Pacific Academy of Higher Education & Research
Department of Orthodontics and Dentofacial Orthopaedics,
Pacific Dental College & Hospital, Udaipur
Seminar on
CRANIOFACIAL BIOLOGY – ADHESIVE MOLECULES
AND MECHANISM OF ADHESION
Presented by
Dr. Kangjam Sylvia
1st Year Post Graduate
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CONTENT
1. INTRODUCTION
2. EXTRACELLULAR MATRIX
3. CELL ADHESION MOLECULES
4. CELL JUNCTION
5. MECHANISM OF ADHESION
6. CLINICAL IMPLICATION
7. CONCLUSION
8. REFERENCE
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INTRODUCTION
Remodelling changes in paradental tissues are considered essential in effecting orthodontic tooth
movement. The force induced tissue strain produces local alteration in vascularity as well as cellular and
extracellular matrix re cognization leading to the synthesis and release of various neurotransmitter,
cytokines, growth factors and metabolites of arachidonic acid.
EXTRACELLULAR MATRIX
Extracellular matrix is a complex combination of secreted proteins that is involved in holding cells and
tissues together. It is the noncellular component that provides not only essential physical scaffolding for the
cellular constituents but also inhibits biochemical and biomechanical cues that are required for tissue
morphogenesis, differentiation and homeostasis.
FUNCTION:
1) ECM helps organise cells into tissues and coordinates their cellular function like differentiation,
migration, polarity of cells and adhesion.
2) It served as a respiratory for inactive or inaccessible signalling molecules.
3) Regulating intercellular communication
4) Embryonic development and formation of the nervous system and other tissue.
CLASSIFICATION:
1) STRUCTURAL PROTEINS
- Collagens
- Elastins
2) PROTEIN POLYSACCHARIDE COMPLEX
- Proteoglycans
3) ADHESIVE GLYCOPROTEINS
- Fibronectins
- Laminins
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COLLAGEN:
- It is the main structural protein in ECM
- It is the most abundant protein in mammals 25-35% of the whole body protein content
- It is a triple helix of elongated fibril called collagen helix
- Mostly found in fibrous tissues such as tendons, ligaments and skin
- Fibroblast is the most common cell that produces collagen
- 30 types of collagen are identified and the most common types are from collagen I to V
ELASTIN:
- It is highly elastic and present in connective tissue allowing many tissues to resume their shape
after stretching or contracting.
PROTEOGLYCAN:
- They are composed of a core protein to which glycosaminoglycans are attached
- GAGs consist of repeating disaccharide subunits
- They have diverse role in regulating connective tissue structure and permeability.
FIBRONECTIN:
- They are the abundant multi-adhesive matrix proteins that play a key role in migration and cellular
differentiation, blood clotting process
- During cell movement, the pathways of fibronectin guide cells to their destinations.
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- It is also found in saliva, which helps prevent colonisation of the oral cavity and pharynx by
potentially pathogenic bacteria.
LAMININ:
- It is the most abundant glycoprotein in basement membrane, has binding domains for ECM and
cell surface receptors.
CELL ADHESION MOLECULES
Cell adhesion molecules are glycoprotein located on the cell surface. They are involved in binding with
other cells or with the extracellular matrix.
CLASSIFICATION:
1) Cadherin
2) Integrin
3) IgG superfamily
4) Selectin
Cell adhesion receptors can form homophilic and heterophilic adhesions.
CADHERIN:
- The cadherins are calcium dependent adhesion molecules that plays important role in cell adhesion
by forming desmosomes.
- They have 3 subclasses: a) Neural cadherin
b) Placenta cadherin
c) Epithelial cadherin
INTEGRIN:
- Integrins are diverse and large group of hetrodimeric glycoproteins
- They participate in cell-cell adhesion in binding and interaction of cells with components of the
ECM such as fibronection.
IgG SUPERFAMILY:
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- They are calcium independent transmembrane glycoproteins
- They form the cell adhesion molecules in nervous system.
SELECTIN:
- They are a family of divalent cation dependent glycoproteins
- They are carbohydrate binding protein which plays an important role in many host defence
mechanism
- Subclasses: a) Endothelial selectin
b) Platelet selectin
c) Leukocyte selectin
CELL JUNCTION
Cell junction is the connection between the neighbouring cells or the contact between the cell and
extracellular matrix. It is also called membrane junction.
It is classified into 3 types:
a) Occluding junction: -Tight junction
b) Communicating junction: -Gap junction
c) Anchoring junction: - Adheren junction
- Focal adhesion
- Desmosome
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- Hemidesmosome
TIGHT JUNCTION
Tight junction is the intracellular occluding junction that prevents the passage of large molecules. It is also
called as zonula occludens. This type of junction is present in the apical margins of epithelial and
endothelial cells.
STRUCTURE:
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- It is made up of a ridge which has two halves
- One half pf the ridge is from one cell and another half is from the other cell
- They fused and occupy the space between the two cells
- Each half of the ridge consists of tight junction strands.
FUNCTION:
1) Strength and stability
2) Selective permeability/gate function
- They form a selective barrier for small molecules and a total barrier for large molecules
3) Fencing function
- They prevents the lateral movement of proteins and lipids in cell membrane and thus act as a fence.
