycle occurring
o Isotonic
 No change in tension: tension in the muscle remains constant; Muscle is
changing in length
 Concentric
 tension rises to meet the resistance, then remains the same as the
muscle shortens
 Eccentric
 muscle lengthens due to the resistance being greater than the force
the muscle is producing
o Isometric
 Tension rises then remains constant but no shortening occurs
o How force is varied in vivo
 Frequency of action potentials
 Recruitments of motor units
37
Giles Kisby
GE Y1 Musculoskeletal


Filament overlap
Velocity of contraction
Frequency of action potentials:
o
Temporal Summation occurs if a second stimulus is applied before completion of
relaxation
 Additional influx of Ca2+ promotes a second contraction which is added to
the first
 Stronger overall force results
o
Tetanus is rapid multiple stimulations which will fuse into a smooth continuous total
contraction
 Abundant intracellular calcium provides continually available binding sites
on actin for cross-bridge cycling
 The maximum force achievable will result from the tetanus due to maximal
Ca2+ release
 Fatigue will eventually occur as ATP is exhausted /Ca escapes through PM
Recruitments of motor units:
o
o
o
Greater percent of motor neurone pool recruited with an increasing force
requirement
Henneman's size principle states that in order to move a load motor units are
recruited from smallest to largest
This also equates to slow  FFR  FF
38
Giles Kisby
GE Y1 Musculoskeletal
Filament overlap:
o
o
o
Maximum force is achieved at intermediate overlap
When overlap is too great the filaments become constrained / not enough space in
the sarcomere for the filaments to move into upon further movement
When overlap is too little there are too few heads engaged to achieve maximum
force
 Aside: at heart the pericardial sac will prevent overextension therefore the
force is just seen to increase with length / preload
Velocity of contraction:
o
o
The greater the velocity in the flexion direction the weaker the force will be
The greater the velocity in the opposite direction to the flexion direction the
stronger the force will be until a maximum is reached (muscle acting as brake);
 [is because more crossbridges can be attached as are not needing to reel in
the weight]
39
Giles Kisby
GE Y1 Musculoskeletal

-
“hence bodybuilders do exercises beyond their strength where are acting as
brake”
Relaxation:
o Once the membrane has repolarised, the calcium channels in the sarcoplasmic
reticulum close.
o The sarcoplasmic Ca-ATPase [SERCA] pumps calcium back into the reticulum, causing
a decrease in calcium concentration in the cytoplasm.
o This causes calcium dissociation from troponin, resulting in inactivation of myosin
binding sites on actin, and hence muscle relaxation.
40
Giles Kisby
GE Y1 Musculoskeletal
14/03/14: Molecular basis and features of the muscular
dystrophies: (Matthew Pickering)
Los (from slides/booklet):
Define muscular dystrophy.
Explain how muscular dystrophies may be inherited. Give one example of X-linked,
autosomal recessive and autosomal dominant muscular dystrophy.
Explain how these conditions manifest clinically (NB detailed knowledge of individual
syndromes is not required).
Explain the histological differences between myopathy and dystrophy.
Explain the significance of an elevated blood level of creatine kinase (also termed creatine
phosphokinase and referred to commonly by physicians as ‘CK’ or ‘CPK’).
Notes
-
Disorder of neurons = neuropathy : typically distal dysfunction (hands / feet)
Disorders of skeletal muscle = myopathy : typically proximal dysfunction (shoulders / hips):
o GENETIC

Muscular dystrophies [the focus of this lec]

o
Dystrophies (or muscular dystrophies) are a subgroup of myopathies
characterized by muscle degeneration and regeneration. Clinically,
muscular dystrophies are typically progressive, because the muscles'
ability to regenerate is eventually lost, leading to progressive weakness
 e.g. Duchenne muscular dystrophy
 eg Beckers muscular dystrophy
 eg Limb-girdle dystrophy
 Metabolic myopathies
 defects of glycogen metabolism: e.g. myophosphorylase deficiency
 defects in lipid metabolism: e.g. carnitine deficiency syndrome
 Mitochondrial myopathies
o complex multisystem disorders
o myopathy is common
 Congenital myopathies
 a cause of ‘floppy infant’
ACQUIRED
 Autoimmune inflammatory myopathies
 polymyositis
 dermatomyositis
 Toxin / drug induced
 alcohol
 steroid myopathy (glucocorticoids)
 Endocrine:
 Cushing’s syndrome
41
Giles Kisby
GE Y1 Musculoskeletal

