Basic Science Review

OITE

8/18/2016
Grand Rounds
 Genetic mutations
FGFR2 Apert's syndrome
FGFR3 Achondroplasia
COMP Pseudoachondroplasia
EXT1/EXT2 MHE
Sulfate transport gene Diastrophic dysplasia
CBFA Cleidocranial dysplasia
Carbonic anhydrase Osteopetrosis
COL1A1 Osteogenesis imperfecta
COL2A1 Kneist syndrome
Absent dystrophin Duchenne's muscular dystrophy
Abnormal dysrophin Becker muscular dystrophy
LMX1B Nail-patella syndrome
Peripheral myelin protein 22 Charcot Marie Tooth
Fibrillin Marfan syndrome
Fibrous dysplasia / McCune
Gs protein alpha subunit
Albright
Homogentisic acid Ochronosis / alkaptonuria
Cystathionine Homocystinuria
 Genetic mutations
FGFR2 Apert's syndrome
FGFR3 Achondroplasia
COMP Pseudoachondroplasia
EXT1/EXT2 MHE
Sulfate transport gene Diastrophic dysplasia
CBFA Cleidocranial dysplasia
Carbonic anhydrase Osteopetrosis
COL1A1 Osteogenesis imperfecta
COL2A1 Kneist syndrome
Absent dystrophin Duchenne's muscular dystrophy
Abnormal dysrophin Becker muscular dystrophy
LMX1B Nail-patella syndrome
Peripheral myelin protein 22 Charcot Marie Tooth
Fibrillin Marfan syndrome
Fibrous dysplasia / McCune
Gs protein alpha subunit
Albright
Homogentisic acid Ochronosis / alkaptonuria
Cystathionine Homocystinuria
 Genetic mutations
FGFR2 Apert's syndrome
FGFR3 Achondroplasia
COMP Pseudoachondroplasia
EXT1/EXT2 MHE
Sulfate transport gene Diastrophic dysplasia
CBFA Cleidocranial dysplasia
Carbonic anhydrase Osteopetrosis
COL1A1 Osteogenesis imperfecta
COL2A1 Kneist syndrome
Absent dystrophin Duchenne's muscular dystrophy
Abnormal dysrophin Becker muscular dystrophy
LMX1B Nail-patella syndrome
Peripheral myelin protein 22 Charcot Marie Tooth
Fibrillin Marfan syndrome
Fibrous dysplasia / McCune
Gs protein alpha subunit
Albright
Homogentisic acid Ochronosis / alkaptonuria
Cystathionine Homocystinuria
 Cell types in bone
Osteoblast Osteoclast Osteocyte

Osteoblast
Osteoclast
Osteocyte

http://courses.washington.edu/conj/bess/bone/bone2.html
 Cell types in bone
Osteoblast Osteoclast Osteocyte

Osteoblast Bone forming

Osteoclast
Osteocyte

http://courses.washington.edu/conj/bess/bone/bone2.html
 Cell types in bone
Osteoblast Osteoclast Osteocyte

Osteoblast Bone forming

Osteoclast Bone resorbing
Osteocyte

http://courses.washington.edu/conj/bess/bone/bone2.html
 Cell types in bone
Osteoblast Osteoclast Osteocyte

Osteoblast Bone forming

Osteoclast Bone resorbing
Osteocyte Bone maintenance

http://courses.washington.edu/conj/bess/bone/bone2.html
 Cell types in bone
Osteoblast Osteoclast Osteocyte
Mesenchymal stem cells can differentiate into adipocytes,
chondrocytes, and osteoblasts.
What transcription factor that directs mesenchymal cells into the
osteoblast lineage?

(also known as CBFA-1)

Cleidocranial dysplasia (AD)

???
 Cell types in bone
Osteoblast Osteoclast Osteocyte
Mesenchymal stem cells can differentiate into adipocytes,
chondrocytes, and osteoblasts.
What transcription factor that directs mesenchymal cells into the
osteoblast lineage?

RUNX2
(also known as CBFA-1)

Cleidocranial dysplasia (AD)

???
 Cell types in bone
Osteoblast Osteoclast Osteocyte
Mesenchymal stem cells can differentiate into adipocytes,
chondrocytes, and osteoblasts.
What transcription factor that directs mesenchymal cells into the
osteoblast lineage?

RUNX2
(also known as CBFA-1)

Cleidocranial dysplasia (AD)

???
Transcription factor that controls the differentiation
of mesenchymal cells to chondroblasts

SOX 9
 Cell types in bone
Osteoblast Osteoclast Osteocyte

What is the precursor cell to an osteocyte?

