Osteoclasts, blasts, and cytes Flashcards
The cell in bone that is responsible for resorbing (removing) bone. It is a multinucleated cell of hematopoietic origin (macrophage/monocyte lineage)
Osteoclast
The cell in bone that is responsible for forming new bone. It is of mesenchymal origin
Osteoblast
The cell that is embedded in the mineralized bone matrix. It is derived from an osteoblast which has become entrapped in the mineralized bone.
Osteocyte
the process by which mature/damaged bone is removed by osteoclasts and replaced with new bone (i.e. bone is replaced but there is no net gain)
Bone remodeling
the process by which bone size/shape is changed by independent actions of osteoblasts and osteoclasts (e.g. adding new bone without prior resorption or removing bone without replacing it). Can occur during longitudinal growth of bone or in response to an increase in mechanical loading of the bone. Modeling can lead to a net gain or loss of bone.
Bone modeling
A disease of impaired mineralization due to mutations in the gene for alkaline phosphatase (TNSALP) that results in reduced amounts or no alkaline phosphatase.
Hypophosphatasia
A disease due to mutations in the RUNX2 gene. Patients have partly or completely missing clavicles and supernumerary teeth.
Cleidocranial Dysplasia
(A.k.a. “Stone man syndrome”) – a disease in which there is ectopic mineralization in non-skeletal soft tissues, leading to sheets, plates of bones forming across the ribs, joints, etc. This restricts the movement of the skeleton. The disease is due to mutations in the BMP type I receptor (ACVR1) that make it hyperresponsive to BMP ligands.
Fibrodysplasia Ossificans Progressiva
These are diseases due to mutations in the gene for sclerostin (SOST). Reduced amounts of sclerostin lead to increased bone mass.
Sclerostosis and Van Buchem’s disease
a disease of impaired osteoclast function that leads to bones that are abnormally dense but brittle and prone to fracture. The disorder is caused by mutations in genes important for osteoclast resorption.
Osteopetrosis
a disease of low bone mass that occurs due to the inability of bone formation to keep up with bone resorption (i.e. not all the bone that is resorbed is replaced, so there is a net loss in bone mass). Usually seen in post-menopausal women and/or the aged population (male and female).
Osteoporosis
a drug that inhibits bone resorption
Anti-resorptive agent
a drug that stimulates bone formation
Bone anabolic agent
a fancy word for bone that forms in the wrong place
Heterotopic bone formation
a fancy word for a cell that can sense mechanical (deformation) input
Mechanosensor
a fancy word for bone that is dead and does not have viable osteocytes
Osteonecrotic bone
Osteoblasts, chondrocytes, myoblasts, and adipocytes differentiate from a __________ precursor
common mesenchymal precursor
_____ produces large amounts of ECM proteins (mainly collagen type 1) which then mineralizes (osteoid); the lifespa is weeks
osteoblasts
RUNX2 and Osterix seen in osteoblasts are ____
transcription factors
Alkaline phosphatase seen in osteoblasts are
enzymes
Type 1 collagen, osteopontin, osteocalcin, and bone sialoprotein seen in osteoblasts are
ECM proteins
___ is a master TF for bone; essential bone and tooth development; heterozygous mutation of _____ in humans results in cleidocranial dysplasia (CCD)
RUNX2
_____ is autosomal dominant mutation characterized by haploinsufficiency of RUNX2; clavicles partly or completely missing, supernumerary teeth, prognathic mandible due to hypoplasia of maxilla
Cleidocranial dysplasia
____ is a key transcription factor for osteoblast differentiation that is downstream of RUNX2; critical for osteoblast differentiation; controls expression of osteoblast genes (type 1 collagen, osteocalcin, and osteopontin)
Osterix
___ and ___ are key signaling pathways that regulate osteoblast differentiation
BMPs and WNT / Beta-catenin
____ is originally purified from bone extracts that induce bone formation when implanted in muscle; required for skeletal development / maintenance of adult bone homeostasis, promote differentiation from early osteoprogenitor cells, important in fracture healing; mutations result in inherited skeletal disorders in humans
Bone morphogenetic proteins (BMP)
___ is a heterotopic bone formation resulting in ribbons, sheets, or plates of bone in extraskeletal sites; bone forms in response to tissue trauma; mutations in BMP type 1 receptor that causes mild constitutive activation
Fibrodysplasia ossificans progressiva (FOP)
____ signaling pathway is important in determining bone mass
WNT B-catenin
High and Low Bone mass phenotypes are due to mutations in _____
LRP5
Enzyme highly expressed in osteoblasts/odontoblasts, hydrolyzes pyrophosphate (natural inhibitor of mineralized, thereby increasing local phosphate concentration) which promotes mineralization; mutations are associated with hypophosphatasia