 Thyroid disease
Acquired metabolic myopathy
 K, Mg, Ca, P abnormalities due to diet etc
 vitamin D deficiency
 uraemia, hepatic failure
-
Creatine phosphokinase
o Abundant in heart, skeletal muscle and brain and raised in blood when:
 Skeletal muscle pathology
 All types of muscular dystrophies (nb usually normal in neurogenic
muscle disease)
 Rhabdomyolysis [lysis of skeletal muscle cells]
o Alcohol
o Crush injury
o Drugs
 Muscle injury
o trauma,
o surgery,
o intra-muscular injections
 Autoimmune inflammatory muscle diseases
o Dermatomyositis
o Polymyositis
 Myocardial infarction
 Some cases of brain injury e.g. stroke
o CRE: = creatinine blood test measures the level of creatinine in the blood.
 Creatinine is a waste product that forms when creatine breaks down;
creatine, creatinine and CPK will all be raise in muscle injury as above
-
Muscular dystrophies:
o = Inherited group of disorders characterized by muscle wasting and weakness
o Genetic heterogeneity
o Clinical heterogeneity
 e.g. childhood vs. adult onset
 e.g. cardiac vs respiratory involvement
o X-linked dystrophies
 Duchenne muscular dystrophy
 X linked recessive = 2/3; sporadic = 1/3
 most common muscular dystrophy; considered a mainly proximal
muscle weakness problem
 mutations in the dystrophin gene on Xp21(locus 21 on X)
42
Giles Kisby
GE Y1 Musculoskeletal
o


mutations result in severe reduction or absence of
dystrophin in skeletal and cardiac muscle
o many diff mutations possible; typically are out of frame
o one third have no family history i.e. de novo mutations
relatively high
o Dystrophin is an intracellular protein linking intracellular
actin of sarcomeres with the ECM; dystrophin loss gives loss
of protection against contraction induced damage to the cell
(so muscular dystrophy results)
o Absence of dystrophin results in muscle fibre damage,
abnormal intra-cellular calcium entry, cell death
dystrophin isoforms are expressed in brain (therefore deficiency
results in mental retardation in ~30%)
Clinical features
o Young onset: symptoms typically occur before age of 6 years
o progressive muscle weakness:
 initially legs and pelvis (Gower’s sign: difficulty rising
from the floor)
 abnormal gait
 wheelchair bound by teenage years
o spinal scoliosis
o muscle contractures [muscle and its tendons shorten,
resulting in reduced flexibility] in the legs due to fibrosis of
damaged muscle fibres
43
Giles Kisby
GE Y1 Musculoskeletal
o
o
o
respiratory insufficiency due to respiratory muscle weakness
feeding difficulties in late stages
mortality in late teenage years / early twenties [eg due to
cardiomyopathy]

o mental retardation in ~30%
Diagnosis
o Examination
 Clinical signs as above
o Creatine phosphokinase (CPK)
 massive elevation (since birth) 10-100x normal
range
o Molecular genetic testing
 screen for commonest mutations
 in 90% genotype-phenotype correlation can be
deduced
o Muscle biopsy
 In a dystrophy
 Muscle fibre degeneration and regeneration
 Fibres of all sizes randomly arranged in
muscle fascicle
 Accumulation of fibrous tissue and fat
within the muscle
 In a atrophy
 changes are due to motor neurone damage;
this only affects fibres belonging to the
motor units whose axon has been damaged
(ie observe healthy muscle next to wasted
motor units)
44
Giles Kisby
GE Y1 Musculoskeletal

