Lecture 43: Biochemistry of Bone Formation Flashcards
what are the 4 phases of skeletal development
-migration
- interaction with epithelial cells
-interaction leads to mesenchymal condensation
-followed by differentiation to chondroblasts or osteoblasts
what are the types of bone formation
endochondral bone formation and intramembranous bone formation
describe what happens in 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 especially bones that bear weight and have joints
- fracture repair sites
describe intramembranous bone formation
direct transformation of mesenchymal cells to osteoblasts
where does intramembranous bone formation occur
- cranial vault, some facial bones, parts of mandible and clavicle
-fracture repair sites
how do blood vessels invade the forming bone
VEGF produced by hypertrophic chondrocytes
when does the secondary ossification center appear
around the time of birth
what is the mechanism by which intramembranous ossification works
-mesenchymal cells condense to produce osteoblasts which deposit osteoid
- osteoid matrix calcifies/osteoblasts become arranged along calcified region of the matrix
- some osteoblasts trapped in bone matrix become osteocytes
what is the first type of bone produced developmentally
woven bone
when is woven bone produced
when osteoblasts need to form bone rapidly such as in embryonic development, fracture healing, and disease states
what is immature woven bone remodeled and replaced with
lamellar bone
describe woven bone
-disorganized structure
-randomly oriented collagen fibrils
-increased cell density
-reduced mineral content
describe lamellar bone
-highly organized
-bone lamellae concentrically arranged around central canal containing blood vessels and nerves
-parallel oriented collagen fibrils
-mechanically stronger
what is lamellar bone further classified into
compact (cortical) bone and cancellous (spongy) bone
what is another name for woven bone? lamellar bone?
woven - primary
lamellar - secondary
what are they 3 types of bone cells
osteoclasts, osteoblasts, osteocytes
what do osteoblasts, chondrocytes, myoblasts and adipocytes all differentiate from
a common mesenchymal progenitor
where are osteoblasts located
cuboidal cells of bone forming surfaces
what do osteoblasts produce
large amounts of ECM proteins (especially type 1 collagen) called osteoid which then mineralized
what is the lifespan of osteoblasts
weeks
what are transcription factors for osteoblasts
RUNX2 and Osterix
what are the ECM proteins that make up osteoblasts
type 1 collagen, osteopontin, osteocalcin, bone sialoprotein (BSP)
what pathway do RUNX2 and Osterix work in
beta catenin
what is RUNX2 essential for
bone and tooth development
what does a heterozygous mutation of RUNX2 result in
cleidocranial dysplasia
what are the symptoms of cleidocranial dysplasia
-autosomal dominant
- delayed ossification of midline structures
- clavicles partly or completely missing
-late closing of fontanelle
- supernumerary teeth
-prognathic mandible due to hypoplasia of maxilla
what transcription factor does RUNX2 induce
Osterix
what osteoblast genes does osterix control expression of
-type 1 collagen
-osteocalcin
-osteopontin
what are mutations in osterix associated with
osteogenesis imperfecta type 7
what are some key signaling pathways that regulate osteoblast differentiation
BMPs, WNT/Beta catenin,
what are BMPs
originally purified from bone extracts that induce bone formation when implanted in muscle
what are BMPs required for
skeletal development/maintenance of adult bone homeostasis
what do BMPs do
-promote differentiation from early osteoprogenitor cells
-fracture healing
what do mutations in BMPs lead to
skeletal defects/disorders
what is fibrodysplasia ossificans progressiva (FOP)
heterotrophic bone formation (bone forming in soft tissues)
what happens in FOP
-ribbons, sheets, plates of bone in extra skeletal sites - fuses joints, ribs
- bone forms in response to tissue trauma
what mutation is involved in FOP
BMP type 1 receptor
what does a mutation in the BMP type 1 receptor in FOP do
causes mild constitutive activation and overactivation with BMP ligand binding
-acquired responsiveness to activin A
what is the Wnt/ beta catenin pathway important in
determining bone mass
what do activating mutations in Lrp5 lead to
high bone mass in humans
what do inactivation mutations in Lrp5 lead to
low bone mass
what is the first phase of mineralization initiated by
matrix vesicle
what does the second phase of mineralization involve
propagation of mineralization on collagen fibers
what are matrix vesicles
extracellular membrane bound vesicles produced by osteoblasts
what do matrix vesicles contain
transporters and enzymes involved with the generation of phosphate and uptake of calcium and phosphate into the vesicle to reach high enough concentrations to initiate mineralization
where is alkaline phosphatase highly expressed
in osteoblasts and odontoblasts
what does alkaline phosphatase do
hydrolyzes pyrophosphate which is a natural inhibitor of mineralization- thereby increasing local phosphate concentration, promoting mineralization
what are mutations in the alkaline phosphatase gene associated with
hypophosphatasia
what is hypophosphatasia
rare heritable rickets/osteomalacia
what is hypophosphatasia caused by
mutation in human alkaline phosphatase gene -TNSALP
what is HPP characterized by
impaired mineralization of skeleton/dentition, leg bowing, rachitic rosary, early tooth loss, waddling gait, muscle weakness, seizures
what are ENPP1 mutations associated with
syndrome of spontaneous infantile arterial and periarticular calcification
a mutation in what components will affect mineralization
ENPP1, TNSALP, Anx5, PHOSPHO1
what are osteocytes
terminally differentiated osteoblasts embedded in bone matrix
what percentage of bone cells are osteocytes
over 90%
what is the lifespan of osteocytes
decades
are osteocytes quiescent cells
no they are active cells with key functions in bone
what is the transcription factor of osteocytes
Mef2c
what are the early osteocyte markers
-E11/gp38/podoplanin
-dentin matrix protein-1 (DMP1)
- matrix extracellular phosphoglycoprotein (MEPE)
- phosphate regulating endopeptidase homolog, X linked (PHEX)
what is the late osteocyte marker
sclerostin (SOST)
what are some potential functions of osteocytes
-mechanosensors
-control bone resorption and bone formation
-regulate mineralization
-regulators of mineral homeostasis- both calcium and phosphorus
-regulate activity of osteoblasts and osteoclasts
what is sclerostin expressed in
mature osteocytes, cementocytes, odontoblasts
what does sclerostin do
antagonizes Wnt/beta catenin signaling pathway , limits bone formation
what does the deletion or mutation of SOST gene result in
sclerosteosis or Van Buchem’s disease
what happens in Sclerosteosis
increased bone mass, especially obvious in craniofacial skeleton
what genes do osteocytes express that are important in phosphate homeostasis
FGF23
DMP1
PHEX
what endocrine role do osteocytes play
regulation of phosphate homeostasis
