L6.Reg of ECM: MMPs & TIMPs Flashcards
What is an MMP?
MMP = Matrix Metalloprotein. MMPs degrade ECM components such as collagen, elastic fiber, PGs, and adhesive proteins.
How many MMPs are there? What, if any, ECM components are MMPs incapable of degrading?
~25 MMPs. As a group capable of degrading all ECM components
What are the 3 major MMPs responsible for fibril collagen Degradation?
MMP1, MMP8, & MMP13
Also know as Collagenase-1, -2, & -3.
Briefly describe the 3 domain structures for Collagenase-1, -2, & -3 (MMP1,8,13)
- Propeptide domain: Must be removed following release from cell in order to activate MMP = CYSTINE SWITCH.
- Catalytic Domain: Contains Zn. W/o Zn MMP inactive.
- Hemopoxin Domain: Binding Domain. Binds to ECM substrates and TIMPs.
What are the 3 ways that MMP prevalence is regulated?
- Regulation of Gene Transcription by inducers =
- ECM proteins
- Inflammatory Cytokines (TNF-a, IL-1)
- Growth Factors (PDGF, TGF-B)
Fibrilar collagens are very resistant to proteinases b/c of their compact triple helical structure and their intermolecular cross-linked fibrils. These structures don’t allow MMPs to infiltrate the collagen. So how do MMPs initiate the break down of Collagen?
MMPs attack at two very specific Cleavage Sites
-B/t Gly775 and Ile776 alpha1
-B/t Gly775 and Leu776 alpha2
This cleavage always results in one long chain and one short chain. Allows MMPs to infiltrate collagen after initial breakdown and convert to gelatin.
What are the major domain receptors that mediate collagen formation & breakdown?
Discoidin Domain Receptors 1 & 2 (DDR1 & DDR2)
How do MMPs help in the modulation of GFs?
MMPs cleave inactive GFs from ECM components.
What role do MMPs play in bone remodeling?
MMPs are released by stromal cells and osteoblasts. They breakdown surface hypomineralized bone to create a surface structure suitable for osteoclasts to carry out bone resorption.
How do MMPs play a role in cancer metastasis?
Excess MMP production from malignant cancer cell and surrounding cells causes angiogenesis towards the are of increased [MMP]. Allows malignant cell to enter bloodstream & receive nutrients.
What two cancer therapies involving MMPs have shown promise?
- Blocking of VEGF and betaFGF receptors, which induce increased transcription of MMPs
- MMP2 inhibitors
Why are MMPs in the periodontal ligament so important?
- MMPs in the PDL are important b/c the PDL has a very high collagen turnover rate. Thus, MMPs are constantly active degrading collagen.
Note: This means that PDL collagen is the mot IMMATURE collagen of anywhere. - Due to high rates of inflammatory response due to periodontal disease, MMPs are often overstimulated which can lead to bone loss.
What is a proposed treatment for Perio Disease that involves the inhibition of MMPs? How does it work? What is a problem associated with this?
The use of low doses of tetracycline. Tetracycline binds to Ca and Zn, both essential metals for the catalytic activity of MMPs. A problem with this solution, however, is that it blocks MMPs everywhere which could lead to collagen build up, developmental issues, and slower wound healing.
MMPs can also play a deleterious role in the formation of ROOT caries. What are the 2 sources of these MMPs and how are they activated?
- Host MMPs are activated by low pH (from bacterial acid production) and can cause cavitation in dentin.
- S. Mutan derived MMPs also degrade dentin matrix in root caries.
What are TIMPs?
TIMPs = Tissue Inhibitors of MetalloProteinases.
- Endogenous specific inhibitors of MMPs @ tissue level.
- Expression of TIMP controlled during normal tissue remodeling (disruption –> disease)
