Padget's disease of bone

Question 0

Osteoporosis

Answer 0

A generalised and significant reduction of bone mass-> catabolism exceeds anabolism
Increased osteoclast activity of increased formation
Family of disorders in which systemic bone density reduction but the patient at risk of spontaneous fractures
>50 years, 1/3 women, 1/12 men

Question 1

Bone remodelling

Answer 1

Osteoblasts and osteoclasts control bone remodelling-> continuous bone turnover on a micro scale
5-10% of bone replaced each year
Osteoblast-> bone formation-> anabolism
Osteoclast-> bone reabsorption -> catabolism
Macrophages recruited from blood-> osteoclast precursors -> to bone surface-> committed osteoclasts -> mature in to resorption multinucleated activated osteoclasts
NF-Kb -> transcription factor activates formation and maturation of osteoclasts
-> secrete H and lytic enzymes-> degrade bone mineral and collagen matrix-> generate resorptive lacunae-> ecto resorption
Osteoblasts precursors mature-> move in to lacunae and replace osteoclasts-> deposit new bone

Question 2

Osteopetrosis

Answer 2

A generalised and significant increase of bone mass as a result of anabolism > catabolism

Question 3

Padget’s disease

Answer 3

Increased and disorganised bone remodelling
More dense bone with abnormal architecture -> mechanically weak
Resorption=deposition
Increased osteoclast activity and/or production-> secondary increase osteoblasts activity
3% of over 55s
In discrete areas-> padgetic lesions
Bone deformity and increased susceptibility to fractures

Question 4

Clinical presentation of Padget’s disease

Answer 4

Radionuclide bone scan-> any dark areas indicate increased intense uptake-> padgetic lesions 
Bone deformity 
Multiple sites but discrete regions
Many patients asymptomatic
30% ->
Bone pain
Skeletal deformities
Deafness
Neurological symptoms
Pathological fractures 
< 1% osteosarcoma 
Majority of adult hood sarcoma in pdb patients

Question 5

PDB causes

Answer 5

Viral-> paramyxovirus, possible measels
Environment-> arsenic?
Genetic

Question 6

Genetic factors in PDB

Answer 6

Familial clustering of PDB -> 15-40% of affected indiviudals have at least one effected first degree relative
Lots of families show autosomal dominant inheritance
5 chromosomes effected
5q35 (PDB3) produces mutated SQSTM1
5q31 (PDB4)

Question 7

RANK-NFkB signalling pathway

Answer 7

RANK-> receptor activator of NFkB on cell surface-> ligand binds and activates signalling cascades involving tumour necrosis factor receptor associated factor 6 (TRAF6), sequestosome 1 (SQSTM1), p62 that activate NFkB in the nucleus
NFkB-> nuclear factor kB
RANK is highly expressed on osteoclasts-> lead to increased expression of genes which encode proteins required for osteoclastogenesis and osteoclast activity
RANK ligand-> expressed by osteoblasts-> usually bound to osteoprotogenin-> instead binds RANK on osteoclasts-> natural regulation

Question 8

Familial expansive osteolysis and expansive skeletal hyperphosphatasia

Answer 8

Rare PDB like disorders
FEO-> 18q21-22-> 6aa insertion in RANK signal peptide
ESH-> 5aa insertion
RANK protein doesn’t reach the cell surface -> intracellular RANK signals activation of NFkB without RANK-L binding-> increased, unregulated osteoclastogenesis/osteoclast activity

Question 9

Juvenile hyperphosphatasia

Answer 9

Rare PDB like disorder
Mutation in 8q24-> deletion in osteoprotogernin gene
RANK-L can activate NFkB all the time -> increased osteoclastogenesis/osteoclast activity

Question 10

5q35 linked PDB

Answer 10

PDB3
Most common familial PDB -> 20%
>30 mutations in SQSTM1 -> scaffold protein which binds TRAF6 and regulates its ubiquitination
Cause activation of NFkB
Correlation between disease extent and ability of different my tations to activate NFkB

Question 11

Mutations in other part so the RANK-NFkB pathway

Answer 11

Cause PDB like symptoms
VCP mutations-> cause IBMPFD
VCP regulates the Proteasomal degradation of IkB-> allows NFkB to enter nucleus and potentiated signalling
-> gain of function wrt signalling

Question 12

Different phenotypes produced by mutations in the RANK-NFkB pathway

Answer 12

Stem cell differentiation to myeloid precursor-> CSF1
Myeloid precursor differentiation to osteoclast precursor-> RANK, OPG
Osteoclast precursor fusion to immature osteoclast-> TM7SF4
Osteoclast maturation-> SQSTM1, VCP, OPTM, NFkB

Question 13

Treatments

Answer 13

Old-> bisphosphonates-> bind with high affinity so very effective but non selective -> promote osteoclast death
New-> denosumab-> RANK-L targeted antibody, mimics OPG