Oral tissues; osteoblasts, osteocytes, and osteoclasts

bisphosphonate and BONJ

-2-3% in cancer pop. on BPs -affects maxilla and mandible

Signaling pathways that regulate osteoblast differentiation

-BMPs; bone morphogenetic proteins (only during proliferation) -WNT/B-catenin; signaling pathway (during all stages of osteoblast differentiation)

Characteristics of osteoblasts

-Derived from mesenchymal stem cells -Plump, cuboidal cells located on bone forming surfaces -Produce large amounts of extracellular matrix proteins (esp. collagen 1) = osteoid -lifespan in weeks

What must an osteoclast do?

-Differentiate/diffuse -adhere to bone surface -produce acid to dissolve material -produce proteases to breakdown extracellular matrix components -respond to factors regulating osteoclast survival/activity

Firbodysplasia Ossificans Progressiva (FOP)

-Heterotropic bone formation (bone in soft tissues) -ribbons, sheets, or plates of bones -bones form in response to tissue trauma -mutations in BMP type 1 receptor -mutation makes receptor hypersensitive to BMP2

osteocyte marker proteins (gene signature)

-Mef2c (transcription factor) -E11/gp38/podoplanin, DMP1, MEPE, PHEX (early osteocyte markers -Sclerostin (SOST) (late osteocyte marker)

Three main bone cell types

-Osteoclasts, osteoblasts, and osteocytes

Growth factor regulation of osteoclast formation/function

-RANKL (required for osteoclast fusion and diff.) and M-CSF(promotes proliferation/survival) both essential for OCL differentiation -RANKL inhibited by OPG

Key transcriptional regulators of osteoblast differentiation

-Runx2 (beta-catenin), Osterix (beta-catenin), and beta-catenin

Mutations of Sclerostin

-SOST gene -deletion/mutation; Sclerosteosis or Van Buchem's disease -increased bone mass, esp. in craniofacial skeleton -antibodies to scleostin; in preclinical/clinical trials as anabolic treatment for osteoporosis

mutations associated with osteoporosis

-TCIRG1 -CIC7 -Cathepsin K

Gene signature of osteoblasts (marker proteins)

-Transcription factors; Runx2, Osterix -Enzymes; Alkaline phosphatase -ECM proteins; Type 1 collagen, osteonectin, osteopontin, osteocalcin, BSP

LRP5 mutations and high bone mass

-Wnt-beta signaling pathway important in determining bone mass -activating mutations in LRP5 lead to higher bone mass -inactivating LRP5 mutation leads to lower bone mass

types of osteopetrosis

-autosomal dominant; adult/benign type (few symptoms) -autosomal recessive; infantile/malignant type (fatal if untreated)

function of osteoclasts

-bone resorbing cells -responsible for; -bone resorption during normal growth and remodeling -removal of alveolar bone during tooth eruption -resoption of tooth roots of primary teeth -removal of alveolar bone during orthodontic tooth movement -bone loss in pathological conditions

how does bone repair damage?

-by continuously removing bone via osteoclasts and being rebuilt by osteoblasts (AKA Bone Remodeling)

Osteoclast characteristics

-derived from same precursors as macrophages (hematopoietic lineage) -mature osteoclasts= multinucleated -express proteases for removing ECM proteins -express proteins that act as proton pumps to generate H+ions (reduces pH to dissolve material) -lifespan; short, in days

Alkaline Phosphatase

-enzyme highly expressed in osteoblasts and odontoblasts -PPI, natural inhibitor of mineralization, thereby increases local phosphate concentration; promotes mineralization -mutations in alkaline phosphatase gene (TNSALP) associated with hypophosphatasia

Sclerostin

-gene name; SOST -mature osteocyte marker -highly expressed in mature osteocytes, cementocytes, and odontoblasts -negative regulator of bone formation; antagonizes Wnt/beta catenin signaling pathway -thought to act as brake to limit bone formation -mice with sclerostin gain of function mutation had low bone mass

osteoclastic resorption

-important for normal bone growth -growth occurs at epiphyseal plate -modeling; must occur to maintain bone shape

BMPs role in osteoblasts

-induce bone formation when placed in muscle -required for dev. of adult bone -promote differentiation from early osteoprogenitory cells -important in fracture healing -naturally occuring mutations lead to inherited skeletal disordres

Osterix

-key transcriptional factor for osteoblasts -downstream of Runx2, which it is introduced by -controls expression of osteoblast genes; Type 1 collagen, osteocalcin, osteonectin, osteopontin -human mutations also associated with OI

Osteoblast differentiation

-like chondrocytes, myoblasts, and adipocytes, osteoblasts differenciate from common mesenchymal precursor

Osteoporosis

-loss of bone mass, asssociated with aging or menopause -defined as patient with BMD > 2.5 standard deviations below average -more likely to fracture -1 in 3 women, 1 in 5 men over 50 -

transcriptional regulators of osteoclast formation/function

-master factor; NFATc1 -C-fos and NfkB are downstream and also important

Runx2

-master transcription factor in bone -also important in osteoblast differentiation (during maturation) -essential for bone and tooth dev. -mice w/o fail to mineralize skeleton -heterozygous mutation in RUNx2 in humans leads to Cleidocranial Dysplasia (CCD)

function of osteocytes

-mechanosensors (control responses of bone cells to mechanical loading) -control bone resoption and bone formation (by regulating osteoclast and osteoblast activity) -regulate mineralization -reguators of mineral homeostasis- both calcium and phosphorus

treatments for HPP

-new recently approved treatment; bone-targeted enxyme replacement therapy; TNSALP recombinant enzyme with a 10 amino acid bone targeting peptide sequence

Impaired osteoclast function

-often leads to osteopetrosis -failure in osteoclast formation or failure in function -bones abnormally dense and prone to fracture -failed resorption affects bone growth -can be accompanied by scoliosis

mature reorbing osteoclast

-osteoclasts attach via alphaVB3 integrins to form sealed zone -CAII generates protons -Cl- and HCO3- remove excess bicarbonate -chloride channel maintains charge neutrality

osteocytes as regulators of phosphate homeostasis

-osteocytes express several genes important in phosphate homoestasis; -PFP23; fibroblast growth factor -DMP1; dentin metrix protein-1 -PHEX; x-linked -MEPE

osteocyte differentiation

-preosteoblast --> osteoblast --> preosteocyte --> osteoid osteocyte --> mineralizing osteocyte --> mature osteocyte

Hypophosphatasia (HPP)

-rare heritable Rickets/Osteomalacia -more than 289 mutations in TNSALP gene -reduces activity of alkaline phosphatase -impaired mineralization of skeleton/dentition, leg bowing, rachitic rosary, early tooth loss, waddling gait, muscle weakness, seizures -varying severity -expert dental care is important

ruffled border

-specialized part of osteoclasts -raises surface area for reabsorption

Cleidocranial Dysplasia

-supernumerary teeth and abnormal shoulder mobility -autosomal dominant -delayed ossification of midline structures of body (esp. membranous bone) -clavicles gone or partially gone -late closing of fontanelle -protruding mandible

characteristics of osteocytes

-terminally differenciated osteoblasts -embedded in bone matrix -make up over 90% of bone cells -long dendritic processes -previously thought to be "quiescent cells" -now known to be an active cell type with key functions in bone -no "master" transcriptional gene indentified yet -lifespan of decades

functions of bisphosphonates

-used to treat osteoporosis (given orally) -IV used to treat myeloma/bone metastatic cancers -high affinity for hydroxyappatite