alkaline phosphatase
rare heritable rickets/osteomalacia; mutations in human alkaline phosphatase gene (TNSLAP); characterized by reduced activity of alkaline phosphatase, impaired mineralization of skeleton, leg bowing, rachitic rosary, early tooth loss, waddling gait, muscle weakness, seizures; vary severity from perinatal lethal to adult onset or mild forms only affecting dentition (dependent on degree of loss of function of alkaline phosphatase)
hypophosphatasia
terminally differentiated osteoblasts embedded in bone matrix that make up over 90% of all bone cells with long dendritic processes; active cell type; lifespan is decades
osteocytes
Mef2c in osteocytes is a _____
transcription factor
E11/gp38/podoplanin, Dentin matrix protein-1 (DMP1), matrix extracellular phosphoglycoprotein (MEPE), and phosphate regulating endopeptidase homolog, X- linked in osteocytes are ____
early osteocyte markers
Sclerostin in osteocytes is a _____
late osteocyte marker
Mechanosensors that control responses of bone cells to mechanical loading, control of bone resorption and bone formation regulating osteoclasts and blasts, regulate mineralization, and regulators of mineral homeostasis are potential functions of _____
osteocytes
____ is highly expressed in mature osteocytes, cementocytes, and odontoblasts, negative regulator of bone formation that antagonizes Wnt/B catenin signaling, thought to act as brake to limit bone formation
Sclerostin
Deletion or mutation of SOST (sclerostin) results in _______ characterized by increased bone mass especially obvious in craniofacial skeleton and antibodies to to sclerostin
Sclerosteosis (Van Buren’s disease)
____ establishes the osteocytes as a key target cell for development of new treatments for diseases of bone loss and overgrowth
sclerostin
____ express several genes important in phosphate homeostasis including FGF23, DMP1, and PHEX
Osteocytes
____ are derived from same precursors as macrophages, when mature are multinucleated, express proteases for removing ECM proteins, express proteins that act as proton pumps to generate H+ that reduce pH to dissolve material; have specialized ruffled border to increase surface area in resorption compartment; lifespan is short (days)
osteoclasts
____ is responsible for bone resorption during normal bone growth and remodeling, removal of alveolar bone during tooth eruption, resorption of tooth roots of primary teeth, removal of alveolar bone during orthodontic tooth movement, and bone loss in pathological condition
osteoclasts
What is the master transcription factor of osteoclasts?
NFATc1
____ and _____ are downstream of NFATc1 and important in osteoclast formation
C-Fos and NFkB
___ promotes proliferation and survival of osteoclast precursors
M-CSF
_____ ( member of TNF superfamily) is required for osteoclast fusion and differentiation
RANKL
___ is a natural inhibitor of RANKL
OPG
_____ needs to differentiate/fuse, adhere to the bone surface, produce acid to dissolve material, produce proteases to breakdown ECM protein, and respond to factors that regulate osteoclast survival/activity
osteoclast
Osteoclasts attach via _____ integrins to form sealed zone
avB3
In a mature resorbing osteoclast, ____ generates protons
Carbonic anhydrase 2
In a mature resorbing osteoclast, Vacuolar type H+ ATPase pumps protons into _____ that creates acid pH
resorption lacuna
In a mature resorbing osteoclast, ____ and ___ exchanger on basolateral surface removes excess bicarbonate
Cl and HCO3
In a mature resorbing osteoclast, ___ maintains neutrality
Chloride channel
In a mature resorbing osteoclast, ______ also released into resorption lacuna to digest matrix proteins
Cathepsin K
___ can be due to failure in osteoclast formation or function; bones are abnormally dense and prone to fracture, failed osteoclastic resorption affects bone growth remodeling and tooth eruption; can be accompanied by scoliosis, nerve compression in head and face, impaired marrow function, enlarged liver or spleen, dental abnormalities, short stature, slow growth, and recurrent infetions
Osteopetrosis
a patient with Bone mineral density of > 2.5 standard deviations below average for a healthy young female or male.
Osteoporosis
- Amino bisphosphonates
- Hormone replacement therapy
- Selective Estrogen Receptor Modulators (SERMs)
Anti-resorptives that are current treatments for osteoporosis.
(1) current or previous treatment with a bisphosphonate
(2) exposed, necrotic bone in the maxillofacial region that has been present for at least 8 weeks
(3) no history of radiation therapy to the jaws
thought to be caused by suppression
of bone turnover due to Bisphosphinate inhibition of osteoclast activity
Bisphosphonate Associated Osteonecrosis of the Jaw (BONJ)
