Bone, joints, and soft tissue Flashcards
bone matrix is 65% inorganic mineral (hydroxyaptite, responsible for hardness), 35% osteoid (mainly type 1 collagen with smaller amount of osteonectin (calcium-binding glycoprotein), osteocalcin (aka osteopontin from osteoblasts, involved in bone mineralization, formation, calcium homeostasis)
the Hydroxypatitin also serve as storage fro 99% of the body calciumand 85% of the body phorphorus.
what are woven bone and lamellar bones?
woven bone- prouced rapidly (fetal development or fracture repair), but haphazard arrangement of collgan fibers imparts less integrity
lamellar bone is the more slowly formed bone that has parallel collagen fibers
osteoblast are derive from osteoprogenitor cells (pluripotent mesenchymal stem cells)
osteocytes- long-lived cells responsible for local bone calcium and phosphate homeostasis and translate mechanical forces derived from osteoblasts
osteoclasts-short-lived that resorb bones and driven by M-CSF, IL-1, TNF
endochondral ossification-during embryogenesis, most bone generated by conversion of cartilages
- central portion of the mold is digested by chrondroblasts creating a medullary canal, while stimultaneously, the ostoblast deposit cortical bone beneath the nascent periosteum (primary center of ossification) at the diaphysis producing radial bone growth
at longitudinal end (epiphysis)-secondary center of ossification soon a cartilage growth plate form sandwiched between two ossification centers where chrondrocytes undergo proliferation, hypertrophy, apoptosis (the apoptotic zone gets invaded my capillaries to bring nutritents to osteoblasts to synthesize osteoid.
new bones form at the bottom of the growth plate resulting in longitudinal bone growth.
Intermembranous ossification (flate bones)- formed by osteoblast directly adheres to fibrous layer of tissue derived from mesenchyme with a cartilage mold. bone enlargement occurs by addition deposition on preexisting surface (appositional growth)
driven by GH (on resting chrondrocytes for proliferating) and T3 (proliferating chondrocytes to induce hypertrophy)
homeostasis and remolding
peak bone mass achieved in early adulthood after cession of skeletal growth- fourth decade: resorption>formation–> skeletal
the balance betweem resorption and formation is modulated by RANK, RANKL, osteoprotegerin (OPG) influenced by hormones
- RANK: receptor activator for NFkB on osteoclast precursors- when stimulated by RANKL, activaates NFkB which is essential for generation and survival of osteoblasts and marrow
- RANKL expressed on osteoblasts and marrow stromal cells
OPG: is a decoy receptor made by osteoblasts to bind RANKL and prevent nteraction with RANK (build)
other signaling pathway are WNT/beta-catenin, M-CSF, paracrine
- balance between bone formation and resorption is modulated by what signaling?
- which factors promote bone building
- which factors promote breakdown?
- RANK and WNT
- estrogen, testosterone, vit D
- PTH, IL-1, glucocorticoids
developmental disorder of bones
- developmental anomalies due to abnormal mesenchymal cell migration or differentiation
- transcriptional defect of homeobox genes, cytokines, cytokine receptors - aplasia
- supernumerary digit
- syndactyly or craniosynostosis
- dysplasia
- dysostosis
- absence of bone or entire digit
- extra bones or digits
- abnormal fusion of bones
- global disorganization of bone and cartilage (mutation of genes controlling development or remodeling
short terminal phalanges of thumb and big toe?
AD, patent fontanelles, delayed closure of cranial sutures, Wormian bones (extra within cranial sutures), delayed eruption of secondary teeth, primitive clavicles, short height?