 Cell types in bone
Osteoblast Osteoclast Osteocyte

What is the precursor cell to an osteocyte?

Osteoblast
 Cell types in bone
Osteoblast Osteoclast Osteocyte

What is the precursor cell to an osteocyte?

Osteoblast
 Cell types in bone
Osteoblast Osteoclast Osteocyte

What is the precursor cell to an osteoclast?

 Cell types in bone
Osteoblast Osteoclast Osteocyte

What is the precursor cell to an osteoclast?

Myeloid progenitors that also form monocytes
 Cell types in bone
Osteoblast Osteoclast Osteocyte

What is the precursor cell to an osteoclast?

Myeloid progenitors that also form monocytes
 Cell types in bone
Osteoblast Osteoclast Osteocyte

What effect does PTH have on osteoclasts?

Describe the RANK/RANKL mechanism.
 Cell types in bone
Osteoblast Osteoclast Osteocyte

What effect does PTH have on osteoclasts?

Describe the RANK/RANKL mechanism.
PTH attaches to receptor on osteoblast
Osteoblast secrete RANKL
RANKL attaches to RANK on osteoclast
Stimulates differentiation into mature osteoclast
 What drug is given to mimic this process
Teraperatide  PTH 1-34, N-Terminus

What is critical about delivery of this drug

Pulsitile – must be pulsitile otherwise there will be
an increase in bone resorption
 Cell types in bone
Osteoblast Osteoclast Osteocyte

What effect does PTH have on osteoclasts?

Describe the RANK/RANKL mechanism.
PTH attaches to receptor on osteoblast
Osteoblast secrete RANKL
RANKL attaches to RANK on osteoclast
Stimulates differentiation into mature osteoclast
 Cell types in bone
Osteoblast Osteoclast Osteocyte
Role of Osteoprotegerin in the RANK/RANKL mechanism?
 Cell types in bone
Osteoblast Osteoclast Osteocyte
Role of osteoprotegerin in the RANK/RANKL mechanism?
Binds to RANKL and prevents bone resorption
 Cell types in bone
Osteoblast Osteoclast Osteocyte
Role of osteoprotegerin in the RANK/RANKL mechanism?
Binds to RANKL and prevents bone resorption
 Cell types in bone
Osteoblast Osteoclast Osteocyte
Role of osteoprotegerin in the RANK/RANKL mechanism?
Binds to RANKL and prevents bone resorption

What cell type produces osteoprotegerin?

 Cell types in bone
Osteoblast Osteoclast Osteocyte
Role of osteoprotegerin in the RANK/RANKL mechanism?
Binds to RANKL and prevents bone resorption

What cell type produces osteoprotegerin?

Osteoblasts
 Cell types in bone
Osteoblast Osteoclast Osteocyte
Role of osteoprotegerin in the RANK/RANKL mechanism?
Binds to RANKL and prevents bone resorption

What cell type produces osteoprotegerin?

Osteoblasts

What is denosumab (Prolia)?

 Cell types in bone
Osteoblast Osteoclast Osteocyte
Role of osteoprotegerin in the RANK/RANKL mechanism?
Binds to RANKL and prevents bone resorption

What cell type produces osteoprotegerin?

Osteoblasts

What is denosumab (Prolia)?

RANKL monoclonal antibody, treatment for osteoporosis
by inhibiting RANKL activity
 Effect of COX-2 on fracture healing?
COX-2 required for enchondral ossification

What type of ultrasonography can accelerate

fracture healing?
Low-intensity pulsed
30 mW/cm2 pulsed wave (OITE 2011, #273)

Antibiotic that inhibits fracture healing?

Quinolone (also toxic to chondrocytes)
 Synthetic Bone Grafting
(calcium phosphate, calcium sulfate, calcium carbonate, corraline hydroxyapatite)

Synthetic graft with highest compressive strength? (2010, #166)

 Synthetic Bone Grafting
(calcium phosphate, calcium sulfate, calcium carbonate, corraline hydroxyapatite)

Synthetic graft with highest compressive strength? (2010, #166)

Calcium phosphate
Resorption rate of calcium phosphate vs calcium sulfate?
 Synthetic Bone Grafting
(calcium phosphate, calcium sulfate, calcium carbonate, corraline hydroxyapatite)

Synthetic graft with highest compressive strength? (2010, #166)

Calcium phosphate
Resorption rate of calcium phosphate vs calcium sulfate?
Calcium phosphate degrades very slowly
Calcium sulfate is rapidly resorbed (Sulfate = Speedy)
 BMP Types
Increasingly nuanced – Potentially not indicated… however

