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197 Cards in this Set
- Front
- Back
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Through esteogenesis and allograft, the bone can be expanded?
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1mm / day
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other than osteogenesis and allograft, what is another way of letting bones catch up?
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place a pin in the faster growing bones growth plate (this will halt growth) then allow for the other bone to catch up.
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axial skeleton=
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central axis (skull, vertebral column, ribs, sternum, sacrum)
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Appendicular skeleton=
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limbs and girdles
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number of bones in typical adult skeleton ?
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206 bones
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how many bones are present at birth?
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270, this number decreases to 206 in adulthood due to fusion.
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what type of cell contains dendrites in order to communicate with eachother?
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osteocytes
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the 4 cell fates of mesenchymal progenitors
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Myocytes, adipocytes, chondrocytes, and osteoblasts.
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Cbfa1 KO
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knock out showed normal cartilage formation, but had no formation for bone.
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Ectoderm becoems
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nervous system and skin
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Mesoderm becomes?
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heart muscle and skeletal muscle
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Endoderm becoems?
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digestive system
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Pancreas comes from the ?
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endoderm
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regulators of anterior cell fates:
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BMP and Wnt antagonists
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regulators of posterior cell fates.
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Wnts, BMPs and FGFs
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What controls the left-right polarity in mammalian embro?
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cilia, they are thought to be mechanical sensors.
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Three cell lineages that make up the vertebrate skeleton:
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neural crest cells (ectoderm), Paraxial mesoderm, lateral plate mesoderm.
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neural crest cells
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(ectoderm) branchial arch derivatives of the craniofacial skeleton.
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paraxial mesoderm
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craniofacial skeleton and most of the axial skeleton
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Lateral plate mesoderm
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skeleton of the limbs.
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Most of bone tissue comes from?
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mesoderm
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Bone formation
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Mostly 2 step process: 1. set up bone matrix 2. mineralization (Ca2+ and P-)
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membranous formation is associated with?
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high beta-catenin signalling, RUNX2 and OSX, VEGF-A (GF)
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Endochondral bone formation is associated with?
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low beta-catenin signalling, SOX9, RUNX2 and OSX (low to high), VEGF-A (low to high), and bone collar (diaphysis)
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What is SOX9?
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TF that determines fate of molecular stem cells to differentiate into chondrocytes.
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Bone should only form on ?
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solid surface.
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If mineralization occurs in other places other than the skeleton, what can occur?
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kidney disease (kidney stones)
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What is Cleidocranial dysplasia?
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missing clavicle due to Runx2 autosomal dominant mutation.
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endochondrial bone formation makes the bone?
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longer
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membraneous bone formation makes the bone?
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thicker
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Where are primary ossification centers?
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in the center of the bone
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Where are secondary ossification centers?
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at the ends of the bone and form much later than the primary centers.
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Hypotrophic chondrocytes
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They die through apoptosis, the signal for endothelial cells to come, they have receptors of VGFR which will form new blood vessels.
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Scerlotomes migrate to the ventral region to form ?
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vertebrate bodies
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Scerlotomes migrate dorsally around the neural tube to form?
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neural arches of vertebrae
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Scerlotomes migrate laterally to form?
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rib in the thoracic region.
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key steps in limb skeletal patterning
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1. establishment and outgrowth of the limb bud 2. Condensation 3. Joint formation at the boundary between two adjacent condensations or within a single condensation. 4. Cartilage formation and bone formation.
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Cartilage in long bone:
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you do not want mineralized, this is called arthritis
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the three sources of signals affecting patterns in limb formation:
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apical ectodermal ridge- makes FGFs
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Three sources of signals affecting pattern in limb formation:
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apical ectodermal ridge, Zone of polarizing activity, and interdigital mesenchyme
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the apical ectodermal ridge has cell responsible for >
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making FGF a growht factor involved in producing SHH
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Zone of polarizing activity is responsible for >
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making SHH
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Interdigital mesenchyme is responsible for?
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Production of BMPs
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If you remove the apical ectodermal ridge (AER) early in development then what happens?
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only the humerous will form and no Radius or ulna or fingers.
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If you implat zone of polarizing activity in two locations then what happens?
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forms a double hands structure. (it determines which side includes the small digit)
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what happens when you remove mesenchyme early in development?
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You will end up losing a digit.
