ECM homeostasis Flashcards
lecture 10
What is the extracellular matrix (ECM)?
A network of fibrous proteins and hydrated proteoglycans surrounding cells in tissues, providing strength, support, and communication.
Why is the ECM not an inert framework?
It actively guides cell migration and polarity, supports intercellular communication, and is involved in tissue remodelling.
How is a healthy ECM maintained?
Through a balance of synthesis and breakdown of matrix molecules.
Name three critical roles of the ECM.
- Provides strength and support to tissues.
- Guides cell migration and polarity.
- Permits intercellular communication.
What happens if there is an imbalance in ECM turnover?
It leads to diseases such as tissue scarring, fibrosis, cancer, arthritis, or metastasis.
What enzymes are responsible for ECM breakdown?
Proteinases (biological scissors).
What are the main categories of proteinases?
- Aspartic proteinases
- Cysteine proteinases
- Threonine proteinases
- Serine proteinases
- Metalloproteinases
What conditions favour the activity of different proteinases?
Low pH: Aspartic and certain cysteine proteinases (e.g., Cathepsin D, B, K).
Neutral pH: Serine and metalloproteinases (e.g., Elastase, MMPs).
Name three subfamilies of metalloproteinases and their roles.
- MMPs (Matrix Metalloproteinases): Breakdown ECM components.
- ADAMs: Membrane-bound modifiers of ECM.
- ADAMTS: Secreted ECM proteases like aggregenases.
What is the role of MMP-7?
Influences neutrophil migration and releases VEGF and TNF-α for angiogenesis.
Which MMPs are involved in collagen degradation?
Collagenases (MMP-1, -8, -13, -18).
How are metalloproteinases regulated?
- By α2 macroglobulin in blood.
- By Tissue Inhibitors of Metalloproteinases (TIMPs), which block active sites.
What activates metalloproteinases?
Removal pf the pro-region by other proteinases, exposing the catalytic Zn2+ binding domain.
How does the ECM damage influence repair?
ECM fragments stimulate cell signalling through receptors (integrins and PRR) to regulate further synthesis or inflammation.
What role do ECM fragments play in inflammation?
They activate receptors like PRRs, triggering inflammatory cytokine production (e.g., IL-1, TNF-a, TGF-β).
What maintains ECM homeostasis during stress?
ECM fragments induce synthesis of new ECM components.
How does excessive ECM breakdown lead to cancer?
By promoting tumour survival, migration, and tissue invasion.
What happens if ECM feedback induces excessive inflammation?
It leads to irreversible ECM loss and tissue damage.
Why is ECM remodelling crucial during development?
It allows for tissue morphogenesis and proper organ formation.
What roles do MMPs play in wound healing?
MMP-1 facilitates keratinocyte migration.
MMP-7 releases VEGF and TNF-α for angiogenesis.
What are the key domains of MMPs?
- Catalytic domain (binds Zn2+ for substrate specificity).
- Haemopexin domain (mediates substrate binding).
Which MMPs lack the haemopexin domain?
MMP-7, -23, -26.
How many genes encode proteinases in the human genome?
570 genes (~2% of all genes).
Which proteinase category is most abundant?
Metalloproteinases (191 genes).
How can ECM breakdown be monitored?
By detecting neo-epitopes generated by specific MMPs or ADAMTS enzymes.
Which enzymes generate cartilage fragments like hyaluronic acid (HA) neo-epitopes?
ADAMTS-4 and -5.
Name three diseases linked to ECM breakdown.
Arthritis, fibrosis, and cancer.
How does ECM turnover influence tumour suppression?
Balanced ECM turnover prevents the creation of an environment that supports tumour invasion.
What is the role of metalloproteinases in angiogenesis?
They release growth factors (e.g., VEGF) essential for forming new blood vessels.
How does inflammation influence ECM catabolism?
Inflammatory cytokines (e.g., TNF-α, IL-1) stimulate metalloproteinase activity, accelerating ECM breakdown.
What happens during ECM remodelling in embryonic development?
Controlled breakdown and synthesis of ECM guide cell differentiation and tissue formation.
What is the role of TIMPs in cancer prevention?
They inhibit metalloproteinase activity, limiting excessive ECM breakdown that facilitates tumour invasion.