BMP 2
BMP 7
BMP 4
BMP 3
 BMP Types
Increasingly nuanced – Potentially not indicated… however

BMP 2 – Acute open tibial fractures

BMP 7 – Tibial non-unions (7 comes after 2  nonunion comes
after fracture)

BMP 4 – Gene mutations associated with fibrodysplasia

ossificans progressiva (Dr. Kaplan)
BMP 3 – NO osteogenic activity
 Calcium dietary requirements
Children
600 mg/day 2000
Adolescents/young adults (10-25) Lactating
1,300 mg/day
Adults 1500
750 mg/day Adolescents
Pregnant Pregnant
1,500 mg/day Post-menopausal
Post-menopausal
1,500 mg/day 750
Lactating Adults/children
2,000 mg/day
 What hormone is made by chief cells of the parathyroid
gland?
PTH

What hormone is made by clear cells of the thyroid gland?

Calcitonin

What is the effect of calcitonin on bone resorption?

Inhibits osteoclastic bone resorption

What stimulates calcitonin release: low/high calcium?

High serum calcium
 Calcium regulation
Ca Ph
1,25-Vit D
PTH

PTH → osteoblasts → osteoclast resorption → increase serum Ca 2+

PTH →proximal tubules → decrease phosphate reabsorption

- increase in urinary Ph excretion
- decrease in serum Ph
PTH →increased 25-OH to 1,25-OH2 vit D conversion

1,25-OH2 vit D → increase gut absorption of Ca 2+

 Primary hyperparathyroidism
Primary problem?
Chief cells in parathyroid gland
produce too much PTH
Effect of PTH on bone? Effect of PTH on kidneys?

Increase serum calcium Effect of PTH on gut? Increase urine phosphate

PTH→osteoblast→osteoclast resorption (proximal tubules)
Decrease serum phosphate
Serum Ca Increase gut absorption of Ca/Ph
by converting 25 to 1,25 vit D in kidney
Serum Phos
Urine Phos HYPERCALCEMIA
1,25 Vit D Treat with surgical parathyroidectomy
 Hypercalcemia
Hyperparathyroidism
Hypercalcemia of malignancy

Hypocalcemia
Hypoparathyroidism
Pseudohypoparathyroidism
Renal osteodystrophy
Rickets
 Hyper Hypo Pseudohypo
Defect in PTH receptor

PTH
Serum Ca
Serum Phos
Urine Phos
1,25 Vit D

Disorder associated with pseudohypoparathyroidism

Albright hereditary osteodystrophy

Appearance of hands and feet in Albright hereditary osteodystrophy

Short 1st, 4th, and 5th metacarpals and metatarsals
 Renal Osteodystrophy
Chronic renal disease
(elevated BUN/Cr, low GFR)

What are two types of renal

osteodystrophy?

High turnover Low turnover

Impaired phos excretion Aluminum toxicity
High PTH Low PTH
 Nutritional Rickets
Vitamin D Calcium Phosphate

Vitamin D Ca Phos

Ca/Phos PTH Vitamin D

Vitamin D
PTH
 Most common form of rickets
Familial hypophosphatemic rickets
(vitamin D resistant rickets)

What inheritance pattern?

X-linked dominant (not X recessive!)
 Sex linked dominant disorders
1) Hypophosphatemic rickets
2) Lori Weil dyschondrosteosis

Madelung deformity

Result of disruption of the volar ulnar physis of the distal radius (radial inclination, radiopalmar tilt).
Disease with low levels of alkaline phosphatase
Hypophosphatasia

What urine test can diagnose hypophosphatasia?

Increased urinary phosphoethanolamine
Ocular disorders

Inferior lens dislocation

Superior lens dislocation

Retinal detachment
Ocular disorders

Inferior lens dislocation

Homocystinuria (AR)

Superior lens dislocation

Retinal detachment
Ocular disorders

Inferior lens dislocation

Homocystinuria (AR)

Superior lens dislocation

Marfan’s (AD)

Retinal detachment
 Ocular disorders

Inferior lens dislocation

Homocystinuria (AR)

Superior lens dislocation

Marfan’s (AD)

Retinal detachment
Spondyloepiphyseal dysplasia (SED)
 Ocular disorders

Inferior lens dislocation

Homocystinuria (AR) – look down to pee

Superior lens dislocation

Marfan’s (AD) – marfanoid habitus = Tall look up

Retinal detachment
Spondyloepiphyseal dysplasia (SED)
t(12;22) Clear cell chondrosarc

t(11;22) Ewing’s

t(9;22) Chondrosarcoma

Synovial sarcoma
t(X;18)