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Shh mutants:
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most of sclerotomal derivatives such as spinal column missing with the exception of some rib cartilages, distal limb structures are also missing, cartilage missing in the elbow joint.
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FGF is involved in?
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proper limb development.
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No FGF expression =
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no limb formation
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hetero FGF expression=
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shorter limbs.
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More FGF induced=
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longer limbs.
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when do the primary ossification centers form in the fetal skeleton?
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for between 8 and 12 weeks in the vertebrae and long bones.
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When does mineralization occur in the fetal skeleton?
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most of it occurs in the third trimester.
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When do secondary ossification centers form in the fetal skeleton?
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34th week of gestation, they form in the femurs, most epiphysis are cartilaginous at birth.
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Calcium in fetal life?
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it mainly comes from mother. Fetus can reabsorb calcium , so we dont lose any. Calcium is supplied to the bone tissue, and very small amounts are released from the bone tissues.
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In the absence of PTHrP what happens?
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blood calcium levels of the fetus falls to the maternal level.
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in the absence of PTH what happens?
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the blood calcium levels in the fetus fall well below the maternal concentration.
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Placental calcium transfer is regulated by?
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PTHrP regulates the calcium transfer from mother accross the placenta into the fetus. (NOT PTH)
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result of maternal hypercalcemia?
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suppresses fetel parathyroids
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result of maternal hypocalcemia?
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fetal hyperparathyroidism (PTH levels stimulated) this leads to bone demineralization to increase calcium levels.
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mineralization of fetus occurs?
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later parts of pregnancy (premature babies) will not receive the right levels of calcium, easy fix, give more calcium
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Peak bone mass in humans is at what age?
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20 and 30 years old.
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Dual-Energy X-ray Absorptiometry (DXA)
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2D measurement, regional BMD is problematic during growth when size and shape change with age.
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Quantitative computed tomography (QCT)
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volumetric measurement, assesses both volume and density of bone in the axial and appendicular skeletons.
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Difference between men and woman with respect to bone size and density.
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Bone density is usually conserved, but males have larger bone size.
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Endochondral bone formation
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cartilage first then bone tissues
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Intramembranous bone formation
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Bone formed directly on the surface.
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Ihh and PTHrP negative feedback loop.
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Cells in the tip of long bone make PTHrP (locally regulated and not seen in blood) This stimulates the cells and proliferation of chondrocytes takes place. Once PTHrP diffuses down and level are less and less, it can no longer inhibit Ihh which stimulates cells to become osteoblasts and proliferate. This is a negative feedback loop.
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primary spongia=
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immature bone tissue, calcified bone, and other bone tissues
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secondary spongia
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the remodeled bone tissues.
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4 zones of the growth plate
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undifferentiated or resting cartilage zone, zone of proliferating cartilage, hypertrophic cell zone (maturation zone), and Zone of provisional cartilage.
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Undifferentiated or resting cartilage cell (zone )
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immediately adjacent to the epiphysis, supplies the developing cartilage cells, injury to this layer results in cessation of growth.
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Zone of proliferating cartilage.
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length is created by active growth of cartilage cells, cartlage cells become aligned into well defined columns, it is at base of these columns that mitotic activity is found.
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hypertrophic cell zone
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chondrocytes become swollen and vacuolated in process of maturation leading to cell death, no active growth in this layer, cells nearer to methpysis begin to undergo changes that ultimately lead to their destruction
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zone of provisional cartilage
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longitudinal bars of cartilage matrix become calcified, calcification of matrix is required for subsequent steps.1. Invasion of cartilage cells by blood vessels from metaphysis, 2.destruction of cartilage cells,
3.formation of bone along remaining walls of calcified cartilage matrix by ostoblasts from diaphysis. |
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Ihh
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stimulates chondrocyte proliferation and growth plate formation, in mutants long bone is not formed will and will have short extremities. mutants also show an absence of PTHrP expression
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Ptc1
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Ihh's membrane -receptor. mutants will have same effect as Ihh mutants. (problems in chondrocyte proliferation and growth plate formation= shorter extremeties if any)
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PTH and PTHrP
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share a receptor, without the receptor, growth plate is smaller and endochondral bone growth is less.