Management
o Corticosteroids
o

Management of complications; examples:
 Spinal fusion for scoliosis
 Non-invasive ventilation
 Feeding aids, gastrotomy
 ACE inhibitors for cardiomyopathy
o Experimental gene therapy approaches
Beckers muscular dystrophy
 X linked recessive
 Less common and less severe than Duchenne muscular dystrophy
o ‘patient walking in their teens’
 Many due to ‘in-frame’ dystrophin gene mutations so less
dysfunction
o partial expression of truncated but functional protein
o Heterogeneity of presentation due to the exact nature of
the mutation
 As with other dystrophies: Hypertrophic proximal weakness (ie the
hypertrophy is the fibrosis / lipid deposition)

Cardiomyopathy common (two thirds of cases)

o
Malignant hyperthermia on exposure to muscle relaxants (e.g.
suxamethonium) and halogenated inhaled anaesthetics (e.g.
isoflurane)
o Ie due to the overstimulation causing excessive ATP use and
thus heat generated
Autosomal dystrophies
 Limb-girdle muscular dystrophy
 Ie name indicates is a proximal dystrophy
 has dominant and recessive forms
o Autosomal dominant (LGMD1) form
o Autosomal recessive (LGMD2) form
 Complex group of disorders as diverse clinical features
o Nomenclature based on the deficient protein is commonly
used:
 E.g. laminin → ‘laminopathy’,
 Eg. dysferlin → ‘dysferlinopathy’
 Muscle biopsy key investigation
o Dystrophic changes
o Absence of specific muscle protein
 Raised CPK
45
Giles Kisby
GE Y1 Musculoskeletal
21/03/14: Musculoskeletal examination and synovial fluid
analysis: Matthew Pickering
Los (from booklet):
Define and perform the GALS (Gait, Arms, Legs, Spine) examination
Define the following commonly used rheumatological terms: arthritis, arthralgia, subluxation,
synovitis
Distinguish the pattern of joint disease in Rheumatoid arthritis, Osteoarthritis and Reactive Arthritis
Summarise the importance of arthrocentesis and its general contraindications and potential
complications
Summarise the clinical features of gout
Describe the crystals seen within the synovial fluid in gout
Recognise the role of synovial fluid examination in septic arthritis
Notes
Nb Crepitus = grating, crackling or popping sounds and sensations experienced under the skin and
joints
-
Definitions:
o Arthritis - refers to definite inflammation of a joint(s) i.e. swelling, tenderness and
warmth of affected joints
o Arthralgia - refers to pain within a joint(s) without demonstrable inflammation by
physical examination
o Dislocation - articulating surfaces are displaced and no longer in contact
o Subluxation - Partial dislocation
o Valgus deformity - lower limb deformity whereby whereby distal part is directed
away from the midline e.g. hallux valgus
o Varus deformity - lower limb deformity whereby whereby distal part is directed
towards the midline e.g. varus knee with medial compartment osteoarthritis
46
Giles Kisby
GE Y1 Musculoskeletal
NOTE:
-
‘sero-negative spondyloarthropathies’: [each are expanded upon later]: DHTK: (NB detailed
knowledge of these conditions is not required): Seronegative spondyloarthropathy (or
seronegative spondyloarthritis) is a group of diseases involving the axial skeleton and having
a negative serostatus. "Seronegative" refers to the fact that these diseases are negative for
rheumatoid factor
o Ankylosing spondylitis
 a chronic inflammatory disease of the axial skeleton with variable
involvement of peripheral joints and nonarticular structures. AS is a form of
spondyloarthritis, a chronic, inflammatory arthritis
 spinal fusion; enthesopathy; HLA-B27
o Reiter’s syndrome = reactive arthritis
 develops in response to an infection in another part of the body
 lower limb asymmetric oligoarthritis with axial involvement
o Arthritis associated with psoriasis (psoriatic arthritis)
 psoriasis = chronic relapsing/remitting immune-mediated skin disease
characterized by red, scaly patches, papules, and plaques, which usually itch
o Arthritis associated with gastrointestinal inflammation (enteropathic synovitis)
-
GALS EXAMINATION:
o Gait
o Arms
o Legs
o Spine
-
GALS EXAMINATION:
47
Giles Kisby
GE Y1 Musculoskeletal
o
o
o
o
Gait



