11/8: Biochemistry of Bone Formation Flashcards
What are the 4 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
What type of bone formation is indirect?
Endochondral
What bone formation is when mesenchyme forms cartilage template first,
which is later replaced by bone?
Endochondral
What bone formation occurs in most bones and during fracture repair?
Endochondral
What type of bone formation is direct?
Intramembranous
What bone formation occurs with the transformation of mesenchymal cells to
osteoblasts (no cartilage intermediate)?
Intramembranous
Where does intramembranous formation occur and contribute to?
Cranial vault, some facial bones; contribute to fracture repair
When does growth plate fusion occur?
age 14-20 in humans
What is produced by hypertrophic
chondrocytes attracts blood vessels to
invade?
Vascular endothelial
growth factor (VEGF)
When do secondary
ossification center
appears?
Time of birth
What do mesenchymal cells condense to produce?
Osteoblasts
What do osteblasts deposit?
Osteoid (unmineralized) bone matrix
What do some osteoblasts trapped in bone matrix become?
Osteocytes
What is the first type of bone produced developmentally?
Woven bone (aka primary bone)
When does woven bone get produced?
When osteoblasts need to form bone rapidly:
- embryonic development
- fracture healing
- disease states (e.g. Paget’s Disease)
What is immature woven bone remodeled and replaced with?
Lamellar bone (aka secondary bone)
Describe the structure of woven bone
- Disorganized structure
- Randomly oriented collagen
fibrils (lower birefringence
w/ polarized light) - Increased cell density
- Reduced mineral content
Describe the structure of lamellar bone
- Highly organized
- Bone lamellae concentrically
arranged around central canal
(Haversian canal) containing
blood vessels, nerves. - Parallel oriented collagen fibrils
(more birefringence w/
polarized light) - Mechanically stronger
What is secondary bone further classified into?
Compact (cortical) Bone and Cancellous
(trabecular/spongy) Bone
What is compact bone?
Cortical/haversion
What is cancellous bone?
Spongy/trabecular
What are the 3 main types of bone cells?
Osteoclasts
Osteoblasts
Osteocytes
What do osteoblasts, chondrocytes, myoblasts and adipocytes differentiate from?
A common mesenchymal precursor
What are osteoblasts derived from?
Mesenchymal stem cells
What do osteoblasts produce?
Large amounts of ECM proteins (collagen type I) = osteoid, which then mineralize
What is the lifespan of osteoblasts?
weeks
What are osteoblast marker proteins that are transcription factors?
Runx2
Osterix
What are osteoblast marker proteins that are enzymes?
Alkaline phosphatase
What are osteoblast marker proteins that are ECM proteins?
- Type I collagen
- Osteopontin
- Osteocalcin
- Bone sialoprotein (BSP)
What are the key transcriptional regulators of osteoblast differentiation?
Proliferation
Maturation
Terminal differentiation
What is the master transcription factor for bone?
Runx2
What is Runx2 essential for?
Bone and tooth development
What does a heterozygous mutation in Runx2 result in?
Cleidocranial dysplasia (CCD)
What transcription factor does Runx2 induce?
Osterix
What is osterix critical for?
Osteoblast differentiation
What does osterix control expression of?
Osteoblast genes:
Type 1 collagen
Osteocalcin
Osteopontin
What does a human mutation in SP7 (osterix) associate with?
Osteogenesis imperfecta type XII
What are two key signaling pathways that regulate osteoblast differentiation?
BMPs and WNT/B-catenin signaling pathway
What are originally purified from bone extracts that induce bone
formation when implanted in muscle?
BMPs
What are BMPs required for?
skeletal development/maintenance of adult bone
homeostasis
What promotes differentiation from early osteoprogenitor cells?
BMPs
What does Naturally occurring mutations in BMPs or their receptors result
in?
Inherited skeletal disorders in humans
What is FOP (fibrodysplasia ossificans progressiva)?
Heterotopic bone formation (bone forming in soft tissues)
What is FOP a result from?
Mutation in BMP type 1 receptor
What is Wnt-β-catenin signaling pathway
important in determining?
Bone mass
What does activating mutations of Lrp5 lead
to?
High bone mass in humans and vise versa
What is the first phase of mineralization initaited by?
Matrix vesicle
What does the second phase of mineralization involve?
Propagation of mineralization on collagen fibers
What are the stages in Matrix vesicle (MV) mediated mineralization?
Phosphate compounds -> pyrophosphate (PPi) -> monophosphate ion Pi (aka PO43-)
What enzyme highly expressed in osteoblasts/
odontoblasts?
Alkaline phosphotases
What does alkaline phosphotases hydrolyze?
Pyrophosphate
What is a natural inhibitor of mineralization,
thereby increasing local phosphate
concentration – promotes mineralization?
Pyrophosphate
What is mutations in alkaline phosphatase gene (TNSALP) associated with?
Hypophosphatasia
Mutations in what is associated with syndrome
of spontaneous infantile
artieral and periarticular
calcification – similar
phenotype in KO mice?
ENPP1
Mutations in what are associated
with hypophosphatasia
(impaired
mineralization)?
TNSALP (TNAP)
What in knockout mice doesn’t show abnormal skeletal development?
Anx5
Deletion of what in mice may cause impaired
mineralization, including
in MV?
PHOSPHO1
What are terminally differentiated osteoblasts?
Osteocytes
What is the lifespan of osteocytes?
Decades
What cells are embedded in the bone matrix?
Osteocytes
What are transcription factors in osteocytes?
Mef2c
What are early osteocyte markers?
- E11/gp38/podoplanin
- Dentin matrix protein-1 (DMP1)
- Matrix extracellular phosphoglycoprotein
(MEPE) - Phosphate regulating endopeptidase
homolog, X-Linked (PHEX)
What are late osteocyte markers?
Sclerostin (SOST)
What are functions of osteocytes?
- Mechanosensors (control responses of bone cells
to mechanical loading) - Control bone resorption and bone formation (by
regulating osteoclast and osteoblast activity) - Regulate mineralization
- Regulators of mineral homeostasis-both calcium
and phosphorus
What is highly expressed in mature osteocytes, cementocytes, odontoblasts?
Sclerostin
What is a Negative regulator of bone
formation?
Sclerostin
What does Deletion or mutation of SOST gene results in?
Sclerosteosis or van buchem’s disease
What is a key target
cell for development of new treatments for
diseases of bone loss and overgrowth?
Osteocyte
Osteocytes express several genes important in
phosphate homeostasis:
FGF23 (fibroblast growth factor-23)
DMP1 (dentin matrix protein-1)
PHEX (phosphate regulating endopeptidase homolog, x-linked)
What play an endocrine role in regulation of
phosphate homeostasis?
Osteocytes
