Biochemistry of Bone Formation Flashcards
What are the two types of bone formation?
endochondral and intramembranous
What are the four phases of skeletal development?
- migration of preskeletal cells to sites of future skeletogenesis
- interaction of these cells with epithelial cells
- interaction leads to mesenchymal condensation
- followed by differentiation to chondroblasts or osteoblasts
Characteristics of endochondral bone formation:
-indirect
-mesenchyme forms cartilage template first, which is later replaced by bone
Where does endochondral bone formation occur?
in most bones of the skeleton
-bones that bear weight and have joints
What type of bone formation occurs during fracture repair?
endochondral bone formation
Characteristics of intramembranous bone formation:
-direct
-transformation of mesenchyme cells to osteoblasts (no cartilage intermediate)
Where does intramembranous bone formation occur?
cranial vault, some facial bones, parts of the mandible and clavicle
What attracts blood vessels to invade during endochondral bone formation?
chondrocytes release VEGF
When does growth plate fusion usually occur?
around age 14-20 in humans
When do secondary ossification centers appear?
around the time of birth
What do osteocytes made by mesenchymal cells do?
deposit osteoid (unmineralized) bone matrix
What happens to the osteoid matrix?
calcifies/osteoblasts become arranged along calcified region of thematrix
What do the osteoblasts that get trapped in the bone matrix become?
osteocytes
What is the first type of bone produced?
woven bone (primary bone)
When is woven bone made?
when osteoblasts need to form bone rapidly
-embryonic development
-fracture healing
-disease states
What replaces woven bone?
lamellar bone
Characteristics of woven bone:
-disorganized
-randomly oriented collagen fibrils
-increases cell density
-reduced mineral content
Characteristics of lamellar bone:
-highly organized
-concentrically arranged around a central canal containing blood vessels and nerves
-parallel oriented collagen fibers
-mechanically stronger
What are the two types of secondary bone?
compact and cancellous bone
What is compact bone?
cortical/haversian
What is cancellous bone?
spongy/trabecular
What are the three types of bone cells?
-osteoclasts
-osteoblasts
-osteocytes
What are osteoblasts derived from?
mesenchymal stem cells
What do osteoblasts look like?
plump, cuboidal cells located on bone forming surfaces
What do osteoblasts make a lot of?
extracellular matrix proteins (collagen type I)
What is the lifespan of osteoblasts?
weeks
What are transcription factors for osteoblasts?
Runx2
Osterix
What enzymes are associated with osteoblasts?
alkaline phosphatase
What extracellular matrix proteins are associated with osteoblasts?
-type I collagen
-osteopontin
-osteocalcin
-bone sialoprotien (BSP)
What does a heterozygous mutation of RUNX2 case?
cleidocranial dysplasia
Symptoms of cleidocranial dysplasia:
-autosomal dominant
-haploinsufficiency of RUNX2
-delayed ossification of midline structures of bone
-clavicles partly or completely missing
-late closing of fontanelle
-supernumerary teeth
-protruding mandible
Osterix controls expression of waht osteoblast genes?
-type I collagen
-osteocalcin
-osteoporin
What does human mutation in osterix associated with?
osteogenesis imperfecta type XII
What are BMPs associated with?
-skeletal development
-differentiation from early osteoprogenitors
-in fracture healing
What is fibrodysplasia ossificans progressiva?
causes bone to form in the wrong places
-extra skeletal sites
-bones form in response to tissue
-mutations in BMP type I receptor
What is being researched as a treatment for fibrodysplasia ossificans progressiva?
antibodies against activin A and kinase inhibitors selective for mutation receptors
Activating mutations of Lrp5 cause:
high bone mass
inactivating mutations in Lrp5 cause:
low bone mass
What initiates the first phase of mineralization?
matrix vesicle mediated mechanism
What does the second phase of mineralization involve?
propagation of mineralization on collagen fibers
What is the matrix vesicle?
extracellular membrane bound vesicles produced by osteoblasts
30-1000nm in diameter
what is inside the matrix vesicle membrane?
calcium and phosphate transporters and enzymes that generate phosphate
What are the stages of MV mineralization?
-amorphous mineral on MV membrane
-HA crystal growth inside MV
-mineral crystals disrupt MV membrane
What is alkaline phosphatase?
enzyme highly expressed in osteoblasts/odontoblasts
What does alkaline phosphatase do?
hydrolyze pyrophosphate increasing phosphate concentration
-promote mineralization
Mutations in alkaline phosphatase genes are associated with?
hypophosphatasia
What is hypophosphatasia?
rare heritable rickets/osteomalacia
-reduced activity of alkaline phosphatase
-impair mineralization
-varying severity
TNSALP mutations associated with:
hypophophatasia
PHOSPHO1 deletion causes:
impaired mineralization
ENPP1 mutations associated with:
syndrome of spontaneous infantile arterial and periarticular calcification
Characteristics of osteocytes:
-terminally differentiated osteoblasts
-embedded in bone matrix
-90% of all bone cell s
-long dendritic processes
-lifespan of decades
Transcription factors associated with osteocytes:
Mef2c
Early osteocyte markers:
-E11/gp38/podoplanin
-DMP1
-MEPE
-PHEX
Last osteocyte marker:
SOST
Potential functions of osteocytes:
-mechanosensors
-control bone resorption and bone formation
-regulate mineralization
-regulate mineral homeostasis
(calcium and phosphorus)
What is sclerostin (SOST)
negative regulator of bone formation
-antagonize Wnt/beta-catenin signaling
Where is SOST expressed?
mature osteocytes, cementocytes, and odontoblasts
Deletion of SOST in humans causes:
Sclereosteosis/ Van Buchems
What are side effects of sclerosteosis/Van Buchems?
increase bone mass, especially obvious in craniofacial skeleton
How do osteocytes play an endocrine role?
regulate phosphate homeostasis
