OE L39 Orthodontic Tooth Movement: Biohemistry

Question 1

Outline how mechanical forces induce tooth movement.

Answer 1

Mechanical signals must be converted into biochemical signals -> cell-ECM interactions are altered -> intracellular signals are induced -> extracellular consequences

Question 2

What is meant by the term mechanochemical signal conversion?

Answer 2

The coversion of mechanical force into a biological response.

Question 3

Describe the extracellular events of mechanochemical signal conversion.

Answer 3

• Tension applied to matrix, matrix component structure altered
• Strcutural alterations in matrix cause integrins to interact with the matrix
• Integrins recruited and translocated, integrins activate different signalling pathways
• Signalling pathways either cause ECM degradation or synthesis

Question 4

Describe the intracellular events of mechanochemical signal conversion.

Answer 4

• Structural reorganisation of cytoskeleton
• Signal propagation from adhesion sites to the nuclues, drives production of transciption factors which promote production of new proteins
• New proteins may adjust cell functions

Question 5

Describe the events of mechanochemical signal conversion with regards to fibronectin.

Answer 5

• Fibronectin present in the ECM
• Integrins interact with fibronectin via binding motif called RGD-loop
• Binding of a5β1 integrin can only occur when loop is close to synergy site, in the strecthed state the loop and synergy site are far away and cannot interact
• Instead avβ3 integrin binds, activates focal adhesion kinase (FAK)
• FAK activates intracellular kinases which bind to promoter regions of AP-1 transcription factor
• Leads to AP-1 synthesis which activates target genes

Question 6

What are the consequences of AP-1 transcription factor activation?

Answer 6

• AP-1 upregulates MMP synthesis

- MMPs degrade ECM components

Question 7

Name some MMPs.

Answer 7

• MT1-MMP (membrane assocaited MMP, secreted as pro-enzyme and activated by Furin)
• Collagenases: MMP-1,8,13 (proteolytic cleavage of peptide bonds)
• Gelatinases: MMP-2,9 (degrades fragments left behind by collagenases so they can be absorbed by the body)

Question 8

Which MMP is most prevalent in bone?

Answer 8

MMP-13

Question 9

How is MMP-13 activated?

Answer 9

• MMP-13 is produced as a proenzyme
• MT1-MMP cleaves the pro-domain
• Activates MMP-13

Question 10

How does MMP-13 degrade bone ECM?

Answer 10

• Collagenases such as MMP-13 cleave the collagen triple helix into a ¾ and ¼ fragment
• The collagen fragments have altered integrin binidng properties
• Therefore signalling events are altered

Question 11

What is the main function of MT1-MMP?

Answer 11

• Regulates osteoclastogenesis
• Cleaves RANKL from the pre-osteoblast
• Reduces osteoclastogenesis
• In MT1-MMP null mice rapid osteoclastogenesis is induced

Question 12

Which pathways other than mechanotransduction regulate signalling in bone?

Answer 12

• GFs
• Wnt signalling
• BMP/TGF-β signals
• G-coupled receptors
• Ca2+ channels

Question 13

How is bone deposition regulated on the tension side?

Answer 13

• Some resoprtion occurs which causes TGF-β release from the ECM
• Causes osteoclast precursor cells (monocytes) to lose RANK expression so osteoclastogenesis is prevented
• TGF-β1 promotes matrix production and osteoblast differentiation
• TGF-β blocks MMP produciton

Question 14

What are the effects of TGF-β on the ECM?

Answer 14

• Increases protein synthesis and secretion from cells, including proteoglycans and collagen fibres