Arms






Legs





Spine










smoothness and symmetry of leg, pelvis and arm movements
normal stride length
ability to turn quickly
Look for normal girdle muscle bulk and symmetry
Look to see if there is full extension at the elbows
Are shoulder joints normal?
Examine hands palms down with fingers straight
Observe supination, pronation, grip and finger movements
Test for synovitis at the metacarpo-phalangeal joints (MCP joints)
Look for knee or foot deformity
Assess flexion of hip and knee
Look for knee swellings
Test for synovitis at the metatarso-phalangeal joints (MTP joints)
Inspect soles of the feet
Is paraspinal and shoulder girdle muscle bulk symmetrical?
Is the spine straight?
Are the iliac crests level?
Is the gluteal muscle bulk normal?
Are there popliteal swellings?
Are the Achilles tendons normal?
Are there signs of fibromyalgia?
Are spinal curvatures normal?
Is lumbar spine and hip flexion normal?
Is cervical spine normal?
Then, after the GALS screen should perform a detailed examination of any abnormal joint(s)
identified in the GALS screen:
-
The fundamentals aspects of locomotion to examine are:
o the nature of the joint abnormality
o the extent (distribution) of the joint involvement
o Any other features of diagnostic importance
-
The fundamentals aspects of locomotion to examine are:
o the nature of the joint abnormality
 Is there inflammation?
 Swelling
 Warmth
48
Giles Kisby
GE Y1 Musculoskeletal



 Erythema
 Loss of function
 Tenderness
Is there irreversible joint damage?
 Joint deformity
 Crepitus
 Loss of joint range or abnormal movement
Is there a mechanical defect?
 May due to inflammation, degenerative arthritis or trauma
 identified by:
o painful restriction of motion in absence of features of
inflammation
o instability
Examples:
 Swelling is present in: GOUT
o Acute gout is a good example of arthritis
o Tissue deposition of monosodium urate (MSU) crystals
occurs to give:
 Gouty arthritis
 Tophi (aggregated deposits of MSU in tissue) eg ear
o Commonly affects the metatarsophalangeal joint of the big
toe (‘1st MTP joint’)
 Gout is known as podagra when it involves the big
toe
o Abrupt onset
o Extremely painful
o Joint red, warm, swollen and tender

Swelling is present in: ENTHESOPATHY:
o = pathology at the enthesis i.e. the site where ligament or
tendon inserts into bone
o examples include:
49
Giles Kisby
GE Y1 Musculoskeletal





plantar fasciitis
Achilles tendinitis
ANKYLOSING SPONDYLITIS
REACTIVE ARTHRITIS
Joint deformity may occur in: ANKYLOSING SPONDYLITIS
o It is a chronic inflammatory disease affecting:
 Sacroiliac joints and spine: May lead to spinal fusion
and deformity
 Entheses resulting in chronic enthesopathy
 Non-axial joints – usually hips and shoulders
o Strong association with HLA-B27
o Rheumatoid factor is negative: It is part of a group of
conditions termed ‘sero-negative spondyloarthropathies
50
Giles Kisby
GE Y1 Musculoskeletal
o
the extent (distribution) of the joint involvement
 determine number of joints involved:
 polyarthritis
> 4 joints involved
 oligoarthritis
2-4 joints involved
 monoarthritis
single affected joint
 note if involvement is symmetrical
 note the size of the involved joints
 is there axial involvement?

