Basic Sciences Flashcards
What is the difference between Haversian and Volkmann canals?
Vascular canals in the bone
- Haversian canals are oriented along the long axis of the bone
- Volkmann canals are oriented transversely.
What are the two types of bone (microscopic structural classification)
- Woven bone (not stress oriented)
- Lamellar bone (stress oriented)
What induces osteoblast differentiation?
- BMP stimulates mesenchymal cells to become osteoprogenitor cells
- Platelet derived growth factor (PDGF) and Insulin derived growth factor (IDGF) induces osteoblast differentiation
Describe Osteoclast activation
- PTH receptor on osteoblast bind to PTH = Expression of RANKL
- RANKL binds to RANK receptor on osteoclasts = activates = bone resorption
What binds to the RANKL of osteoblasts and inhibits RANK activation (inhibits osteoclast activity)?
Osteoprotegrin (OPG)
- TRICK: OsteoProtects by binding to RANKL and preventing activation of RANK on osteoclasts.
What are the precursors to osteoclasts?
Myeloid hematopeitic cells from monocyte/macrophage lineage cells
Name of site of bone resorption where ruffled borders meet the bone surface
Howship’s Lacunae
What is Cathepsin K?
Major proteolytic enzyme that digest organic material at the ruffled borders
Mechanism of action of bisphosphonates?
Prevents formation of ruffled borders of osteoclasts and prevents production of acid hydrolases
Mutation of Cathepsin K leads to what disease?
Pycnodysostosis (increased bone density, short stature, brittle bones)
How do osteocytes communicate with adjacent osteocytes?
Gap junctions in canaliculi
Osteoprogenitor cells become different cells under different conditions….in what condition do they become Osteoblast, collagen, fibrous tissue?
- Osteoblast (“the marathon runner”)
- LOW strain + HIGH oxygen
- Collagen (“Collagen gets Choked”)
- INTERMEDIATE strain + LOW oxygen
- Fibrous tissue
- HIGH strain
What type of collagen makes up bone?
Type 1 (90% of organic material of bone)
What ORGANIC material is responsible for
- the compressive strength
- the tensile strength of the bone matrix?
- Collagen = tensile strength
- Proteoglycans = compressive strength
What is the most abundant non-collagenous protein in bone matrix?
Osteocalcin (10-20% of total)
- Promotes mineralization and bone formation
- Stimulated by 1,25 dihydroxyvitamin D3
- Inhibited by PTH
- MARKER OF BONE TURNOVER (in serum and urine)
What are the inorganic components of bone?
- Calcium Hydroxyapatite (gives compressive strength)
- Brushite (osteocalcium phosphate)
Blood supply to long bones comes from 3 sources
- Periosteal (low pressure system)
- Metaphyseal-epiphyseal
- Nutrient arteries (HIGH pressure system)
Direction of arterial blowflood in bone (mature vs immature)
- Mature = CENTRIFUGAL (inside out)
- High pressure nutrient arteries inside and low pressure periosteal flow
- Venous is opposite (centripedal)
- Immature = Centripedal
- Low pressure from periosteal blood flow dominates
What % of endosteum is devascularized from reaming during IMN insertion?
Reaming nail devascularizes 50-80% of endosteal blood supply
What is the pattern of blood flow in bone after fracture?
- Centripedal (outside in)
- Nutrient artery blood flow disrupted and periosteal blood floor predominates.
Name factors that stimulate bone resorption
- RANKL
- PTH
- IL-1
- 1,25 - hydroxyvitamin D
- Prostaglandin E2
- IL-6 (Myeloma)
- MIP-1A (Myeloma)
Bone loss per year after 25 yo?
- 0.3-0.5%/ year after skeletal maturity
- 2-3 % / year for untreated postmenopausal women
IL-1 vs IL-10, which one causes bone resorption which one causes bone formation.
- IL-1 (one finger, fuck you bone)
- activates osteoclasts and caused bone resorption.
- PTH stimulate osteoblast to secrete IL-1 and IL-6 activating osteoclasts and increase M-CSF (Macrophage colony-stimulating factor) = more osteoclasts.
- IL-10 (double high five to bone)
- Bone formation
What is the affect of PTH on the kidney and intestine?