Brachydactyly type D and E: HOXD13
Cleidocranial dysplasia: RUNX2
1. most common skeletal dysplasia and major cause of dwarfism
- AD, FGFR3 gain of function
- retarded cartilage growthL short proximal extremities, NL trunk length, enlarged head, bulging forehead, depression root of nose
2. most common lethal form of dwarfism
- different FGFR3 GOF
- micromelic shortenin of limbs, frontal bossing, relative macocephaly, small chest cavity (resp. insufficinecy), bell-shaped abdomen
die soon after birth
- defect of which receptor cause either osteoporosis or osteopetrosis
- mutation of what receptor cause decreased or absent osteoclasts
- achondroplasia
- Thanatophortic dysplasia
- LPR5 receptor
- mutation of RANKL
this is a type 1 collagen disease and most common inherited disorder of connective tissue (blue sclera-decrease collagen content causing translucent sclera that permit visualization of underlying choroid, hearing loss-impeded conductiom due to abnormalities of bones in the middle ear, dental imperfections-due to denin deficiency)
-AD mutation fo alpha 1-2 chains of type 1 collagen (mutated collagen and no triple helix)
type 2 (AR): no triple helix, uniformly fatal in uterom bone fragility with multiple intrauterine fractures
type 1 (AD): normal life-span, childhood fractures tha decrease frequency followinf puberty
-mutation of type 2 collagen
Osteogenesis imperfecta (brittle bone disease)
type 1: most common and mildest
collagenn structure is normal though the amount is below normal
most fractures before puberty (less frequency with age)
- normal lifespan
- normal-near normal stature
- loose joints and low muscle tone
- blue sclerae (blue, purple, or gray)
- triangular face
- tendency toward spinal curvature
- absent or minimal bone deformity
- brittle teeth
- hearing loss beginning in early 20s or 30s
type 2: most severe form
collagen is imporperly formed
frequently lethal at or shortly after birth, due to respiratory problems
numberous fracure and sever bone deformity
small stature with underdeveloped lung
Tx for OI: surgical”rodding” of long bones
exercise, healthy weight, good nutrition, dont smoke or take steroids
this disease is called marble bone disease due to mutation of CLCN7-which encodes proton pumps on surface of osteoclasts on (Chr 8;q22)
carbonic anhydrase 2 deficiency
-CA2 is required by osteoclast and renal tubular cells (acidification of urine) generate protons from CO2 and water
–acidification of osteoclast solubilize hydroxyapatite
the bone of these patients lack medullary cavity, bulbous ends of long bones (Erlenmeyer flash shaped), neural foramina are small and compress nerves
there is a severe infanile form (AR) affecting children of mediterranean and Arab race)
-cranial nerve deficit: optic atrophy, deafness, facial paralysis
-postpartum mortality: fracture, anemia, hydrocephaly
mild form (AD) dx in adulthood with repeated fractures and mild cranial nerve deficits and anemia
osteopetrosis
lysosomal storage diseases that affect degradation of dermatan sulfate, heparan sulfate, keratan sulfate
mostly affecting acid hydrolase enzyme
affects mesenchymal cells: maucopolysaccharides accumulates in the chondrocytes (causing apoptotic death) and in extracellular space to affect the structure of articular cartilage
short statures, chest wall abnormalities, and malformed bones
mucopolysaccharidoses
decreased bone mass 1-2.5 SD below the mean
osteoporosis: osteopenia severe enough to increase risk of fracture
1. at least 2.5 SD below the mean
1. atraumatic or vertebral compression fracture siginies osteoporosis
1. most common form are senile and postmenopausal
physical activity, muscle strength, diet, and hormonal state make important contribution
osteopenia is the decreased bone mass that can lead to osteoporosis
osteoporosis
once the maximal skeletal mass is attained, small deficits in bone formation accures with every bone cycle
- age-related changes: senile osteoporosis, low turnover due to decrease proliferative and biosynthetic potential (low capacity to make bone) and decrease cellular response to growth factors
- physical activity- mechanical forces stimulate normal bone formation, loss bone seen in immobility, paralysis, atronauts in zeron gravity, load magnitude influences bone density by increasing number of load cycle; resistance exercise is better
- genetic factors: LRP5 (receptor on osteoblast cells) single gene defect, few cases
- calcium nutritional state: adolescent girls have insufficient calcium in period of rapid growth restrict the peak bone mass
(decrease Ca, increase PTH, decrease Vit D)
- hormonal influences: postmenopausal osteoporosis= accelerated bone loss
- decades post menopause: yearly reduction
estrogen deficiency: major role, 40% of postmenopausal women have osteoporosis
-this increases both resorption and formation but mostly resorption
IL6, TNF=alpha and IL1 have play
tx fro breast cancer can increase bone loss and increase condition
morphology of osteoporosis
1. normal bone, but decreased quantity
2.postmenopausal women habe increase osteoclast activity
-trabecular: perforated, thinned and lose interconnections which –> microfractures and vertebral collapse
3. senile: cortex thinned by subperiosteal and endosteal resorption, Haversian system widened
the cortex gets thinner to but at a slower rate than the trabeculae
how do you increase risk?
causcasian, light colored hair and eyes, not eating enough calcium, too much phosphorus , smoke,
dx with bone mineral density test (DEXA-scan)-early sign may not show on xray
blood test is to check for secondary causes like renal, hepatic failure, hyperthyroidism
what is clinical course?