Examples:
 rheumatoid arthritis
o bilateral
o symmetrical
o involvement of large and small joints
 reactive arthritis
o lower limb (predominantly) asymmetrical oligoarthritis
o axial involvement
 gout
o inflammation of the first metatarsophalangeal joints
[*****************]
51
Giles Kisby
GE Y1 Musculoskeletal
o
Any other features of diagnostic importance

Examples:
 RHEUMATOID ARTHRITIS
o SUBCUTANEOUS NODULES

GOUT
o TOPHI – subcutaneous deposits of uric acid

Systemic lupus erythematosus
o MALAR RASH
52
Giles Kisby
-
GE Y1 Musculoskeletal
SYNOVIAL FLUID ANALYSIS
o Used to test for
 Infection
 crystal arthritis [different crystals]
 Gout
o Needle shaped  birefringence negative
o Monosodium Urate

Pseudogout
o Brick shaped  birefringence positive
o
o
o
Calcium pyrophosphate dihydrate (CPPD)
crystals
normally: Colourless or pale yellow transparent viscous film covering synovium and
cartilage with few cells
Synthesized by synovial lining cells of synovium
 Two types of synovial lining cells:
 “type A” = macrophage-like
 “type B” = fibroblast-like: secrete the hyaluronic acid which results
in the increased viscosity of synovial fluid [Synovial fluid is viscous
fluid rich in hyaluronic acid]
 synovium collagen is Type I collagen
53
Giles Kisby
GE Y1 Musculoskeletal
o
Abnormal increase in synovial fluid volume is termed ‘synovial effusion’
 osteoarthritis
 due to abnormal mechanical stimulation with damage to cartilage
and bone
 synovitis, gout, rheumatoid arthritis
 due to inflammation
 septic arthritis
 due to infection ie bacteria in joint due to injury, impaired defence
etc
54
Giles Kisby
GE Y1 Musculoskeletal
21/03/14: Rheumatoid arthritis, Osteoarthritis and Reactive
arthritis: (Matthew Pickering)
Los (from booklet):
Define the term ‘reactive arthritis’ and summarise how it may present.
Recognise that ‘reactive arthritis’ is part of a family of inflammatory arthritic syndromes termed
‘seronegative spondyloarthroapthies’ (NB detailed knowledge of these conditions is not required).
Summarise the pathogenesis, clinical features and management of rheumatoid arthritis.
Explain the importance of anti-CCP antibodies in rheumatoid arthritis.
Notes
-
REACTIVE ARTHRITIS
o 20 – 40 YRS
o URETHRITIS
o sterile inflammation in joints
 Reactive arthritis is distinct from infection in joints (septic arthritis)
o occurs following/after infection especially urogenital (e.g. Chlamydia trachomatis)
and gastrointestinal (e.g. Salmonella, Shigella, Campylobacter infections) infections
 Symptoms follow 1-4 weeks after infection and this infection may be mild
o Reactive arthritis may be first manifestation of HIV or hepatitis C infection
o Important extra-articular manifestations include:
 Enthesopathy
 Skin inflammation
 Eye inflammation
o Associated with HLA-B27
o M>F [“males more likely to have HIV”]
o musculoskeletal symptoms of reactive arthritis
 ARTHRITIS – ie joints
 Asymmetrical
 Oligoarthritis (<5 joints)
 Lower limbs typically affected: large joints
 ENTHESITIS – ie tendons
 Heel pain (Achilles tendonitis)
 Swollen fingers (dactylitis)
 Painful feet (metatarsalgia due to plantar fasciitis)
 SPONDYLITIS – ie spine
 Sacroiliitis (inflammation of the sacro-iliac joints)
 Spondylitis (inflammation of the spine)
o Treatment:
 Non steroidal: NSAIDs
 Steroidal: intra-articular corticosteroid therapy
55
Giles Kisby
-
GE Y1 Musculoskeletal
o
Rheumatoid arthritis vs. Reactive arthritis:
o
Septic arthritis vs. Reactive arthritis
OSTEOARTHRITIS
o Chronic slowly progressive disorder
o Cartilage changes
 reduced proteoglycan
 reduced collagen
 chondrocyte apoptosis
o failure of articular cartilage that typically affecting joints of the hand (especially
those involved in pinch grip), spine and weight-bearing joints (hips and knees)
 Joints of the hand
 Distal interphalangeal joints (DIP)
o Osteophytes at the DIP joints are termed Heberden’s nodes
 Proximal interphalangeal joints (PIP)
o Osteophytes at the PIP joints are termed Bouchard’s nodes
 First carpometacarpal joint (CMC)
56
Giles Kisby
GE Y1 Musculoskeletal