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FGF
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fibroblast growth factor. It is secreted by the cell and it inhibits proliferation of cells in the bone. If you remove it or its receptors, mice will have longer bones. (decreases chondrocyte prolif, Ihh production and terminal differentiation of chondrocytes)
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BMP
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opposite effects of FGF. It incraeses chondrocyte proliferation, Ihh production and terminal chondrocyte differentiation.) Mutation in this will lead to shorter mice tails.
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BMP2
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acts as a disulfide linked homodimer and induces bone and cartilage formation. it is a candidate as a terinoid mediatior. Plays a key rold in osteoblast differentiation.
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Intramembranous bone formation
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Occurs independently of preexisting model Mesenchymal cells receive a signal (yet unknown) that causes them to commit to osteoblastic lineage
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Endochondral bone formation
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Occurs via replacement of a cartilaginous structure
- Cartilage proceeds through a state of hypertrophy and becomes calcified - mediated by chondrocytes - Calcified cartilage is later removed by invasion of osteoclasts and blood vessels |
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woven bone
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produced both by intra and endo bone formation. poorly organized matrix scaffolding with deposit of hydroxyapatite. This is later remodeling by osteoclasts to achieve lamellar bone.
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In order to make an arthritis model, What ligaments do you cut?
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The ACL the anterior cruciate ligament.
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cancellous bone
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also known as trabecular bone or spongy bone is found normally in the ends of long bone. but it less dense, softer and weaker than corticle bone. It is also found in the interior of the vertebrae. It is highly vascular and has a greater surface area tan corticle bone allowing for metabolic activity.
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Corticle bone.
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Strongest of bone tissues, accounts for around 80% of the skeletal weight.
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woven bone :
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contains irregularly organized collagen fibers. Forms very rapidly in areas post fracture. Eventually the body will remove the woven bone and replace it with bone containing less material and higher strength.
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lamellar bone,
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characterized by higher organization of collagen fibers, this is what replaces woven bone. It needs a flat surface to lay down on. Its appearance looks like plywood.
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in children what is thicker?
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the periosteum is thicker because it contains more stem cells.
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patient can heal normally if?
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periosteum is intact because this contains the stem cells needed for regeneration.
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where are mesenchymal cells located in the bone?
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in the periosteum
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What is important to the cortex?
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the thickness and porosity.
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What is important in trabecular bone?
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the thickness, structure (connectivity, number, and seperation.
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Where does diaphyseal drift occur?
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in bone tissues with curvature such as the ribs.
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Metaphyseal cut back occurs in?
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most long bones.
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bone formation occurs at the?(in remodeling)
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perosteal surface
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resorption occurs at? (in remodeling)
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the endosteal surface.
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Are resorption and formation coupled in remodeling?
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no. They occur at the same place but at different times.
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bone remodeling unit=
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the area where osteoclasts break down bone and osteoblasts replace bone in a small area.
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Cacellous bone remodeling occurs?
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on the surface?
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Cortical bone remodeling
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is also called intra cortical remdeing, (osteoclasts "dig" a hole and osteoblasts are recruited and begin laying down new bone tissue.)
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quick summary of the quantum concept of bone remodeling
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In quiescence there are Lining cells (inactive osteoblasts that protect bone surface), next activation occurs and single celled pre-osteoclasts (single nuclear) fuse together to form osteoclasts with numerous nuclei., Next is the reversal phase (not much known), Next Formation occurs by osteoblats laying down osteoid that becomes new bone, And the osteoblasts go into quiesence again and become lining cells.
The Cement is the remaining old bone after remodeling and is a way of determining the depths of resorption cavities. |
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Where do pre osteoclasts come from? (POCs)
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derived from blood cells or the bone marrow.
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What is the bone structural unit?
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the amount of new bone formed during remodeling.
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Remodeling timeline of bone. (activation, Resorption, reversal, formation, mineralization)
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activation 10 days, resorption 21 days, reversal 5 days, formation 90 days, mineralization 200 days.
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main difference between bone modeling and remodeling?
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in modeling R and F occur in different places and in remodeling R and F occur in the same place.
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How many days do you need to form new bone tissue?
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about 300 days.
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What happens to cells when they have finished rebuilding an area of bone?
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The osteoclasts and most of the osteoblasts undergo apoptosis. The remaining osteoblasts become lining cells and osteocytes.
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Osteoclasts come from?
