Biochemistry Of Bone Formation- Exam V 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
- Mesenchymal condensation
- Cell differentiation
During the migration phase of preskeletal cells during skeletal development , where do they migrate to?
The future sites of skeletogenesis
During skeletal development, the interaction of what types of cells leads to mesenchymal condensation?
Epithelial-mesenchymal interaction
Following the condensation phase of skeletal development, what can the cells differentiate into?
Chondroblasts or osteoblasts
What is the indirect method of bone formation?
Endochondral
In endochondral bone formation, what does the mesenchyme first form?
Cartilage template
In endochondral bone formation, the cartilage template forms in what shape?
Shape of future bone
In endochondral bone formation, the cartilage template will later be replaced by:
Mineralized bone tissue
What type of bone formation occurs in most bones in the skeleton, especially bones that bear weight and have joints?
Endochondral bone formation
What process of bone formation involves direct bone formation?
Intramembranous
In Intramembranous bone formation, describe the transformation of cells
Direct transformation of mesenchymal cells to osteoblasts (no cartilage intermediate)
What type of bone formation is restricted to the cranial vault, some facial bones, and parts of the mandible and clavicle
intramembranous bone formation
What type of bone formation contributes or occurs during fracture repair?
both Endochondral and intramembranous
In step 1 of Endochondral bone formation- the mesenchymal cells will initially condense to form _____, that will show the future shape of the bone
cartilage model
In step 2 of endochrondral bone formation- after the cartilage model is formed, differnetaon and formation of ____ occur.
a mineralized collar (sleeve of bone)
In step 3 of endochrondral bone formation- the collar mineralization causes the chondrocytes in the center to undergo:
hypertrophy
When chondrocytes swell up, change their gene expression patterns and start to calcify. They also secrete a growth factor
hypertrophy
When the chondrocytes undergo hypertrophy, what growth factor do they secrete?
VEG F (vascular endothelial growth factor)
In step 4 of endochrondral bone formation - What does the VEG F secreted by the chondrocytes during hypertrophy do?
attracts blood vessels to invade
The primary ossification center in Endochondral bone formation is in:
medullary cavity
In Endochondral bone formation when the blood vessels invade the cartilage template, what do they bring in with them?
osteogenic precursor cells & osteoclasts
In endochrondral bone formation, osteoclasts will resorb the :
mineralized cartilage matrix
In endochondral bone formation, what process occurs by the osteogenic precursor cells?
osteogenesis
In endochondral bone formation, the osteogenesis from the osteogenic precursor cells brought in by the blood vessels causes the formation of: (2)
the marrow cavity and trabecular bone
In endochondral bone formation of a long bone, what occurs ~age 14-20?
growth plate fusion
Key transcriptional regulators of osteoblast differentiation: Key transcriptional regulators of osteoblast differentiation: It is imperative that the Runx2, Osterix, and B-catenin act:
Appropriate amount of time
Key transcriptional regulators of osteoblast differentiation: What transcriptional regulator functions to push the osteogenic precursor to the immature osteoblast?
Runx2 & Beta-catenine
Key transcriptional regulators of osteoblast differentiation: If beta-catenin acts on the mesenchymal cells too early in proliferation, what will result?
It will inhibit the transition from mesenchymal stem cells to osteochondrogenic precursers
Key transcriptional regulators of osteoblast differentiation: What trascriptional regulators function to push the immature osteoblast to the mature osteoblast in the maturation phase:
Osterix & B-catenin
If Runx 2 acts on the immature osteoblast for too long during the maturation phase, what is the result?
It will prevent further differentiation
What transcriptional factor is responsible for the transition of mature (matrix producing) osteoblasts to the terminally differentiated states?
B-catenin
What are the terminally differentiated states of the osteoblast?
osteocyte, lining cells, apoptosis
Label the green boxes for the appropriate transcriptional factors acting: (OSTEOBLAST DIFFERENTIATION)
left to right:
Runx2 & B-Catenin
Osterix & B-Catenin
B-Catenin
B-Catenin is involved in:
WNT signaling pathway
____ comes on at an early stage pushing the precursors from the chonrogenic to the osteoblastic phenotype
Runx2
_____ comes on in a later phase pushing the immature osteoblast to a mature osteoblast:
Osterix
If you take a mouse and KO the Runx2 gene, you end up with a mouse with:
only a cartlaginous skeleton, doesn’t ever mineralize to bone
In humans with a complete knockout of Runx2, this will result in a:
non-viable fetus
A heterozygous mutation of Runx2 in humans causes:
cleidocranial dysplacia (CCD)
Runx2 is a master transcription factor essential for:
bone and tooth development
Cleidocranial dysplasia is caused by what type of mutation?