- Stimulates enzymatic conversion of 25-(OH)-vitamin D3 to 1,25-(OH)2-vitamin D3 (ACTIVE form)
- Increases absorption of Ca++ in kidney (increase serum Ca++)
- Increase excretion of Po4- from kidney
- Increase gut absoprtion of Ca++ (affect of 1,25-(OH) vitamin D3
What are the effects of activated vitamin D (1,25(OH)2 vitamin D3)
- Increase kidney and gut absorption/ resorption of Ca++
- Promotes the mineralization of osteoid matrix produced by osteoblasts.
- NOTE: Vitamin D deficiency causes osteomalacia/ Rickets
- Phenytoin (Dilantin) causes impaired metabolism of vitamin D.
What is the function of Thyroid hormone on bone?
- Regulates skeletal growth at the physis by stimulating:
- Chondrocyte growth
- type X collagen synthesis
- alkaline phosphatase activity
When does the appendicular system form during gestation?
- 4-8 weeks
- Limb bud development is under the control of fibroblast growth factors (FGF)
- TRICK: Finger Growth Fast (FGF)
- Mutation in FGF = Apert syndrome (acrocephalosyndactyly)
What regulates limb bud formation?
- “Shh” (Sonic HedgeHog) is expressed by the notochord and regulates limb bud formation
- limb bud grows outwards into ectoderm.
- bud is a combo of the lateral plate mesoderm and somatic mesoderm.
What is the first signaling center to appear (proximodistal) limb patterning? Hint: a defect of ____ will result in proximal limb truncation/ central deficit (ie Cleft hand)
AER
TRICK: AEROSMITH—–rock on sign with hand!!
In Anteroposterior (radioulnar - radial = anterior and ulnar = posterior) limb growth, what signaling center appears and determines limb polarity?
- ZPA (Zone of polarizing activity)
- along posterior (aka ulnar) limb and expresses Shh.
- ZPA duplication = MIRROR HAND
- Higher concentration of “Shh” in side of Small finger (ulnar)
- Lower concentration of “Shh” radially
NOTE:
ULNAR (where Shh supposed to be high)
- more Shh = more fingers
- Less Shh = less fingers
RADIAL (where Shh supposed to be low)
more Shh = LOSS OF THUMB
What gene is expressed in dorsal ectoderm and regulates dorsal-ventral growth of limb?
- Wnt genes
The Spinal Column (vertebra) originate from which structures?
- Somites
- pairs of mesodermal structures that develop cranial to caudal
- MORE SPECIFICALLY:
- The sclerotome layer of the somite will become the vertebral bodies and annulus
What does the notochord become?
- Nucleus pulposus and anterior vertebral bodies
What forms the PNS?
What forms the spinal cord?
- Neural crest = PNS
- Neural tube = spinal cord
What are the 3 ossification centers of the vertebrae?
- Centrum (anterior body)
- Neural Arch (posterior elements, pedicles)
- Costal elements (TP or ribs, lateral mass)
What type of collagen is associated with enchondral OSSIFICATION?
type X collagen
What is Hueter-Volkmann Law?
- Compression across physis slows longitudinal growth
- Tension accelerates longitudinal growth
In the hypertrophic zone of physis, what regulates chondrocyte maturation (hypertrophy/calcification)?
- Parathyropid related peptyides
- Expression regulated by Indian Hedgehog gene
Name the zones of the physis and associated diseases
Name the types of bone formation?
- Endochondral
- (initial production of cartilage gets replaced by bone - secondary # healing, long bone growth, embryonic)
- Intramembranous
- (direct bone production with mesenchymal diff. into osteoblast, flat bones, primary bone healing, distraction osteogenesis)
- Appositional
- (width, periosteum)
Name a condition with defects in intramembranous ossification?
- Cleidocranial dysplasia
- Remember that clavicle (considered flat-ish and formed by intramembranous bone formation)
- Mutation in CBFA1 (aka Runx2) on chromosome 6.
What regulates intramembranous bone formation?
-
Wnt pathway and Hedgehog signaling
- beta-catenin = induces cells to form osteoblasts = bone formation
- Sclerostin = inhibits Wnt Pathway = decrease bone formation
TRICK: Sclerostin Sucks (decrease bone formation)
What are the modes of bone healing and there associated strain?
- Primary bone healing = < 2% strain
- Secondary bone healing = 2-10% strain
What are the stages of bone healing?
