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Neuroectoderm
- Neural crest cells
- Anterior cranial base
- Cranium
- Oromaxillofacial skeleton
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Mesoderm
- Post-cranial skeleton
- Posterior portion of cranial base
- Appendicular skeleton
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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
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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
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Endochondral
- Ossification of cartilaginous precursor
- Long bones
- Cranial base, mandible
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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
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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
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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
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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
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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.
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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
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haversian canal
where neurovascular bundle lies
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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;
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canaliculi
the space where the osteocytic processes are distributed for cell-cell communication
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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
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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
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osteoprogenitor cells
give rise to bone
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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
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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
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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
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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.
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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
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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
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beta-catenin
- pathway downregulates sclerostin,
- so that there are lower amounts of osteocytes > bone loss
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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
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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
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Cbfa1 heterozygous
- have problem that resembles cleidocranial dysplasia
- fontanells open, clavicles missing
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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
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Osterix
- transcription factor that is involved in osteoblastic differentiation
- not as bad, downstream from Cbfa1
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Osteoclast Markers
- Morphology (multinucleation, ruffled border)
- Tartrate resistant acid phosphatase (TRAP)
- Calcitonin receptor
- Vitronectin receptor
- MMP-9, cathepsin K
- Hormone responsiveness
- Bone resorption
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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
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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
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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
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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
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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
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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
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bone stores growth factors
BMP is not present in large amounts, but is very osteogenic
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Bone Regulators
- Stimulators
- IGF-I, IGF-II, TGF-b, BMPs, FGF, PDGF
- Inhibitors
- IL-1, TNF-
- Bimodal regulators
- PTH, 1,25-(OH)2D3, prostaglandins, FGF-2, glucocorticoids
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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
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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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