Rhabdomyosarcoma
t(2;13)
Myxoid liposarcoma
t(12;16)
t(12;22)

t(11;22)

t(9;22)

t(X;18)

t(2;13)

t(12;16)
t(12;22) Clear cell chondrosarc

t(11;22)

t(9;22)

t(X;18)

t(2;13)

t(12;16)
t(12;22) Clear cell chondrosarc

t(11;22) Ewing’s

t(9;22)

t(X;18)

t(2;13)

t(12;16)
t(12;22) Clear cell chondrosarc

t(11;22) Ewing’s

t(9;22) Chondrosarcoma

t(X;18)

t(2;13)

t(12;16)
t(12;22) Clear cell chondrosarc

t(11;22) Ewing’s

t(9;22) Chondrosarcoma

Synovial sarcoma
t(X;18)

t(2;13)

t(12;16)
t(12;22) Clear cell chondrosarc

t(11;22) Ewing’s

t(9;22) Chondrosarcoma

Synovial sarcoma
t(X;18)

t(2;13) Rhabdomyosarcoma

t(12;16)
t(12;22) Clear cell chondrosarc

t(11;22) Ewing’s

t(9;22) Chondrosarcoma

Synovial sarcoma
t(X;18)

Rhabdomyosarcoma
t(2;13)

t(12;16)
Myxoid liposarcoma
 Transcription Factor

Ewing’s EWS-FLI1

Cleidocranial dysplasia CBFA-1

 Immunoglobulins
IgE
Allergic response

IgM
Rheumatoid factor

Infection response IgG

Mucosal surface IgA

Hemophilia inhibitor
IgG
M-spike in MM
IgG (50%), IgA(25%)
 Diagnosis?
1 2

Posteromedial tibial bowing Anterolateral tibial bowing

Calcaneal valgus NF-1
 Diagnosis?

Iliac horns
Pathognomonic for Gene involved?
nail patella syndrome LMX1B
Diagnosis?
 OSAE 2012, #34
A child with bilateral fracture of the olecranon
apophysis should be evaluated for what
disorder?
 OSAE 2012, #34
A child with bilateral fracture of the olecranon
apophysis should be evaluated for what
disorder?

Osteogenesis imperfecta
COL 1A1
 2009 OITE #21

9yo M with bilateral thigh pain. History of precocious puberty.

Exam reveals multiple café-au-lait spots. AP pelvis and frog leg
lateral hip radiographs are shown. His condition is linked to an
abnormality in:

1. G protein function
2. Osteoclastic function
3. Vitamin D metabolism
4. Sulfate transporter gene
5. Type I collagen formation

McCune-Albright syndrome 1. Precocious puberty

2. Café-au-lait spots
What will the x-ray show? 3. Polyostotic fibrous dysplasia
 2009 OITE #49
2mo M evaluated for short stature and severe clubfeet. Exam
shows swelling of pinnae of ears. Appearance of hands/feet
shown below. What is the diagnosis?

Hitchhiker’s thumb

What gene is involved?

Sulfate transporter

1. Achondroplasia
2. Apert syndrome Inheritance pattern?
3. Congenital syphilis Autusomal recessive
4. Diastrophic dysplasia
5. Cleidocranial dysplasia
Name the type of collagen in:
Meniscus
Name the type of collagen in:
Meniscus
Type I
Name the type of collagen in:
Meniscus
Type I
Fibrocartilage
Name the type of collagen in:
Meniscus
Type I
Fibrocartilage
Type I
Name the type of collagen in:
Meniscus
Type I
Fibrocartilage
Type I
Ligaments
Name the type of collagen in:
Meniscus
Type I
Fibrocartilage
Type I
Ligaments
Type I
Name the type of collagen in:
Meniscus
Type I
Fibrocartilage
Type I
Ligaments
Type I
Hyaline cartilage
Name the type of collagen in:
Meniscus
Type I
Fibrocartilage
Type I
Ligaments
Type I
Hyaline cartilage
Type II
Name the type of collagen in:
Meniscus
Type I
Fibrocartilage
Type I
Ligaments
Type I
Hyaline cartilage
Type II
Tendons
Name the type of collagen in:
Meniscus
Type I
Fibrocartilage
Type I
Ligaments
Type I
Hyaline cartilage
Type II
Tendons
Type I
Name the type of collagen in:
Meniscus Bone
Type I Type I
Fibrocartilage Annulus fibrosis
Type I Type I
Ligaments Bone
Type I Type I
Hyaline cartilage Nucleus pulposus
Type II Type II
Tendons Skin
Type I Type I
 Layer Width (µm) Characteristic Orientation Function
Opposes
Gliding zone (superficial) 40 ↓ Metabolic activity Tangential
shear
Opposes
Transitional zone (middle) 500 ↑ Metabolic activity Oblique
compression
Opposes
Radial zone (deep) 1000 ↑ Collagen size Vertical
compression
Opposes
Tidemark 5 Undulating barrier Tangential
shear
As an
Calcified zone 300 Hydroxyapatite crystals  
anchor
 Marfans
• Marfans – (“marfanoid body habitus)
pectum excavitum
fibrillin
Concern for aortic aneurysm
Autosomal dominant