- Inflammation (aka hematoma formation)
- Repair
- Soft Callus
- Hard Callus
- Remodelling
Type of non-union
- Hypertrophic
- inadequate stability with adequate blood supply/biology
- Atrophic
- Inadequate blood supply/biology and inadequate immobilization
- Oligotrophic
- inadequate reduction (wants to heal but too far to go)
What is the effect of TGF-B on bony healing?
- Transforming Growth Factor-B
- Found in # hematoma
- Stimulates production of Type II collagen and proteoglycans by mesenchymal cells.
- Induces osteoblasts to synthesize collagen,
What are the properties of a bone graft?
-
Osteoconductive (scaffold for bone formation)
- ex: demineralized bone matrices (DBMs)
-
Osteoinductive (factors promoting bone formation)
- ex: BMP (from the TGF-B superfamily) or DBMs.
-
Osteogenic (actual cells that produce bone)
- ex: mesenchymal cells, osteoblasts, osteocytes.
NOTE:
- AUTOGRAFT is GOLD STANDARD (osteoinductive, conductive and genic)
- Fresh or fresh frozen allograft still have BMP, therefore osteoinductive. vs freeze dried does NOT.
Resorption rate fastest to slowest
calcium sulfate > tricalcium phosphate > hydroxyapatite
Explain the antigenicity of allograft
- Class I and II antigen on allograft recognized by host T lymphocytes and elicit immune response.
What is the MOA of calcitonin in the treatment of osteoporosis?
- Inhibition of sclerostin formation and inhibition of osteoclast apoptosis. (OITE)
Where is PTH secreted?
- Chief cells of parathyroid glands (4)
What is the function of PTH?
- response to low serum Ca++
- Increase bone resorption
- PTH receptor on osteoblasts which secrete IL-1 to active osteoclasts
- Increase kidney resorption of calcium (distal convoluted tubule, reminder that most resorption is in proximal c. tubule)
- Decrease kidney resorption of phosphate
- Increase activation of 25-OH vitamin D (Calcidiol) to 1,25-dihydroxyvitamin D3 (active, calcitriol) (which in term increases gut/kidney absoprtion of PO4- and Ca++)
Describe the sarcomere
- H band?
- I band?
- A band?
- Z line?
- Actin thin
- Myosin thick
- TRICK:
- A band = A team (both myosin and actin)
- Only one that stays constant (does NOT shorten with contraction)
- I band = skinnies (only actin)
- H band = huge people (myosin only)
- Z line = site of attachment of actin between side to side sarcomeres
- A band = A team (both myosin and actin)
How does Botox work?
- Blocks release of Ach (acetylcholine) from end plate (Motor endplate)
as compared to myasthenia gravis which attack receptors and results in shortage of Ach receptors.
What are the types of muscle contraction?
- Isometric:
- constrant length
- Isokinetic:
- Constant speed (need cybex machine that keeps speed constant)
- Plyometric:
- Rapid lengthening followed by contraction
- Isotonic:
- constant tension
- concentric - shortens during contraction
- eccentric - lengthens during contraction
Force generated by muscle is MOST dependent on_______
muscle cross-sectional area
What are the components of the stress strain (load-elongation) curve for a ligament/tendon?
- Toe region:
- tightening of loose fibers to resist stress.
- Linear region:
- stiffness = slope (constant)
- Yield point:
- Point where elastic (reversible) becomes plastic (irreversible).
What is the most predominant proteoglycan in tendon? HINT: it regulates collagen fiber diameter
Decorin
TRICK: Decorin regulates Diamter of tenDon
Name the 4 transitional tissues that make up tendon’s insertion into bone (firbocartilaginous enthesis)
- Tendon
- Uncalcified fibrocartilage
- Calcified firbocartilage
- Bone
NOTE:
- Fibrocartilaginous enthesis (direct attachment) to epiphysis/ apophysis
- RTC, achilles
- Fibrous enthesis (indirect attachment)
True or false. Tendons are less viscoelastic (less elastin) than ligaments
TRUE
Name and describe the zones of articular cartilage
- Superficial zone (tangential zone)
- Collagen oriented PARALLEL to joint (shear stress)
- High collagen, low proteoglycans
- Transitional zone (intermediate zone)
- Random orientation of collagen
- Round chondrocytes
- Deep zone (basal layer or radial zone)
- Collagen oriented perpendicular to joint
- HIGH proteoglycans (compressive stress)
- Round chondrocytes in columns
- TIDEMARK
- between superfical uncalcified cartilage and deeper calcified cartilage
- just superficial to subchondral bone
What are the changes in articular cartilage seen in OA vs aging?