4) Maintenance of cell polarity
- Fencing function of the tight function maintains the cell polarity by keeping the proteins in the
apical region of the cell membrane
5) Blood Brain Barrier
- Tight junction in the brain capillaries arises forms the blood brain barrier which prevents the
entrance of many substances from capillary blood into brain tissues.
GAP JUNCTION
Gap junction is the intercellular junction that allows passage of ions and smaller molecules between the
cells. It is also known as nexus.
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STRUCTURE:
- Membranes of the two adjacent cells lie very close to each other and the intercellular space is
reduced from the usual size of 2.5 to 3mm
- Each channel consists of 2 halves
- Each half of the channel is surrounded by 6 subunits of proteins which are called connexins or
connexons.
FUNCTION:
1.The channel permits the passage of substances, which have a molecular weight less than 1000
2. It helps in the exchange of chemical messengers between the cells
3. It helps in rapid propagation of action potential.
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ANCHORING JUNCTION
Anchoring junction are the junction which provide strength to the cells by acting like mechanical
attachments. They are responsible for the structural integrity of the tissues and are present in heart muscle
and epidermis of skin. They are classified into 4 types:
1) adheren junction
2) focal adhesion
3) desmosome
4) hemidesmosome
ADHEREN JUNCTION:
- It is a cell-cell junction which connects the actin filaments of one cell to those of another cell.
- The membranes of the adjacent cells are held together by cadherins
- It is present in the intercalated disc between the branches of cardiac muscle.
FOCAL ADHESION:
- It is cell to matric junction which connects the actin filaments of the cell to the ECM
- This junction connects the cell with their basal lamina
- The transmembrane proteins, integrins hold the cell membrane and the matrix.
DESMOSOME:
- It is cell to cell junction where the intermediate filaments connect two adjacent cells
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- It is also called as macula adherens
- The membranes of two adjacent cells are thickened and become spot like patches
- Intermediate filaments are attached with the thickened patches
- Some other are arranged in radiating fashion
- The transmembrane proteins involved is cadherin.
HEMIDESMOSOME:
- It is cell to matrix junction which connects the intermediate filaments of the cell to the ECM
- It is half desmosome and the thickening of mem brane of only one cell occurs
- They connect the cells with their basal lamina
- The protein involve is integrin.
MECHANISM OF ADHESION
The cell adhesive molecules act as adhesion proteins by following mechanisms:
1) Anchorage with cytoskeleton
2) Homophilic binding
3) Heterophilic binding
4) Binding to laminins
SIGNALING MOLECULES AND METABOLITES IN ORTHODONTIC
TOOTH MOVEMENT
Arachidonic acid metabolites is the main component of phospholipids if the cell membrane and is released
due to the action of phospholipase enzymes. Prostaglandins stimulates bone resorption as they have direct
action as osteoclasts increasing their number and their capacity to form a ruffled border and affect bone
resorption. Cytokines are ECM signalling proteins that act on nearby target cells in cell-cell interaction.
These metabolites, proteins and hormones like growth factors are found to be one of the first messengers
- They bind to a specific receptor on cell membrane
- And produce an intracellular chemical second messenger
- This second messenger then interacts with cellular enzymes
- Evoking a response such as protein synthesis or glycogen breakdown.
The early phase of orthodontic tooth movement always involves an acute inflammatory response
characterised by periodontal vasodilation and migration of leucocytes out of the capillaries. These
migratory cells produce various cytokines, the local biochemical signal molecule that interact directly or
indirectly with the entire population of native paradental cells.
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Cyclic AMP PATHWAY
Cyclic AMP and cyclic GMP are two second messengers associated with bone remodelling. Cyclic
adenosine monophosphate signalling pathway.
It is a well characterised nutrient and hormone regulated signalling pathway. Its role for transmitting the
action of hormones like glucagon, epinephrine, vasopressin. It is synthesised from ATP by an enzyme
Adenylate cyclase
- It is degraded by am phosphodiesterase
- Which hydrolyses it to AMP
- The binding of the hormone to the receptor
- Resulting in production of active GTP bound G-protein alpha subunit.
- Which in turn binds to and activates the AC
- The classical outcome of increased cellular cyclic AMP level is the activation of the cyclic AMP
dependent protein kinase A
- The signal generated by cyclic AMP is then transmitted to the nucleus by cyclic AMP response
element binding protein and activated by PKA
- Leading to the activation of transcriptional program of gluconeogenesis.
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THE PI DUAL SIGNALING SYSTEM
Another second messenger system in relation to orthodontic tooth movement is the phosphoinositide
pathway. Plasma membrane phospholipids as structural components of the cell is an important participants
in signalling.
The phosphotidylinosotides can be phosphorylated and released two fragments and one of it is called PIP2.
An enzyme called phospholipase C chops PIP2 into DAG and IP3. DAG stays in the plasma membrane and
activates the target protein kinase C.IP3 diffuses into the cytoplasm and bind to ligand gated calcium
channels in the endoplasmic reticulum releasing calcium ions and binds to the protein leading to cellular
response.
