Extracellular matrix degradation
What are the four main families of MPPs?
- Collagenases - Stromelysins - Gelatinases - MT-MMPs
When do MMPs occur normally?
- Embryogenesis - Healing - Bone remodelling
How is the ECM degraded?
It is primarily degraded by enzymes e.g. plasmin, ADAMs/ADAMTs family, elastases, etc.
Where does activation of the pro-enzyme occur?
It occurs at the cell surface and is activated by plasmin and/or MT-MMPs
What is the ADAMTS family involved in?
The degradation of aggrecan
What is the function of gelatinases?
They degrade non-helical collagen
What do MMPs do in caries?
They degrade the organic matrix which is predominantly made of collagen
What conditions do MPPs work in?
They work in a neutral pH and require Zn2+ as a cofactor
Why does connective tissue need to be degraded?
- In order to give space for growth and expansion which is important for development - In order to remove damaged tissue such as in wound healing - In order to release factors stored within the ECM and process molecules to produce bioactive factors - Pathological inappropriate degradation e.g. cancer metastasis, arthritis
What MMPs are found in dentine?
- MMP-1 - MMP-2 - MMP-3 - MMP-8 - MMP-9 - MMP-20
Where are these MMPs involved?
- MMP-9 is involved in the early stages of dentinogenesis while MMP-2 is involved in the later stages - MMP-3 is found in the pre-dentine region and is associated with changes in proteoglycans - MMP-20 is exclusively produced by tooth-forming cells and its substrate is amelogenin which is produced by ameloblasts and odontoblasts which are found in enamel
What MMPs do the SIBLING family bind to?
- Osteopontin binds to MMP-2 - Bone sialoprotein binds to MMP-3 - Dentine matrix protein-1 binds to MMP-9
When do MMPs occur pathologically?
- Rheumatoid and osteoarthritis - Periodontal disease - Atheroscleoris
What is the role of MMPs?
- The degradation of the matrix - Involved in the release of membrane anchored growth factors and cytokines - Involved in the release of stored growth factors and cryptic factors - Involved in the control of apoptosis
Describe the characteristics of MPPs
- They are synthesised on demand - They are highly regulated as they activate proenzymes through the removal of the pro-sequence - The active enzyme is inhibited by TIMP in a 1:1 ratio - The enzyme shows pericellular localisation to ensure the reaction only occurs where it is needed
What are the functions of the ADAMs family?
- They may be involved in adhesion and degradation - They have a large number of functions although not all domains are functional
What does ADAMs family stand for?
A disintegrin and metalloproteinase
What disease does the degradation of cartilage result in?
Arthritis
What pathologies are plasmin linked to?
Atherosclerosis, tumour invasions, metastasis, thrombosis as the clots are not adequately degraded
Which MMPs degrade the cartilage?
MMP-1, MMP-2, MMP-3, MMP-9 and MMP-13
Where are gelatinases from?
MMP-2 is from fibroblasts while MMP-9 is from neutrophils and macrophages
Where do MMPs occur?
MMPs occur anywhere where tissue remodelling is required
What produces the host MMPs in the dentine?
Odontoblasts
What is the function of plasmin?
Plasmin degrades some components of the ECM such as fibronectin, laminin and bone glycoproteins
What is synthesis of MMPs activated by?
Synthesis is activated by numerous factors which include: - - Growth factors e.g. EGF - Cytokines - Shape change - Prostaglandins - Mechanical load
What is the ADAMTS family?
The ADAMs family with a thrombospondin domain
What is the significance of MMPs interacting with GAG chains?
The interaction of MMPs with GAGs is shown to concentrate MMPs to particular locations
What stimulates the enzymes?
The release of inflammatory cytokines and it is influenced by mechanical loading on the joint
What is the function of stromelysins?
They activate other MMPs and have a broad substrate specificity with the particular substrate being the protein core of proteoglycans
What is the function of MT-MMPs?
They activate pro-MMP-2
Are MMPs present in the oral cavity?
They are present in various locations in the oral cavity and so can contribute to ECM degradation in normal tooth development and pathogenesis
How are MMPs secreted?
They are secreted in pro-form and so require activation
Where are MT-MMPs found?
They are tethered to the plasma membrane and so are transmembrane
What is the function of matrix metalloproteinases (MPP)?
They are the most important enzymes as they degrade all components of the ECM
What is the function of collagenases (MMP-1)?
They easily cleave the triple helical collagen at a specific site to give 3/4, 1/4 fragments
What is the success rate with synthetic MMP inhibitors?
Very limited success