- OA
- Increased water content
- Decreased stiffness
- Increased chondroitin 4 sulfate: keratan sulfate ratio
- Aging
- Decreased water content
- Increased stiffness
- Decreased chondroitin 4 sulfate: keratan sulfate ratio
NOTE: Advanced Glycosylation End Products (AGEs) increases with age and their accumulation thought to lead to OA
What major transcription factor is involved in differentiation of cells towards the cartilage lineage?
SOX-9
What are the cell types in synovium and which one produced synovial fluid (hyaluronic acid)?
- Type A cells
- antigen presenting ability, superficial layer
- Type B cells
- PRODUCE SYNOVIAL FLUID
- Type C cells
- Unknown function
What is the composition of collagen?
- Triple helix of:
- 2x alpha 1 chains
- 1x alpha 2 chains
Collagen fiber = multiple collagen fibrils aggregated together.
What is an exon (in DNA)?
- an exon is the portion of gene on DNA that codes for mRNA
TRICK:
EXon is EXpressed
What is the type of immune response to metallic orthopaedic implants?
- Type IV
- Delayed-type hypersensitivity reaction
What are translocations?
- Translocations allow expression of genes (oncogenes) that are usuallyp NOT active
- 95% present in sarcomas
- Western blot detects _____
- Southern blot detects _____
- Northern blot detects _____
- SOutwestern blot detects _____
- Western blot detects _____PROTEIN
- Southern blot detects _____DNA
- Northern blot detects _____RNA
- Soutwestern blot detects _____DNA BINDING PROTEIN
Trick:
- SNoW
- DRoP
- Southern = DownNA under
- Western Ortho = Protein junkies (Joey/Yousif/Sahil)
Define toughness of a material and how to calculate it using a stress-strain curve
- Toughness
- Amount of energy per volume a material can absorb before failure (fracture)
- AREA UNDER the stress-strain curve
- J/m3
What is hysteresis?
- Energy dissipation
- characteristic of a viscoelastic material where the loding curve does NOT follow the unloading curve
- The difference between the curves is the energy that is dissipated.
What is Hooke’s law?
- When a material is loaded in the elastic zone:
- Stress is proportional to the strain
Define:
- Brittle material:
- Ductile material:
- Viscoelastic material:
- Isotropic material:
- Anisotropic material:
-
Brittle material:
- linear stress strain relationship up until point of failure (elastic only, little to no plastic deformation)
-
Ductile material:
- large amounts of plastic deformation before failure
-
Viscoelastic material:
- Stress-strain is dependent on duration of applied load and the RATE by which the load is applied (internal friction) - ie ligs and bone
-
Isotropic material:
- same mechanical properties in ALL directions
-
Anisotropic material:
- different mechanical properties DEPENDING on the direction of applied load
Which metal is most prone to crevice corrosion (fatigue cracks due to difference in oxygen tension)?
Stainless steel
How is titanium corrosion resistant?
- Forms a layer of self passivation around it
- Titanium oxide around it that shields it from outside.
Name ways of increasing the stability of an Ex-Fix.
- Contact of ends of #
- LARGER DIAMETER PINS (most important)
- Additional pins
- Decrease bone to rod distance
- Pins in different planes
- Incrase size or number of stacking rods
- Rods in different planes
- Increased spacing between same sided pins
Define antalgic gait
- Gait abnormality secondary to pain resulting in shortened stance phase relative to swing phase.
What is the increase in 5 year mortality after a vertebral fragility fracture?
15% increase in 5-year mortality
What is the FRAX score?
WHo fracture risk assessment tool to calculte 10 year risk of hip fracture and osteoporosis-related #
Define osteopenia an osteoporosis
- Osteopenia: L2-4 lubar density with T-score -1 to –2.5 –> 1-2.5 SD below peak bone mass of a 25 year old individual
- Osteoporosis: L2-4 lumbar density with T score < -2.5 –> 2.5 SD below the peak bone mass of a 25 year old individual.
What is the classification of osteoporosis?
