GDA 5.txt

• Neural crest cells
• Anterior cranial base
• Cranium
• Oromaxillofacial skeleton

• Post-cranial skeleton
• Posterior portion of cranial base
• Appendicular skeleton

• 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

• 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

• Ossification of cartilaginous precursor
• Long bones
• Cranial base, mandible

• 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

• - 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

• 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

• 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

• 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.

• 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

where neurovascular bundle lies

• 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;

the space where the osteocytic processes are distributed for cell-cell communication

• 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

• -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

give rise to bone

• 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

• 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

• 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

• 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.

• molecule that activates osteoclasts help fix micro fractures;
• drugs that block this are in clinical trials right now, to act to increase bone mass

• 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

• pathway downregulates sclerostin,
• so that there are lower amounts of osteocytes > bone loss

• 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

• 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

• have problem that resembles cleidocranial dysplasia
• fontanells open, clavicles missing

• 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

• transcription factor that is involved in osteoblastic differentiation
• not as bad, downstream from Cbfa1

• Morphology (multinucleation, ruffled border)
• Tartrate resistant acid phosphatase (TRAP)
• Calcitonin receptor
• Vitronectin receptor
• MMP-9, cathepsin K
• Hormone responsiveness
• Bone resorption

• 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

• 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

• 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

• 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

• 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

• 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

BMP is not present in large amounts, but is very osteogenic

• 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

• 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

• 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