vertebral fracture of the thoracic and lumbar, loss of height: lumbar lordosis and kyphoscoliosis
complication: of PE and pneumonia,
prevent with exercise and calcium with Vit D
Tx with bisphophonates (decrease ostoclast but inducing apoptosis)
- hormonal therapy
- denosumab (anti-RANKL)
Paget disease
also called osteitis deformans
monsostotic: involves single bone 15% are polyostotic- axial skeleton and femur involved up to 80% of cases
diagnosis in 70s
40-50% are familial
5-10% are sporadic (SQSTM1)
cotton wool on skull xray
paget morphology
hallmark: mosaic patten of lamellar bone seen in sclerotic phase
- jigsaw-like appearance with prominent cement
3 phases:
initial lytic phase: large ostoclasts with 100 nuclei
mixed phase: clasts persist but lots of blasts also, primarily osteoblastic at end stage
final phase: burn-out quiescent osteosclerotic stage
-coarsely thickened trabeculae and cortices that are soft and porous, lacking structural stability, fracture easily
paget disease
wt bearing- bowing of femur and tibia, distorts femoral head–> secondary osteoarthritis
chalk-stick type fractures: long bones of legs
compression fractures of spine prouce–> spinal cord injury and hyphosis
hypervascularity of paget bone warms the overlying skin; increased bloow flow acts as arteriovenous shunt leading to high-outpt heart failure
increased serum alk phosphatease, NL serum calcium and phosphorous
tx with calcitonin and bisphosphonates to suppress sx
ricket: children interferes with deposition of bone in the growth plate
osteomalacia- adults; bone formed during remodeling is undermineralized, predisposing to fractures
all due to vit D deficiency or its abnormal metabolism
Rickets: frontal bossing, squared off head, rachitic rosary of ribs, anterior protrustion of chest, pigeon breast deformity, lumbar lordosis, bowed legs
paget disease
PTH mediates the effect of bone resorption indirectly by increasing RANKL on ostoblasts to activate osteoclasts
-increase resorption of Ca by renal tubules, urinary excretion of phosphates, synthesis of active Vit D and Ca absorption from the gut by inducing RANKL
primary hyperparathyroidism: autonomous
secondary is due to underlying renal disease
hyperphosphatemia of renal failure also suppresses renal alpha1 hydroxylase further impairing vitamin D synthesis
hyperparathyroidism morphology
untreated causes 3 skeletal abnormalities: osteoporosis, brown tumor, osteitis fibrosa cystica
dissecting osteitis- clasts tunnel into the and dissect centrally along the length of tracbeculae creating the appearance of railroad tracks
brown tumor: bone loss predisposes to microfractures that elicit influx of macrophages and ingrowth of reparative fibrous tissue creating a mass of reactive tissue
-brown: vascular, hemorrhage and hemosiderin dposition can undergo cystic degenteration
Von Recklinghausen disease of bone: increase bone cell activity, periteabecular fibrosis and cystic brown tumors is hallmark of severe hyperparathyroidism= generalized osteitis fibrosis cystica
skeletal changes that occurs in chronic renal disease, including those associated with dialysis
-osteopenia, osteomalacia, secondary hyperparathyroidism, growth retardation
histology:
- high turnover osteodystrophy: increase bone resportion and bone formation: resportion> formation
- low-turnover or aplastic disease: adynamic bone (little osteoclastic and blastic activity) and less common osteomalacia
mixed pattern of the disease: areas with high-turnover and low- turn over
renal osteodystrophy pathogenesis
3 mechanism
- tubular dysfucntion: renal tubular acidosis, associated with low pH that dissolves the hydroxyapatite–> demineratlization of the matric and osteomalacia
- generalized renal failure: glomerular and tubular function and decreased phosphate excretion, chronic hyperphosphatemina, hypocalcemia and ultimately secondary hyperparaarthyroidism
- decrease production of secreted factors: kidney cinverts vit D to active form (1,25-OH vitamin D3) and secretes proteins BMP-7
decreased vit D–> hypocalcemia and contributes to secondary hyperparathyroidism
there is a form in kids that is serious
1. leg bend inward or outward (renal rickets) and short stature
definitions
- overlying skin intact
- bone communicates with the skin surface
- bone is fragmented
- ends of the bones at the fracture site are not aligned
- slowely developing fracture that follows a period of the increased physical activity in which the bone is subjected to repetitive loads
- extending only partially through the bone, common in infants when bones are soft
- involving bone weakened by an underlying disease process, such as tumor
- simple
- compound
- comminuted
- displaced
- stress
- greenstick
- pathologic
the healing of fractures
a hematoma fills the fracture gap and surroudn area immediately due to rupture blood vessels
clotted blood–> fibrin mesh seals site and create a gramework for influx of inflammatory cells and ingrowth of fibroblasts and new capillaries
degranulated platelets and migratory cells release PDGF, TGF-B and FGF which activate osteoprogenitor in the perioseum, medullary cavity and surroundinf soft tissue and stumulateosteoclastic and osteblastic activity
end of firt week and soft callus or procallus
(continued)
continued
after about 2 wks the soft callus transformed into bony callus
activation of osteoprogenitor cells deposit subperiosteal trabeculae of woven bone oriented perpendicular to cortical axis and within and medullary cavity
bony callus reaches maxium girth end of 2nd and 3rd week and helps stabilized the fracture site
newly formed cartilage form endchondral ossification, forming a contiguous network of bone with newly deposited bone trabeculae in medulla and beneath the periosteum
weight-bearing on callus while portions not physically stressed are resorbed, callus reduced in size and outline of fratured bone are reestablished as lamellar bone
healing complete with resoration of medullary cavity
osteonecrosis (avascular necrosis)
infarction of the bone and marrow is common causes involves medullary cavity or inolve both the medulla and cortex
most cases are fracture or corticosteroid tx!