- Type 1: Post menopausal
- Type 2: Elderly/ Senile
In hypophasphatasia, what are the abnormal labs (serum and urine)?
- Serum
- decreased serum alkaline phosphatase
- Urine:
- presence of “phosphoethanolamine” is diagnostic
Describe the types of Rickets and there associated lab values
- X-linked hypophosphatemic rickets (most common, familial)
- lose phosphate in kidneys (defective resorption)
- poor mineralization
- Tx: Calcitriol (1,25 DHvitamin D3))
- Vitamin D deficient Rickets (Nutritional)
- Lack of vitamin D (sun/nutrition)
- Tx: 5000 iu/d Vitamin D
- Hereditary vitamin D Dependant Rickets
- Type 1: Can’t make it (can’t make activated vitamin D) - autosomal recessive
- Type 2: Can’t use it (receptors defective)
- Hypophasphatasia
- Can’t make alkaline phosphatase required to make inorganic phosphate require for bone mineralization
What is the common mutation in Autosomal Dominant Hypophosphatemic Rickets (ADHR)
- Mutation causing cleavage-resistant FGF23
- increase in FGF23 = increase renal loss of phosphate
- This mechanism seen in oncogenic osteomalacia (mutation in phosphatonin gene for FGF23.
- Much rarer than X-linked dominant Hypophosphatemic Rickets.
What is pseudohypoparathyroidism and what condition is associated with it?
- PTH resistance (decrease in target cell response)
- Type 1a = ALBRIGHT HEREDITARY OSTEODYSTROPHY
- Short 4th and 5th metacarpals
- “knuckle, knuckle, dimple, dimple”
What are the radiographic findings in scurvy?
-
White line of Frankel
- Sclerotic line at metaphysis
-
Trummerfeld zone
- Transverse radiolucent band in metaphysis just adjacent to Frankel line
-
Wimberger ring
- Ring of increased density surrounding epiphysis
-
Pelkin spur and fracture
- Metaphyseal spurs and #
-
Corner sign of Park
- metaphysea clefts
-
Decreased trabeculae
- Ground-glass osteopenia
Name bone resorption desorders and their causes
- Osteopetrosis
- Defective carbonic anhydrase = decrease resorption
- Pycnodysostosis
- Defective Cathepsin K = decrease resorption
- Osteoporosis
- Decrease estrogen/ postmenopausal
- Corticosteroids
- Hyperparathyroidism
- All increase resorption
- Familial Expansile Osteolysis (FEO)
- RANK mutation = increase resorption
- Hyperostosis
- “Hyperostosis corticalis deformans juvenilis”
- Defective/ decrease in osteoprotegerin (mutation) = increase resorption
What are makers of bone formation (measured in serum)?
- Osteocalcin (ONLY one that is bone specific)
- Alkaline Phosphatase
- C & N propeptides of Type I collagen
What type of immune reaction occurs in response to Orthopaedic hardware?
- Type 4 hypersensitivity reaction (excessive cell-mediated immunity, T-lymphocytes, acquired/adaptive)
What mutation causes X-linked Hypophosphatemic rickets?
Mutation in proteinase PHEX
Trick: peX = X-linked hypophosphatemic rickets
MILLERS
- PHEX regulates FGF-23, which normally prevents the kidney’s reabsorption of phosphate.
- The PHEX gene mutation therefore reduces phosphate reabsorption, leading to hypophosphatemia.
HLA-B27 is associated with which rheumatologic condictions?
- PAIR
- Psoriatic arthritis
- Ank Spond
- Inflx bowel disease
- RA
HLA-DR3 = myastenis gravis and SLE
HLA-DR4 = RA
What is the Paparika sign?
- Punctate bleeding of bone after debridement of bone (usually in osteomyelitis case or nonunion).
What is the Penumbra sign? (Osteomyelitis)
- MR
- Bright signal in surrounding bone
- Dark signal in abcess/sclerotic bone
Describe the MOA of beta-Lactam abx, aminoglycosides, quinolones.
- beta-Lactam abx (penG, Cephalosporin)
- Inhibit cross linking of polysaccharides in CELL WALL
- Aminoglycosides (Gent, Tobramycin)
- Inhibit protein synthesis (30S ribosomal subunit)
- Quinolones (cipro, levo, ofloxacin)
- Inhibits DNA gyrase