o
o
Spine
Weight-bearing joints of lower limbs
 knees and hips
 First metatarsophalangeal joint (MTP)
Caused by:
 Excessive loading on joints
 Abnormal joint components
Radiographic features
 Joint space narrowing
 Subchondral bony sclerosis
 Proliferation of superficial osteoblasts
 Osteophytes
 new bone formation at the joint margins
 Subchondral cysts
 focal superficial necrosis

Radiographic changes in Rheumatoid Arthritis vs. Osteoarthritis:
[Osteopenia refers to bone density that is lower than normal]
57
Giles Kisby
GE Y1 Musculoskeletal
o
-
Management
 physiotherapy
 Weight loss
 Exercise
 Analgesia
 Joint replacement
The following Los are covered in the ‘ARTICULAR PATHOLOGY LECTURE’:
o Summarise the pathogenesis, clinical features and management of rheumatoid
arthritis.
o Explain the significance of a ‘rheumatoid factor’.
o Explain the importance of anti-CCP antibodies in rheumatoid arthritis.
21/03/14: The Connective Tissue Disorders: (Matthew
Pickering)
Los (from booklet):
Summarise the pathogenesis and clinical features of systemic lupus erythematosus (SLE).
Recognise the importance of autoantibody measurement in the assessment of connective tissue
disease and list the important antibodies associated with
(1) systemic lupus erythematosus (SLE),
(2) scleroderma,
(3) Sjogren’s syndrome and
(4) polymyositis.
List the key features of: (NB detailed knowledge of these conditions is not required)
Sjogren’s syndrome,
scleroderma
polymyositis
Explain what is meant by the term ‘overlap syndrome’ in the setting of connective tissue disease.
58
Giles Kisby
GE Y1 Musculoskeletal
Notes
Nb Arthralgia and arthritis is typically non-erosive (though not in RA)
-
Key conditions
o Systemic Lupus Erythematosus (SLE)
o Sjögren’s syndrome
o Autoimmune inflammatory muscle disease
 Polymyositis
 Dermatomyositis
o Systemic sclerosis (= scleroderma)
o Overlap syndromes
-
Raynaud’s phenomenon
o Raynaud’s phenomenon is most commonly isolated and benign condition but can be
associated with some of the above conditions (cf for further info)
o Painful
o Is Intermittent vasospasm of digits on exposure to cold
o
Typical colour changes – white



