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Current Topics > Bone Research > Flashcards

Bone Research Flashcards

1
Q

Angiogenesis during bone growth
When is it required

A

Bone development and growth
Fracture repair
Bone development
Bone remodelling cycle
Bone disease - pagets, osteaoperosis (ageing)

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2
Q

Paget’s disease

A

Men >70 yrs old
Highly vascularised bones

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3
Q

Rickets

A

Low vitamin D
Not enough calcium
Dysfunction of VGEF , dysfunction of vascularisation

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4
Q

Osteopetrosis

A

Too much bone and vascularisation

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5
Q

Osteoporosis

A

Not enough bone mass, increase fracture risk, decrease vascular use

Sexually dimorphism disease: female more likely due to loss of eatrogen during menopause as eastrogen is pro anabolic
Bone thinning
Decreased vascular growth factors

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6
Q

Bone growth and development

A

Mesenchymal cells directly differentiate into bone by intramembranous ossification - craniofacial skeleton (neural crest) NO CARTILAGE TEMPLATE -has to form quickly as protective layer

These cells can differentiate into cartilage which provided template for bone morphogenetic by endochondral ossification (long bones) CARTILAGE TEMPLATE

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7
Q

Endochondral ossification

A

Cartilage replaced by bone
Cartilage around joints remain

(Hypertrophic) Chondrocytes produce lots of proangiogenic factors eg VEGF and MMP13
Angiogenesis occurs due to blood vessel attraction to VEGF, (remove matrix via MMP9 & 14 to create space for blood vessels) provide bone with nutrients and oxygen
Osteoblasts create the bone

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8
Q

Growth of cartilage model

A

Hypertrophic chondrocytes attract blood vessels by producing VGEF
Development of primary ossification centre
Development of marrow cavity
Decelopment if secondary ossification centre
Formation of articulation cartilage

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9
Q

VEGF couples hypertrophic cartilage remodelling, ossification and angiogenesis during endochondral bone formation

A

Important - VEGF IMPORTANT IN PROCESS OF BONE OSSIFICATION AND MINERALISATION

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10
Q

Vascular endothelial growth factor (VEGF)

A

Angiogenesis - knock out single VEGF allele in mice causes lethal impairment of vascular development
Angiogenesis:formation of new blood vessels from pre-existing vascular use plays central role in adult tissue homeostasis
Pathological processes including wound healing, tissue remodelling, tumour development and growth of atherosclerosis plaques
VEGF-A gene exhibits splice variants isoforms

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11
Q

Studying VEGFs effects in vivo

A

Soluble VEGF receptor chimeric protein
mFlt(1-3)-IgG

VEGFR1/Flt1 is a negative regulator of angiogenesis

VEGFR1 - Decoy receptor little intracellular signaling capacity, bind VEGF at surface of cell and not induce any signalling cascades, takes VEGF and stops it binding from functional receptor
So too much VEGF = up regulation of VEGFR1 so stop endothelial proangogenic response

Make protein modelled on VEGFR1 to stop it binding to VEGFR2 to block the signalling

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12
Q

Angiogenesis

A

VEGFR2 - main receptor, VGEF floats around and binds to tyrosine kinase receptor, phosphorylation of tyrosine kinase molecules causing activation of signalling pathways and genes linked to angiogenesis like endothelial cell migration, proliferation and growth

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13
Q

What was found with injection of BEGFR1 proteins

A

Chimeric protein captures VEGF
Phenotypes seen: reduced CD31 (endothelial cell marker) staining
Increase hypertrophic chondrocyte zone so less bone formation (build up or cartilage cells)
Mineralisation is reduced

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14
Q

Where is VEGF coming from?

A

LacZ tagging of VEGF allele allowing precise analysis of patter of VEGF expression at cellular level
Antibodies not very good for this
LacZ reporter gene into untranslated region of endogenous VEGF locus by homologous recombination

BONE CELLS (OSTEOBLASTS) CAN COMMUNICATE WITH BLOOD VESSELS AND RELEASE VEGF
BONE (FORMING) SURFACES

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15
Q

Can bone cells influence and contribute to the vasculature?

