Ch.

20: Bones, Joints and Soft Tissue Tumors

RANK- part of the TNF family is expressed on the membrane of preosteoclasts

and mature osteoclasts.
RANKL- is expressed by osteoblasts and marrow stromal cells. Unregulated by
factors that stimulate osteoclasts
Osteoprotegerin is a decoy receptor which blocks the actions of RANKL.
Unregulated by factors that
RANK activation leads to active NFkB which drives osteoclast formation,
fusion, differentiation, function and survival

Congenital disorders of bone and cartilage

Abnormalities in a single or group of bones are called dysostoses and can
result in the absence of bones, supernumerary bones, or inappropriately
fused bones; some of these result from mutations in homeobox genes
affecting localized migration and condensation of primitive mesenchymal
cells.
Dysostoses result form abnormalities from localized problems in the
migration of mesenchymal cells and formation of condensations
Aplasia- congenital absence of digit or rib
Abnormalities in bone or cartilage organogenesis are called dysplasias; these
can be caused by mutations that affect signal transduction pathways or
components of the extracellular matrix:
Achondroplasia and thanatophoric dwarfism occur as a
consequence of constitutive FGFR3 activation due to mutations in
FGFR3, resulting in defective cartilage synthesis at growth plates. This
leads to stunted growth
o Achondroplasia affects all bones of enchondral ossification
results in short stature, bowing,
o Thanatophoric- lethal variant- missense mutation FGFR3
Osteogenesis imperfecta (brittle bone disease) is a group of
disorders caused by mutations in the genes for type 1 collagen that
interfere with its normal production, with resultant bone fragility and
susceptibility to fractures.
o Brittle bone disease there is too little bone
o Alpha1 and 2 chains of type 1 collagen are affected- you get
premature degeneration
o Classic finding is blue sclera, hearing loss, small misshapen
teeth
Osteopetrosis is caused by mutations that interfere with osteoclast
function and is associated with dense but architecturally unsound bone
owing to defective bone resorption.
o Bones are stone like, dense, solid like chalk
o Cranial nerve palsies, infection, hepatospelnomegaly

Acquired Diseases of Bone Development and Mass

Nutritional deficiencies can affect bone integrity by altering the quality of the
organic matrix (e.g., vitamin C is involved in collagen cross-linking) or by
 influencing bone mineralization (e.g., vitamin D is involved in calcium
uptake).
Osteoporosis results from decreased bone mass and is clinically significant
because it predisposes bone to fracture. Although osteoporosis is
multifactorial, the two most common forms are senile osteoporosis due to
aging related losses of osteoblast function, and postmenopausal osteoporosis
due to increased osteoclastic activity caused by the relative absence of
estrogen.
o Morphology: loss of bone, thnned cortices and dialted haversian
cancals; osteoclast activity is present but not overly pronounced and
the mineral content is normal.
In postmenopausal- trabecular bone loss is severe
compression factures and collapse of vertebral bodies
Senile- cortical bone loss- fractures on weight bearing bones
o Pathogenesis: bone formation v resorption balance is lost due to age
(decreased cells), hormones (menopause-decline in estrogen and
resulting increase in cytokines, there is also increased RANK activity,
increased osteoclasts), physical activity (reduced activity reduced
stimulation), genetics(vit D polymorphisms), calcium nutritional state,
and secondary causes (glucocorticoids, smoking, alcohol)
o Clinical Course: asymptomatic until fractures start. Now theres DEXA
and pharmacotherphy when diagnosed
Paget disease may result from a paramyxovirus infection in genetically
susceptible persons and is caused by aberrant and excessive osteoclast
activity, followed by exuberantbut structurally unsoundosteoblast
deposition of bone.
o Morphology: Can be solitary
lesion (monostotic) or
multiple sites. The lytic phase
osteoclasts are increased
with increased size and
nuclei, then the mixed phase
has osteoblasts trying to
remodel and eventually you
get a mosaic pattern (jigsaw
puzzle) with haphazard
arranged cement lines. Even
though the blasts increase and the cortex made is softer and weaker
(fractures).
o Pathogenesis: paramyxoiviurs induces IL1 and 6 in the infected cells
alogn with m-csf which might activate osteoclasts. Theres also SQSTM1
gene mutation that leads to increased in osteoclastogenesis
o Clinical Course: increased serum alkaline phosphatase and increased
exceretion of hydroxyproline. Affects monostotic. Can cuse
hypervascularity can lead to CHF, nerve impingement in proliferative
state, deformed long bones; chalk stick fractures
Primary or secondary (due to renal failure) overproduction of PTH
(hyperparathyroidism) results in increased osteoclast activity and bone
resorption, leading to fractures and deformities.
o Rickets is a disorder in children which interferes with the deposition of
bine in growth plates
o Osteomalacia is the adult rickets version, where bone formed during
remodel is undermineralized so predisposed to fractures.
o PTH
Osteoclast activation increase resorption, indirect by RANKL,
increased calcium resorption from the tubules, increase
excretion of phsophates, increase VitD synthesis
Morphology: increased osteoclasts and resorption, diminished
cortical and trabecular bone. Hemosiderian Dissecting ostetistis-
increase number of osteoclasts bring into bony trabeculae.
Cortical cutting
cones- expanding haversian canals
Hyperparathryorid and hypoparathyroid
Brown tumor of hyperparathryoidsim
Osteitis fibrosa cystica