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VITAMIN D AND DIACYLGLYCEROL
Another agent that has been identified as an important factor in orthodontic tooth movement is 1,25,
dehydroxychleocalciferol (1, 25, DHCC). A decrease in serum calcium level stimulates secretion of
parathyroid hormone.
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MOLECULES ASSOCIATED WITH MECHANOTRANSDUCTION
Orthodontic tooth movement is a process involving mechanical signal sensing and transduction with the
result of tissue remodelling of the dental periodontal ligament complex and tooth movement. The bone
remodelling in orthodontic tooth movement requires osteoblastogenesis in tension zone and
osteoclastogenesis in pressure zone and many molecules engaged to induce the cell differentiation and
activation. As YAP/TAZ stands at the central place in signal transduction, they play a part in orthodontic
tooth movement.
The effects of yes-associated protein (YAP)/ PDZ binding motif (TAZ) in orthodontically related cells
during orthodontic tooth movement.
- External forces are transmitted to integrin and adhesion protein through ECM and induce F-actin
- The high level of F-actin enables actin to bind to angiomotion (AMOT)
- So, the inhibitory signals from hippo pathways including SAV/MST and LATS cannot activated
and YAP/TAZ cannot be inhibited by AMOT.
- So, YAP/TAZ is free to enter the nucleus
- The assembly of F-actin also reinforces the connection between the linker of nucleoskeleton and
cytoskeleton (LINC) complexes and focal adhesion
- So, the nucleus is stretched and nuclear pore permeability will be increased to allow YAP/TAZ to
enter the nucleus
- Activated YAP/TAZ combine to other transcriptional factors, TEAD to induce target gene
transcription.
FAK – Focal Adhesion Kinase
SRC – Steroid receptor co activator
TEAD – TEA domain
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CYTOKINES IN ORTHODONTIC TOOTH MOVEMENT
Cytokines are extracellular signalling proteins that act on nearby target cells in low concentration in an
autocrine or paracrine fashion in cell-cell communication. In compression site, fibroblast, osteoblast and
other periodontal ligament cells release PGE2, IL1, IL6, TNF alpha and IL11.
- IL1 and TNF alpha stimulates osteoblast to produce chemokines such as CCL3, CCL2 and CCL5
- CCL212 and cytokine receptor activator for nuclear factor KB ligand (RANKL) and TNF alpha
- They induce chemotactic recruitment of osteoclast precursors to osteolysis site
- Where this cell differentiate into mature osteoclasts through osteoblast osteoclast precursors to
osteolysis site
- PGE2 and cytokines stimulate osteoblast/stromal cells to produce macrophage colony stimulating
factor and RANKL which bind their receptors cFms and RANKL expressed on osteoclast
precursors respectively.
- Damaged osteocytes are also a source of RANKL and macrophage colony stimulating factor
- Other cytokines (ILbeta, TNF alpha, IL11, IL6) growth factors (fibroblast growth factor 2,
epidermal growth factor) and chemokines (CCL2, CCL3, CCL5, CCL7, CCL9, IL8) can increase
osteoclast differentiation, survival and activity.
- However, osteoclastogenesis can be down regulated when 0PG binds to RANKL inhibiting the
RANK/RANKL interaction.
RANK RANKL OPG PATHWAY
RANKL:
- It is receptor activator of nuclear factor kappa B ligand
- Expressed by osteoblasts
- Plays an important role in osteoclast formation, function and survival
RANK:
- It is receptor activator of nuclear factor kappa B
- It is located on osteoclast precursors and mature osteoclasts
OPG:
- It is osteoprotegerin
- Binds to and inhibits RANKL
- Expressed by osteoblast and other tissues including spleen, bone marrow, heart, liver and kidneys
- It is protective against bone loss
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RANKL is a member of tumour necrosis factor (TNF) which binds to its receptor RANK
- Expressed on the surface of osteoclast progenitor cells
- Induces osteoclastogenesis and activates osteoclasts
- Which is a decoy receptor produced by osteoblastic cells
- Resulting in increased bone resorption
- However, RANKL activation of osteoclastogenesis and induction of apoptosis
- RANKL/OPG interaction therefore decrease bone resorption
- Thus, bone remodelling is controlled by a balance between RANK/RANKL binding and OPG
production
CONCLUSION
In conclusion, the role of the chemical mediators such as cytokines, IL, growth factors, RANKL receptor,
OPG in the process of bone remodelling should be considered when planning orthodontic tooth movement.
So it would be easier for the clinicians to design and implement effective appliance that will result in
maximum benefits and minimum tissue damage to the patient.
REFERENCE
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K Sembulingam, Prema Sembulingam – essentials of medical physiology, 6 th edition
Vinod Krishnan; Ze’ev Davidovitch (2006). Cellular, molecular, and tissue-level reactions to
orthodontic force. , 129(4), 4690–2147483647.
Lodish - Molecular Cell Biology - 7th edition
Deng, L., Chen, Y., Guo, J., Han, X., & Guo, Y. (2021). Roles and mechanisms of YAP/TAZ in
orthodontic tooth movement. Journal of Cellular Physiology.
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