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hemopoietic stem cells (HSCs)
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OSteoblasts come from?
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Mesenchymal stem cells (MSCs)
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Osteoporosis =
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skeletal disorder characterized by compromised bone strength predisposing a persone to an increased risk of fracture.
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Bone strength primary reflects?
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the integration of bone density and bone quality.
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What are the two things to measure bone strength?
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bone quality and density
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how to measure bone density?
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measure calcium
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Explain event: There are more osteoblasts than osteoclasts present and there is still more resorption of bone than formation.
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This is because Bone formation takes much longer than bone resorption.
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A technique for quantifying the remodeling process
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Histomorphometry
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Mineralizing surface=
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(LS/BS) = (dL + 0.5 *sL) / B.Pm *100%
this is how much bone surface is covered with label (osteoblasts) |
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Mineral Appositional Rate (MAR)=
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Ir.L.Wi / 6 days
This is how active the osteoblasts are. |
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Bone formation Rate (BFR) =
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(LS/BS) *MAR* 365 days
how much new bone formation in a year. |
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Ir.L.Wi =
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inter-label width. This is if you trace around the perimeter of the double stripped areas and find the total area.
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Bone formation took place between?
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between 5 and 11 days after loading. (there was no bone formation on days 5 or 11)
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in the loaded ulna study, the green represents what and the red represents what?
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Green is bone formation at day 5. The red means bone formation continued from day 5 to 11.
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How fast can we stimulate bone growth from exercise?
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one micrometer / day
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3 abundant components of the ECM
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proteglycans, collagens, soulble ultiadhesive matrix proteins (fibronectin)
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organic materials im bone are mostly?
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type 1 collagen
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main role of ECM
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scaffolding for bone tissue
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characteristic of collagen !
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triple helix and striations
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role of non collagenous proteins
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development (control of embryogenesis), cellular signalling and nucleators of mineralization
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alkaline phosphatase
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made by osteoblasts, practically a marker for them. it is a potential Ca++ carier.
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osteonectin
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regulates collagen fibrillogenesis, binds to GFs, positive regulation of bone formation.
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osteopontin
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binds to cells, inhibits mineralization in bone soft tissues, inhibits remodeling, Effects the size of crystals
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DMP1
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in vitro regulator of mineralization. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism
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Fibronectin
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binds to cells, collagen function, knock out is lethal before development.
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Fibrillin
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regulates elastic fiber formation
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osteocalcin
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regulates activity of osteoclasts and their precursors, may mark the turning point between bone formation and resorption
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Bone mineral"
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hydroxyapatite, Ca, PO4 and OH (90% is calcium)
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Inhibitor of calcification
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pyrophosphate
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stimulator of mineralization
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collagen fibers
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Crystals form in ?
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the collagen fibril holes, this forms a core (nucleation)
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when crystals connect through collagen fibers, what kind of strength is gained?
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compressional
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Dentin and cementum
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involved in secondary mineralization. MAss of newly formed tissue is due principllay to multiplication
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osteomalacia
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deficient or ompaired mineralization of bone matrix (osteoid)
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rickets
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juvenile counterpart of osteomalacia. impaired mineralization of cartilage matrix and a resultant arrest in formation of primary spongiosa
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causitive factor of osteomalacia
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the failure to maintain a serum calcium-phosphorus level sufficient to promote mineralization of newly formed osteoid.
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What is in high levels in osteomalacia patients
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osteon in high levels, its just not getting mineralized.
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the three classes of stem cells
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totipotent, multipotent and pulripotent
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The fertilized egg is considered what class?
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totipotent, it gives rise to all the different types of cells in the body.
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Pluripotent stem cells:
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cells that can give rise to any type of cell in the body except those needed to develop a fetus.
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Things that increase bone mass:
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BMP, Wnt, PTH, Mechanical load, androgens,
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Things the inhibit bone formation
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SOST, Leptin, Immobilization, ageing.
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Things the enhance bone resorption
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Oestrogen deficency, immobilization, and low Ca.
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Things that inhibit bone resorption
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oestrogen, SERMS Biphosphates, calcitonin, Calicium, vitamin D
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these maintain the osteoblast population and bone mass
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osteoprogenitor cells.
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These synthesize bone matrix
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osteoblasts
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These are organized through the mineralized bone matrix that support bone structure
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osteocytes.
