GDA 5.txt

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  1. Neuroectoderm
    • Neural crest cells
    • Anterior cranial base
    • Cranium
    • Oromaxillofacial skeleton
  2. Mesoderm
    • Post-cranial skeleton
    • Posterior portion of cranial base
    • Appendicular skeleton
  3. Intramembranous
    • Radiating ossification of mesenchymal condensation
    • Flat bones
    • Cranium, maxilla, mandible
    • Loosely organized embryonic connective tissue
    • Pluripotent mesenchyme undergoes condensation that leads to differentiation into various cell types, including bone and cartilage
    • Mesenchymal condensations appear during the 4th week in utero
  4. Intramembranous process
    • osteoblasts are developing with osteoids (bone matrix) around it
    • some cells are trapped inside the bone (the osteocytes)
    • these cells form hydroxyapatite to mineralize the osteoid
    • there are also osteoclasts that become associated with the osteoblasts
    • involved in the bone-remodeling unit
    • mineralization occurs, and bone formation occurs through intermembranous ossification
    • NOTE: there is no cartilage at any point
  5. Endochondral
    • Ossification of cartilaginous precursor
    • Long bones
    • Cranial base, mandible
  6. Epiphysis
  7. Endochondral Process
    • begin with mesenchyme,
    • this mesenchyme condenses
    • transform into cartilage secreting molecules associated with cartilage (like Type II collagen);
    • then, they begin distributing themselves in layers-
    • hypertrophic chondrocytes in the center,
    • proliferating chondrocytes superior to that, and
    • resting chondrocytes superior to that
    • once organized, the cells are invaded by a neurovascular bundle
    • - this is when ossification begins, to replace the cartilage
  8. Elongation at epiphyseal plate
    • - as proliferating chondrocytes proliferate, the two ends of the bone are expanding
    • -in epiphyseal plate there will be a secondary ossification center;
    • at some point in growth, the primary and secondary ossification centers fuse- this is when growth stops
    • -the bone that forms perioosteo bone is made in the same way as intramembranous bone;
    • even in long bones, there is this mechanism of bone formation
  9. Alveolar vs Long Bone
    • bone marrow from alveolar bone diffrentiates more than in long bone;
    • there is also more mineralization of the mandible compared to long bone
    • more osteogenic potential in mandible than in long bone
  10. Cortical/Compact bone
    • A thick and dense layer of calcified tissue on the external part
    • 80-90% of the compact bone volume is calcified
    • Has mainly mechanical and protective function
  11. Trabecular/Cancelous bone
    • A network of thin, calcified trabeculae that houses the bone marrow
    • linear striations oriented in the same way that stress is applied to the bone
    • 15-25% of the trabecular bone volume is calcified
    • 70% of the interface of bone with soft tissues is at the endosteal bone surface
    • Has mainly a metabolic function.
  12. osteon
    • unit of cortical bone
    • fomred by osteoblasts arranged in a circular way;
    • trapped inside are osteocytes;
    • formation is around a central neurovascular bundle;
    • connected with each other to form a cortical structure
    • on outer surface is periosteum
    • - have osteoblastic potential,
    • - can become differentiated into osteoblasts, when bone formation is needed, ex in case of fracture
  13. haversian canal
    where neurovascular bundle lies
  14. osteocytes
    • The most numerous, yet least understood, bone cell
    • Develop from osteoblasts that become encased
    • Undergo some cytological dedifferentiation but remain active.
    • Have fine extensions (canaliculi ) that allow for cell-to-cell communication
    • Synthesize certain matrix molecules, regulate mineral deposition and participate in osteolysis.
    • Function as mechanoreceptors
    • embedded in circumferential arrangement;
  15. canaliculi
    the space where the osteocytic processes are distributed for cell-cell communication
  16. osteoblasts
    • produce and line the matrix
    • when not active, they will form a flat appearance
    • resting cells cover bone surface, and will be activated via mechanical or metabolic stimuli, to form bone
  17. Bone Functions
    • -framework- attachments of muscles->movement
    • -protection- brain, heart, lungs, etc
    • -mineral storage and release- calcium is tightly-regulated ion; when there is low calcium, bone is quickly mobilized to release calcium to bring levels back to normal
    • -houses bone marrow- bone marrow has hemopoetic stem cells that form blood, bone, fat cells, muscles, nerve
  18. osteoprogenitor cells
    give rise to bone
  19. osteoclasts
    • Bone resorbing cells
    • Derived from hematopoietic stem cells of the monocyte/macrophage lineage.
    • Have large cytoplasmic processes.
    • Contain some free ribosomes, many mitochondria and lysosomes and 4 to 20 nuclei.
    • At the bone contact, a ruffled border with dense patches on each side (sealing zone) is observed
    • multiple nuclei
  20. Osteoclast Bone destruction mechanism
    • sealing zone
    • proton secretion to lower the pH
    • dissolving the hydroxyapatite
    • secretion of proteases to dissolve the matrix
    • between regulation of low pH and proteases that can function in low pH > destruction of matrix
  21. sealing zone
    • osteoclasts (like a suction cup), which looks like a ruffled border;
    • they isolate the area of resorption-
    • drop the pH, calcium phosphate is released, hormones are secreted
  22. Osteoblasts
    • Bone forming mononuclear cells
    • Derived from bone marrow stromal cells (mesenchymal stem cells)
    • Found as clusters of cuboidal cells that line periosteal, endosteal and trabecular surfaces.
    • Secrete collagen and protein-polysaccharide complexes of bone matrix.