• Ehlers Danlos
 Ehlers-Danlos
• EDS

• Hyperflexability
• Fragile skine
• Easy bruising
• Many other manifestations
• Multiple mutations – classic is Col V
Mechanism of pain generation in
osteoid osteoma
 Mechanism of pain generation in
osteoid osteoma

Responsive to NSAIDs secondary to PGE2 pain generation

PGE requires cyclooxygenase for synthesis
polyMixens – Membrane (not wall)
30s – aMINoglycoside, Tetra – not quite 50
50 S MACRO – and all the other, higher number for the bigger subunit

Most of those we use attack gram + and target the cell wall – vanco/cephalosporins
 Mechanism of Action of Abx
• Rifampin – orange pee/block RNA polemerase
• TMP/SMX - inhibition with PABA in
dihydrofolate synthesis
• Fluoroquinalones – inhibit DNA gyrase –
compromise soft tissue
Mechanism of Abx
 mecA mutation in bacteria
• Different Penacillin binding protein decreases
effectiveness of cell wall targeted abx
• MRSA
• Confers resistance to
Methacillin/nafcillin/oxacillin
 Mechanism of action of common
anticoagulants! (Common topic 1/year)
• Aspirin: irreversible COX inhibition in platelets, - stop 5-7 days prior to
surgery
• Coumadin/Warafarin: Inhibits liver synthesis of factors II, VII, IX, X + Prot
C/S (anticoagulant proteins). Inhibits Vitamin K mediated gamma
carboxylation. Reverese with Vitamin K (competetive inhibition), and
Fresh Frozen Plasma.
• Heparin: Xa through ATIII, protamine sulfate to reverse
• LMWH: similar to above Xa through ATIII, Protamine sulfate can reverese,
less HIT, longer half life
• Fondaparinux, irreversibly binds X thorugh ATIII, is a synthetic
pentasaccharide, has a higher risk of bleeding than LMWH
• Rivearoxaban: Driect Xa inhibitor (not through ATIII) – the river takes you
there directly.
• Hirduin: From Leeches – thrombin IIa inhibitor (dabigatran is an oral
version), no reveersal.
 Aging vs. Arthritis
Parameter
Water content (hydration;
permeability)
Collagen
↓ (Also, the length of the protein core
Proteoglycan content (concentration)
Proteoglycan synthesis
Proteoglycan degradation
Chondroitin sulfate concentration
(includes both chondroitin-4- and -6-
sulfate)
Chondroitin-4-sulfate concentration
Keratin sulfate concentration
Chondrocyte size
Chondrocyte number
Modulus of elasticity
Effect of Aging Effect of Osteoarthritis
↓ ↑
Becomes disorderly (breakdown of
matrix framework)
Content remains relatively Content ↓ in severe osteoarthritis
unchanged Relative concentration ↑ (because of
loss of proteoglycans)
Collagen type VI content ↑
and glycosaminoglycan chains ↓
decreases)
  ↑
↓ ↑↑↑
↓ ↑
↓ ↑
↑ ↓
↑  
↓  
↑ ↓
 Aging vs. Arthritis
Parameter
Water content (hydration;
permeability)
Collagen
↓ (Also, the length of the protein core
Proteoglycan content (concentration)
Proteoglycan synthesis
Proteoglycan degradation
Chondroitin sulfate concentration
(includes both chondroitin-4- and -6-
sulfate)
Chondroitin-4-sulfate concentration
Keratin sulfate concentration
Chondrocyte size
Chondrocyte number
Modulus of elasticity
Effect of Aging Effect of Osteoarthritis
↓ ↑
Becomes disorderly (breakdown of
matrix framework)
Content remains relatively Content ↓ in severe osteoarthritis
unchanged Relative concentration ↑ (because of
loss of proteoglycans)
Collagen type VI content ↑
and glycosaminoglycan chains ↓
decreases)
  ↑
↓ ↑↑↑
↓ ↑
↓ ↑
↑ ↓
↑  
↓  
↑ ↓