Autosomal dominant
CCD result from ____ in Runx2
happloinsufficiency
Inactivating mutation/deletion in one allele:
Haploinsufficiency
Disease characterized by delayed ossification of midline structures of the body (especially membraneous bone)
Cleidocranial dysplasia
In CCD:
- _____ are partly or completely missing
- Late closing of ______
- Describe teeth
- ____ mandible due to _____ of maxilla
- Clavicles
- Fontanelle
- Supernumerary teeth
- Prognathic mandibule (protruding) due to hypoplasia of maxilla
What transcription factor is downstream of Runx2
Osterix
What transcription factor does Runx2 induce?
Osterix
Mice lacking osterix have:
impaired osteoblast fomration
Gene name for Ostrix:
SP7
Osterix contorls expression of what osteoblast genes?
Type 1 collagen, osteocalcin, and osteopontin
Human mutations in SP7 (osterix) are associated with:
osteogenesis imperfecta type 7
What are two important key signaling pathways that regulate osteoblasts differentiation:
BMPS & WNT/B-catenin signaling pathway
What important key signaling pathways comes first when regulating osteoblast differentiation?
BMP2,7
If signaling of the WNT/B-catenin pathway occurs too early, what will occur?
Inhibit the mesenchymal cells from differentiation into osteogenic precursers
Originally purified from bone extracts that induce toe formation when implanted in muscle (ectopic bone assay)
BMPS
BMPs are required for ______ of adult bone homeostasis
skeletal development/ maintenance
BMPs promite differentiation from:
early osteoprogenitor cells
BMPs are importation in:
fracture healing
Knockout of specific BMPs leads to:
skeletal defects:
Naturally occurring mutations in BMPs where their receptors result in:
inherited skeletal disorders in humans
A disease characterized by heterotopic bone formation:
Fibrodysplasia ossificans progressa
Stone man syndrome:
Fibrodysplasia ossifications progressa
Where does the bone form in fibrodysplasia ossificans progressa?
soft tissue
In FOP cases, surgical treatment is not an option because:
bone forms in response to tissue trauma
What is the mutation and what gene causes fibrodysplasia ossificans progressiva
mutation in: BMP type 1 receptor- gene is ACVR1 (single AA substitution)
The mutation involved in FOP causes mild _____ and ____ with BMP ligand binding.
constitutive activation and over activation with BMP ligand binding
In addition to the constitutive activation and over activation with BMP ligand binding, in FOP, there is also aquired responsiveness to:
Activin A
What treatments have been looked into regarding FOP?
Antibodies against active A and kinase inhibitors elective for mutant receptor
WNT/B-catenin signaling:
Under normal circumstances where there is no WNT to simulate its receptor, the B-catenin will be:
phosphorylated by GSK-3beta
WNT/B-catenin signaling:
When B-catenin is phosphorylated by GSK-3Beta,
B-catenin will go be degraded in the cell
WNT/B-catenin signaling:
Describe the receptor for the WNT ligand
LRP5+LRP+Frizzled
WNT/B-catenin signaling:
When WNT binds its receptor complex, that will then come in and phosphorylate the GSK-3B which will now:
release B-catenine
When the GSK-3B releases the B-cat, this allows for the B-Cat to go to the _____ and interact with a protein called ____ and then initiate ____.
nucleus; TCF; initiate gene transcription
WNT/B-catenin signaling:
When the b-catenin is able to get inside the nucleus, interact with TCF and initiate gene transcription, this will ultimately lead to:
Osteogenesis (bone formation)
signaling pathway important in determining bone mass:
WNT-B-catenin pathway
Activating mutation in LRP5 lead to:
high bone mass in humans
Inactivating mutations of LRP5 lead to:
low bone mass
Mechanism of bone mineralization- The first phase of mineralization initiated by:
matrix vesicle mediated mechanism
Mechanism of bone mineralization: The second phase of mineralization involves:
Propagation of mineralization on collagen fibers
Extracellular membrane bound vesicles produced by osteoclasts:
matrix vesicles