 blue  red:
Vasospasm leads to blanching of digit
Cyanosis as static venous blood deoxygenates
Reactive hyperaemia then occurs (transient increase in organ blood flow
that occurs following a brief period of ischaemia)
59
Giles Kisby
-
GE Y1 Musculoskeletal
SYSTEMIC LUPUS ERYTHEMATOSUS
o Prototypic autoimmune disease: B cell hyper-reactivity making autoantibodies
o
o
o
Associated with HLA-DR3 [same as the secondary HLA cause of coeliac (behind
HLADQ2)]
Clinical manifestations:
 Malar rash – erythema that spares the nasolabial fold
 Photosensitive rash
 Mouth ulcers
 Hair loss
 Raynaud’s phenomenon (see above)
 Arthralgia and sometimes arthritis
 Serositis (vs serous tissues: pericarditis, pleuritis, less commonly peritonitis)
 Renal disease – glomerulonephritis (‘lupus nephritis’)
 Cerebral disease – ‘cerebral lupus’ e.g. psychosis
Laboratory manifestations:
 Haematological:
 Haemolytic anaemia
 Lymphopenia
 Thrombocytopenia [relative decrease of platelets in blood]
 Immunological
 Antinuclear antibodies
o Likely accessed by antibodies by translocation of nuclear
antigens to membrane surface in apoptosis and then
impaired clearance of apoptotic cells
o Eg
 Anti-Ro
 Anti-La
 Anti-Sm
 Anti-RNP
 Anti-Scl-70
 Anti-ds-DNA antibodies
o Also some non nuclear!: Anti-tRNA synthetase antibodies
 Anti-double-stranded DNA antibodies
o Correlate with disease activity
 Complement consumption
o Low C4 and C3 due to the Abs activating complement
   Sick lupus patient commonly has Low complement
levels & High serum levels of anti-ds-DNA antibodies
60
Giles Kisby
-
GE Y1 Musculoskeletal
SJÖGREN’S SYNDROME: sjögren’s syndrome
o F>M
o Autoimmune exocrinopathy
 lymphocytic infiltration of especially exocrine glands and sometimes of other
organs (extra-glandular involvement)
 Exocrine gland pathology results in:
 Dry eyes (xerophthalmia)
 Dry mouth (xerostomia)
 Parotid gland enlargement
o Commonest extra-glandular manifestations are:
 non-erosive arthritis
 Raynaud’s phenomenon
o Termed ‘secondary’ Sjögren’s syndrome if occurs in context of another connective
tissue disorder e.g. SLE
o Associated with autoantibodies:
 Antinuclear antibody
 Anti-Ro (ie as does SLE)
 Anti-La (ie as does SLE)
 Rheumatoid factor
61
Giles Kisby
-
GE Y1 Musculoskeletal
INFLAMMATORY MUSCLE DISEASE
o Proximal muscle weakness due to autoimmune-mediated inflammation
o
o
o
o
o
Either with (=“
dermatomyositis”) or without (=“polymyositis”) a
rash
Skin changes in dermatomyositis:
 Lilac-coloured (heliotrope) rash on eyelids, malar region and naso-labial
folds [nb these folds are spared in SLE]
 Red or purple flat or raised lesions on knuckles (Gottron’s papules)
 Subcutaneous calcinosis (ie calcium deposits)
 Mechanic’s hands (fissuring and cracking of skin over finger pads)
Associated with autoantibodies:
 Antinuclear antibody (ie as does SLE)
 Anti-tRNA synthetase antibodies (ie as does SLE)
Elevated CPK, abnormal electromyograpghy, abnormal muscle biopsy (polymyositis
= CD8 T cells; dermatomyositis = CD4 T cells in addition to B cells)
Associated with malignancy (10-15%) and pulmonary fibrosis
62
Giles Kisby
-
GE Y1 Musculoskeletal
SYSTEMIC SCLEROSIS = scleroderma
o Raynaud’s phenomenon
o Thickened skin: fibrotic skin
 Signs:
 Dermal fibrosis
 cutaneous calcinosis
 telangiectasia [small dilated blood vessels near the surface of the
skin or mucous membranes]
o Skin changes may be limited or diffuse
 Diffuse systemic sclerosis
 Fibrotic skin everywhere including proximal to elbows or knees
(excluding face and neck)
 Anti-topoisomerase-1 (=anti DNA gyrase = anti-Scl-70) antibodies
 Pulmonary fibrosis, renal (thrombotic microangiopathy)
involvement
 Short history of Raynaud’s phenomenon
 Limited systemic sclerosis
 Fibrotic skin hands, forearms, feet, neck and face
 Anti-centromere antibodies