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these protect bone surface.
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lining cells.
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The job of osteoblasts is to..
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make proteins that will form the organic matrix of bone and to control mineralization of bone.
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Osteoblasts have receptors for?
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horomones such as vitamin D, estrogen and parathyroid hormone.
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Factors secreted by osteoblasts.
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RANK-ligand to activate osteoclasts. and PHEX which is a protein that helps to regulate the amount of phosphate excreted by the kidney.
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What are responsible for immediate release of calcium from the bone if blood calcium levels are too low?
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lining cells.
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These have receptors for hormones and factors that initiate bone remodeling
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lining cells
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describe active mature osteoblasts
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that have large nucleus, enlarged golgi, extensive ER. They are highly enriched in alkaline phosphatase and vectorially secrete type 1 collagen specialized bone matrix proteins.
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Osteoprogenitor cells come from?
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mainly Mesencymal stem cells from the bone marrow but they can also come from adult peripheral blood, fetal cord blood, fetal liver, blood, bone marrow, tooth pulp and fat.
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4 types of cells that mesenchymal progenitors can differentiate into
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Myocytes, adipocytes, hypertrophoic chondrocytes, and osteoblasts.
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Two factors in mesenchymal stem cells committing to osteoprogenitor
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Stro1+ and Runx2
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Three factors in osteoprogenitor proliferation
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collagen, TGF and osteopontin
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3 factors in matrix maturation
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alkPhos, BoneSialoP, Collagen
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2 factors in mineralization
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osteocalcin and osteopontin
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whats expressed in mature osteoblasts?
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osteocalcin
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The two cell lineages that are derived from mesenchymal cells and can switch between? and what factors is the switch dependent on
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Adipocytes and osteoblasts can go back and forth, in order to become a osteoblast there needs to be increase Runx2 and PPAR
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3 stages of bone nodule formation i nvitro
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1. Proliferation, 2. ECM development and maturation 3. Mineralization
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What promotes the self renewal of MSCs?
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Sca1
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What happens when you knock out sca1
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stem cell population will decrease and you will have lower bone density.
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BMP important for
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Chondro-osteoprogenitor cell specification
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beta Catenin levels
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control Wnt signalling for commitment to chondrocytes (low Beta catenin) and osteoblasts (high beta catenin)
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Osterix
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important for late stage of bone formation
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Runx2
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required for bone formation, If controlls the differentiation of hypertrophic chondrocytes and osteoblasts.
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LEF/TCF
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transduces the Wnt/B-catenin signal to targe genes in the nucleus
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sclerostin
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A BMT antagonist secreted by osteocytes to inhibit osteoblast differentiation and activity, but suppressed by intermittent PTH
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Runx2 KO effects
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deficient bone formation (long bone, Calcaria) Also delays chondrocyte maturation. "null-mutation of Runx2 mice had a cartilaginous skeleton with complete absence of osteoblasts" Osx is not expressed in these KOs
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Osx KO effects.
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cartilage is normal. Runx2 expresses normally.
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Loss of function mutation in LRP5
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autosomal recessive, causing decrease in osteoblast proliferation, low BMD and susceptibility to fractures
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Leptin
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protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism
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ob/ob mice
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defect in leptin
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db/db mice
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defect in leptin receptor
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Leptin levels after eating?
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they rise.
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Leptin is an?
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inhibitor of bone formation through the sympathetic NS
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ob/ob mice have higher?
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BMD that WT becuase they have lower levels of leptin than usual
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high bone mass phenotype in ob/ob mice is due to ____ and not ____
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it is due to leptin deficiency and not obesity
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leptin does not effect?
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bone resorptions, so it must effect osteoblasts and not osteoclasts.
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probable role for osteocytes
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they direct bone remodeling to accomodate mechanical strain and repair fatigue damage.
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osteocytes communicate with lining cells via?
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gap junctions
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osteocyte role in formation
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they sense mechanical strain and signal lining cels to differentiate, or they recruit osteoblasts, new bone is formed.
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Osteocyte role in resorption
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lack of mechanical strain, signals to lining cells to retract, osteoclasts form at site and activate.
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osteocyte markers
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DMP1 and sclerostin
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Mechanical loading and sclerostin
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mechanincal loading increased bone formation and decreased sclerostin staining.
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