    • Typical protein synthesizing cells containing rough endoplasmic reticulum, abundance of ribosomes, and a well developed Golgi aparatus.
    • When quiescent, they line bone surface and are referred as lining cells.
  23. sclerostin
    • molecule that activates osteoclasts help fix micro fractures;
    • drugs that block this are in clinical trials right now, to act to increase bone mass
  24. FGF23
    • cytokine that regulates calcium phosphate homeostasis
    • osteocyte cells that are embedded in bone regulate phosphate levels in the blood, via the kidneys;
    • these osteocytes are not just bone cells, but are collectively an endocrine organ, affecting the kidneys, which are far away

    • PHEX and DMP1
    • downregulate FGF-23- all these molecules are produced by the osteocytes
    • -sometimes, osteocytes get “hungry” and chew up part of themselves- autophagy;
    • but they can recreate themselves if needed
    • but if they eat too much of themselves, they die > apoptosis
  25. beta-catenin
    • pathway downregulates sclerostin,
    • so that there are lower amounts of osteocytes > bone loss
  26. Mesenchymal Stem Cells
    • Either can give rise to many lineages, inc fat, cartilage, and muscle
    • But once it decides to become an osteoblast,
    • it first becomes an osteoprogenitor,
    • then an osteoblast- it can become either a lining cell or an osteocyte embedded in bone
  27. Cbfa1
    • essential for osteoblastic differentiation
    • no Cbfa1 no skeletal ossification-> die
    • without osteoblasts, there is no intramembranous or endochondral bone formation
    • -cbfa regulates histone nucleosomal organization around osteoblastic genes;
    • not a transcriptional factor that associates with promotor area of gene, but instead unfolds nucleosomes to make it more accesible to other transcription factors > can affect the transcription of many genes
  28. Cbfa1 heterozygous
    • have problem that resembles cleidocranial dysplasia
    • fontanells open, clavicles missing
  29. Cleidocranial Dysplasia
    • most mutations in DNA binding site
    • missing clavicles;
    • pts have supernumerary teeth that do not erupt, and retention of primary teeth
    • even with extraction of primary teeth, supernumerary teeth do not erupt
  30. Osterix
    • transcription factor that is involved in osteoblastic differentiation
    • not as bad, downstream from Cbfa1
  31. Osteoclast Markers
    • Morphology (multinucleation, ruffled border)
    • Tartrate resistant acid phosphatase (TRAP)
    • Calcitonin receptor
    • Vitronectin receptor
    • MMP-9, cathepsin K
    • Hormone responsiveness
    • Bone resorption
  32. osteopetrosis
    • NO osteoclasts to resorb bone
    • has a wide spectrum of appearances; from normal appearance to very disabilitated
    • here, bones of face are very dense; no bone marrow, expansion of bones; teeth will not be able to erupt- osteoclasts are needed to resorb roots of primary teeth, and in other parts of development
  33. Bone Remodling Unit
    • refers to the fact that the cells we’ve described individually, actually work together
    • -blue is mineralized bone, pink is non-mineralized bone
    • -osteoclasts resorb bone- when they work, they create a rough surface; as bone is resorbed, they secrete proteins and other proteins are already in the matrix; these proteins activate the osteoblasts (cuboidal), which follow the resorption, and deposit osteoids (seen in pinkish blue)- osteoids then begin mineralizing; along osteoids are lining osteoblast cells
  34. RANKL (RANK ligand)
    • usually on inactive osteoblast
    • activates RANK on preosteoclast, which forms multinucleated cells that resorb bone(osteoclast);
    • resorbed bone is then filled in with activated osteoblasts
  35. osteoclasts
    • receptor for parathyroid hormone is in the
    • osteoclasts then secrete RANKL
    • RANKL is an activator of monocytic cells to fuse and make osteoblasts
    • activated monocytes begin fusing together to form multinucleated cell, that can act to resorb bone
  36. Denosumab
    • a monoclonal antibody against RANKL
    • blocks RANKL, not allowing osteoclasts to be activated > more bone
    • alendronate works same way
    • yet some have osteonecrosis of the jaw:
    • all these pts had severe inhibition of osteoclastic activity;
    • osteoclasts are needed for balance of oral environment
  37. Bone Remodling
    • when we run,
    • we create microfractures;
    • osteocytes sense these forces,
    • and send out sclerostin to activate RANKL expression
    • increase osteoclast resorption of bone
    • once bone is removed (includin microfracture), via cytokine signaling, osteoblasts are activated to fill in the bone gap
  38. bone stores growth factors
    BMP is not present in large amounts, but is very osteogenic
  39. Bone Regulators
    • Stimulators
    • Inhibitors
    • IL-1, TNF-
    • Bimodal regulators
    • PTH, 1,25-(OH)2D3, prostaglandins, FGF-2, glucocorticoids
  40. Bone Resorption Regulators
    • Stimulators
    • PTH, IL-1alpha and beta,
    • IL-6, TNF-, IL-11, prostaglandins, IGF-I, M-CSF, RANKL
    • Inhibitors
    • Calcitonin, estrogen, bisphosphonates
    • Bimodal regulators
    • Prostaglandins, TGF-ß, glucocorticoids
  41. Periapical Inflammation
    • many inflammatory cytokines being secreted, in response to bacterial byproducts;
    • these cytokines activate RANKL, which in turn activates osteoclasts > bone resorption
    • lucencies around roots, and increased trabecular density (due to increased osteoblastic activity)-
    • inflammatory cytokines can activate both osteoclastic and osteoblastic activity;
    • area close to apex there is more bone loss, but in other areas, there is more, denser bone
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GDA 5.txt
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