 Pulmonary hypertension
 Long history of Raynaud’s phenomenon
63
Giles Kisby
GE Y1 Musculoskeletal
-
OVERLAP SYNDROME
o When features of more than 1 connective tissue disorder are present e.g. SLE and
inflammatory muscle disease we can use the term “overlap syndrome”
o When incomplete features of a connective tissue disease are present we can use the
term “undifferentiated connective tissue disease”
o overlap syndromes include “mixed connective tissue disease” (‘MCTD’):
-
Mixed Connective Tissue Disease means Anti-U1-RNP antibody present (ie also in SLE
[TRUE])
o Associated with features of seen in SLE, scleroderma, rheumatoid arthritis, and
polymyositis
Nb no autoantibodies for:
-
Osteoarthritis
Gout
Reactive arthritis
Ankylosing Spondylitis
psoriatic arthritis
enteropathic synovitis
64
Giles Kisby
GE Y1 Musculoskeletal
Revision lecture put up by lecturer (can also use slides direct
to test self):
-
List the key features of rheumatoid arthritis
o Morning stiffness in and around joints
o Symmetrical polyarthritis typically involving the small joints of the hand and/or
wrists
o Subcutaneous nodules
o Rheumatoid factor
o Joint erosions on radiographs
-
Define rheumatoid factor
o Antibodies that recognize the Fc portion of IgG as their target antigen
o typically IgM antibodies i.e. IgM anti-IgG antibody !
-
What substance makes synovial fluid viscous?
o Hyaluronic acid: a non-sulphated glycosaminoglycan
-
Define Reactive Arthritis
o Sterile inflammatory synovitis following an infection whose extra-articular
manifestations may include:
 Enthesopathy
 Skin inflammation
 Eye inflammation
65
Giles Kisby
GE Y1 Musculoskeletal
- List two infections associated with Reactive Arthritis
o Urogenital infections
 E.g. Chlamydia trachomatis
o Enterogenic infections
 E.g. Salmonella, Shigella, Campylobacter infections
o Reactive arthritis may be first manifestation of HIV or hepatitis C
infection
-
Define and give two examples of an enthesopathy
o Inflammation where a ligament, tendon, fascia or capsule insert into bone. Examples
include:
 Achilles tendonitis (painful heel)
 inflammation at insertion of Achilles tendon into calcaneum
 Plantar fasciitis (painful feet)
 inflammation at insertion of plantar fascia
 Dactylitis (swollen digits)
 inflammation at insertion of capsule and ligaments in digits
 Spondylitis (spinal inflammation) in Ankylosing Spondylitis
 inflammation where the outer part (annulus fibrosis) of the intervertebral disc inserts into the vertebral body
66
Giles Kisby
GE Y1 Musculoskeletal
[see above for ans]
-
In a single statement summarise the key pathological finding in osteoarthritis
o Irreversible loss of articular cartilage
-
Define (i) proteoglycan and (ii) glycosaminoglycan and give one example of each
o glycoproteins containing sulphated glycosaminoglycan chains e.g.
 Aggrecan
o [GAGs: are repeating polymers of disaccharides] repeating polymers of disaccharides
e.g.
 Hyaluronic acid (= hyaluronate)
 disaccharides are: glucuronic acid and N-acetyl glucosamine
 UNSULFATED!!
 Keratan sulphate
 disaccharides are: galactose and N-acetyl glucosamine
 Chondroitin sulphate
 disaccharides are: glucuronic acid and N-acetyl galactosamine
-
What is the major (i) collagen and (ii) proteoglycan found in articular cartilage?
o Type II collagen
o Aggrecan
67
Giles Kisby
-
GE Y1 Musculoskeletal
List the major HLA association for each of the following diseases
o Ankylosing Spondylitis & Reactive Arthritis
HLA-B27
 “there be average of 2 words in ‘Ankylosing Spondylitis’ and ‘Reactive
Arthritis’ and 7 syllables (Ankylosing spondylitis = 8, Reactive Arthritis = 6,
average = 7) so HLA-B27”
o SLE
HLA-DR3
 “SLE has 3 letters so HLA-DR3”
o Rheumatoid arthritis
HLA-DR4
 “U will remember that U is fourth letter in rheumatoid so HLA-DR4”
68
Giles Kisby
GE Y1 Musculoskeletal
69