A

Vasculature run through hersian canal

Endothelial cells <> osteoblasts
Osteoblasts can communicate with endothelial cells via angiogenesis signals such as VEGF and endothelial cells can communicate to osteoblasts via osteopenia signals eg BMP2

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16
Q

Hypothesis - cross talk and angiogenesis is bone is primarily driven by osteoblasts

A

Response to external factors eg low oxygen in a fracture or drop in eastrogen due to menopause
Influences VEGF which influence endothelial cells which influence vasculature
Parancrine relationship

17
Q

Bone structure: cortical porosity

A

Low ct - slices of photos for 3D image (bone shape)
High res ct/SEM (bone cortex)

Whole bone > osteonal microstructures > lamellae > extra cellular matrix > fibril

29 yr old lots of hersian channels, age = increase in porosity
Expansion of hole, is there a blood vessel, is it functioning etc. can’t see in humans using imaging

Have to move to mice - 18 months, greater porosity

18
Q

Examining blood vessel structure in adult murine bone by synchrotron and lab uCT analysis

A

Low resolution - miss loads of info
Syncatron light sources - higher resolution using radiation, can see the pores in bone (0.65um resolution)
Stack of images (1000) to created 3D stack, binary images, separate big and small pores, to quanitigy different structures
See differences in disease

19
Q

VEGF DELETION Model

A

Osteocalcin VEGFKO mouse
Looked at vascular structures and bone matrix
Cre-Lox system - floxed allele, mouse with cre recombinase enzyme (driven by osteocalcin) expressed under control of transgenic promoter. Breed to create line that carries both - tissue specific deletion of floxed allele in tissue where cre recombinase is expressed (deleted in only osteoblast cells)

20
Q

VEGF is released by osteoblasts due to hypoxia, mechanical strain and growth factors

A

VEGF bind to VEGF receptors on blood vessels, blood vessels produce factors that couple with bone formation to ensure we get angiogenesis and bone formation in coordinated way

21
Q

Sexual dimorphism of cortic bone following OcnVEGF deletion

A

Adult female mouse vs knock out (not too bad)
Adult male mouse vs knock out (much more severe phenotype, increased bone porosity)

Clinically reduced VEGF in blood associated with osteoporosis

22
Q

Sexual dimorphism in cortical porosity following deletion of VEGF (engineered)

A

Male much worse than females

23
Q

Can bone matrix signatures influence sex specific vascular heterogeneity

A

Surrounding blood vessels in male knock out is unmineralised matrix (imagining)
VEGF KO in bone, dysfunctional blood vessel and then blood vessel cant mineralise the bone properly so mainly collagen based matrix

24
Q

Sec effects of VEGF deletion on ECM occur at lvl of osteoblasts

A

ACP - immature matrix
CAP - mature matrix
Knock out male composition of matrix compared to femal knock out matrix- female have way more mature matrix present (CAP), male has more immature (ACP)

25
Q

Sexually dysmorphia effect of VEGF deletion in endothelial cell function

A

Grew osteoblasts from male and female knock out mice
Condition media put on endothelial cells
Gene expression was sex specific eg increase in igf1 male had decrease of igf1

26
Q

Effect of of VEGF DELETION IN BONE IN MALES AND FEMALES

A

Females conserved mature phenotypes so maintained skeletal integrity

Male had more immature phenotypes in matrix and had increase porosity and fractures

27
Q

Translational benefits of targeting microcirculation

A

Sex specific mechanism controlling matrix production will impact cortical porosity and fracture risk with age
Stratified personalised approaches to fracture prevention and treatment (target vasculature therapies for males and females)
Sex bias towards women around development of OP drugs (because menopause) - health inequality
Need to improve understanding of male and female bone cell biology

28
Q

Tibial macro and microstructure adaptations to prolonged arduous military training in women

A

High resolution scanning - basic training -14 weeks x 3
Look at bone vasculature to see differences over time and sex differences
Women more like to get fractures than men during training have to be removed from training. Why?

29
Q

Army policy - same training

A

Women - more injuries
Men discharges due to overuse injury eg stress fractures - below 1.5%
Women - 4.6 to 11.1%

Same in athletic populations

30
Q

Training = rapid adaptations of tibial density and geometry (14weeks)

A

Extract blood vessels - binary images

Men = higher cortical tissue volume

Significant difference between both cortical tissue volume and canal density between men and women

Fracture model - had higher cortical tissue volume, canal number debsity and volume density

31
Q

Army study conclusion

A

Amend training to those more prone
Women more likely to fractures
Sex bias - health inequalities

Current Topics (4 decks)

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