vascular insufficiency through mechanical injury to blood vessels, thromboembolism, external pressure on vessels or venous occlusion
subchondral- infarct often collapse and may lead to severe secondary osteoarthritis
medullary infarct often are usually small and clinically silent, except occur with Gaucher disease, dysbarism (bends) sickle cell anemia
(morphology)
morphology?
medullary infarct is most common, cortext have collateral flow that saves it
subchondral infarct are triangular or wegdeshaped
dead bone- empty lacunae surround by necrotic adipocytes that frequently rupture
- release fatty acid bind calcium and form insoluble calcium soaps that may persist for life
trabeculae that remain act as scaffolding for deposition of new bone=”creeping substitution”
subchondral infarcts the pace is too slow to be effective, sthere is collapse of the necrotic bone and distortion, fracture and even sloughing of the articular cartilage
osteomyelitis
inflammation of bone and marrow due to infection due to viruses, parasites, fungi, bacteria but most are pyogenic bacteria and mycobacteria
access of bone via
- hematogenous spread
- extension from contiguous site
- direct implantation
healthy kids: hematogenous spread from trival mucosa injuries (defecation or chewinf hard foods) or mineo infection of the skin
adults: often a complication of open fractures, surgical procedures, diabetic infection of the feet
name the microbe?
staph aureus: 1. expresses cell wall proteins that bind the bone matirc components (collagen) to adheres of the bacteria to bone
- more often isolated in pts with GU tract infections or IVDA
- direct spread f inoculum during surgery or into open fractures
- frequent pathogens
- sickle cell patients are predisposed
- C5-9 deficiency
- staphy aureus
- E. coli, psuedomonas, klebsiella
- mixed bacteria
- haemophilus influenzae and group B strep
- salmonella
- neisseria
osteomyelitis acute vs chronic
acute: bacteria proliferate and neurtophils. necrosis of bone cells and marrow 48 hrs
kids: periosteum loosely attached, sizable subperiosteal abscesses may form and dissect for long distances along the bone surfaces
sequestrum- dead bone following subperiosteal abscess
-rupture of periosteum–> soft tissue abscess which can channel to become a draining sinus
sequestrum may crumble and release fragments through the sinus tract
infants (rare adults): epiphyseal infection spreads through the articular surface or along capsular and tendoligamentous insertion into the joints–> septic or suppurative arthritis
-can destory articular cartilage–> permanent diability
chronic after first week, chronic inflammatory cells releases to stimulate resorption, ingrowth of fibrous tissue and deposition of reactive bone at periphery
involucrum: newly deposited bone forms a shell of living tissue around a the segment of deviralized bone
brodie abscess: small interosseous abscess frequently involves the cortex and is walled off by reactive bone
sclerosing osteomyelitis of Garre: Jaw, assocaited with extensive new bone formatin that obsures much of the underlying osseous structures
mycobacterial osteomyelitis-blood boren
sx: local pain, lowgrade fever, chills, wt loss
histo: caseous necrosis and granulmas
spine involvement (traculous spondylitis (Pott disease) - breaks through interveterbral discs to infect ultiple veterbrae and soft tissues
-perment compression fractures–> scoliosis or kyphosis and neurological deficits secondary to spinal cord and nere compression
complication of tyberculous arthritis, sinus tract formation, psoas abscess and amyloidosis
skeletal syphilis
(treponema pallidum) and yaws (treponema pertenue) can invole bone
congenital syphilis: bone lesion appear about 5th month gestation adn fully developed at birth
sabe shin: massive reactive periosteal bone deposition on medial and anterior surfaces of the tibia
acquire syphilis: bone disease may begin early in tertiary stages, 2-5 years after intial infection
-saddle nose, palate, skull and extremities (esp long tubular bones like tibia)
