orthodontic tooth movement Flashcards
how do mechanical forces from otm allow for tooth movement?
mechanical signals must be converted into biochemical signals
cell-ECM interactions are altered
induces intracellular signals
how are mechanical forces converted into a biological response in OTM
integrin - extracellular matrix interactions
- integrins = cell surface receptors
- interact with proteoglycans, fibronectin, collagen
- signalling
outline what occurs during mechanochemical signal conversion in otm
action of integrins
- Integrins interact with molecules of ECM
- Tension alters structure of matrix components
- Integrin interacts
- Influences which integrin interacts with matrix
- Signalling output will be different
- Can change matrix remodelling
- Can alter ECM by cleaving peptide bonds
- Effect on stability of interactions
How fibronectin is affected during mechanical force during OTM
- Fibronectin (Fn) unfolded by force:
- Functional consequences to the integrin/Fn interaction
how does stretching Fibronectin change signal output during OTM
- stretching Fn changes integrin binding preferences and signal output
- Changes in integrin interactions depending on conformation of ECM
- Leads to further downstream signalling
- RGD loop is exposed on surface of fibronectin
- Available to interactions with integrin
- Close to synergy site
- Second binding site for integrin
- Integrin is able to interact with RGD and synergy site
- Stable binding here
- Force applied
- Alterations in structure
- Synergy site and RGD loop are moved and changed structure
- E.g. Site buried
- Not available to interaction with that specific integrin
- Dissociates from molecule
- Free RGD loop
- Allows binding of a different integrin
- Alterations in structure
how is mechanical force transduced into the nucleus
- FAK is activated and leads to phosphorylation of kinases
- focal adhesion kinase
- Can activate intracellular kinases
- Phosphorylation of kinases leads to translocation into nucleus
- Can bind to promoter regions of transcription factor
- AP-1 is synthesised
- transcription factor that regulates matrix
- Further activation of target genes in the nucleus
- AP-1 is synthesised
Consequence of AP-1 transcription factor activation
- AP-1 upregulates genes that degrade the ECM
- MMPs
- Degrade ECM components
- MT1-MMP
- Arises at cell membrane in active form
- Degrades surface proteins and collagens
- Can activate some proMMPs
- MMPs
- ProMMPs
- Secreted in ECM in inactive form
consequences of MMP activity
A tail of ECM destruction
Regulation of osteoclast differentiation
structures of MMPs - how confers function
- MT1-MMP
- Pro domain required to keep MMP inactive
- Is secreted as active form
- MMP-1,8,13
- Have pro domain
- C terminal
- Found in different areas and cells
- MMP-2,9
- 3 fibrobnectin repeats
- Able to degrade products collagenases produce
- Into small peptides
- So body can remove them
how is proteolytic activity of MMPs regulated
- Collagenase (MMP-13) is activated by MT1-MMP at the cell surface
- MMP-13 is produced as a proenzyme
- Proteolytic cleavage dependent on MT1-MMP
- Fully activated form
- Active MMP-13
- Drives hydrolysis of collagen
action of collagen (MMP-13)
- drives hydrolysis of collagen
- Collagen incubated with active MMP-13 and inactive MMP-13
- Collagen is cut into 3/4 and 1/4 fragments
- Fragments have altered integrin binding properties
- Alter signalling responses
how does MT1-MMP regulate orthodontic tooth movement
regulates osteoclast differentiation rates
- Regulation of osteoclastogenesis
- Responsible for RANKL levels in plasma membrane
-
Can cleave RANKL from cell surface of pre-osteoblast
- Responsible for osteoclastogenesis
- Soluble RANKL - can be neutralised with OPG
- Lack of MT1-MMP RANKL accumulation on the cell surface is not neutralisable by OPG
- Activation of RANK signalling in osteoclasts
- Rapid osteoclasogenesis
- MT1-MMP is also collagenase
summary :
MT1-MMP releases RANK-ligand from pre-osteoblasts
Fine-tuning osteoclast numbers
Less bone resorption
In MT1-MMP null mice,
levels of RANKL?
osteoclast differentiation rate?
& what is the outcome
levels of RANKL = very high
osteoclast differentiation rate = very high
- Membrane bound RANK-ligand induces rapid osteoclastogenesis
- Net result:
- rapid bone loss due to increased osteoclast numbers!!!!
summary of removal of bone on compression site
- Cells respond to compression by production of matrix degrading enzymes (MMPs).
- MMPs are activated by an activation cascade and start cleaving the extracellular matrix, including collagen.
- Osteoclast precursors are recruited to the site of damage and undergo differentiation.
- Osteoclasts produce acid proteinases that resorb the bone.
in otm, what induces osteoblast differentiation?
- Proteinase activity releases growth factors from the ECM
- Growth factor signalling leads to osteoblast differentiation
- Induction of new ECM production:
- collagens, proteoglycans & mineralization to bone
