Biochemistry of Collagen and Matrix Disease

What is the ECM?

the acellular component of tissues that provides structural and biochemical support to cells

The ECM provides a mechanical basis for …..

Cell attachment and movement

The ECM transmits ….

force e.g. tendon, ligament, cartilage and bone

The ECM can withstand …..

Compression in cartilage and IVD

The ECM provides what signals?

Survival signals to cells and differentiation signals to stem cells

The ECM is a reservoir for ….

Growth factors

An adult is ….% cells and …% ECM

20, 80

Composition of the ECM

Water

Proteins

Glycoproteins

Proteoglycans

GAGs

How much ECM is water?

50%

What are collagen fibrils?

A common building block of tissues

What is ECM essential for?

• Tissue integrity and mechanical strength

• Cell signalling and tissue organisation

• Resistance to tensile and compressive forces

Collagen accounts for ?% of total protein mass in the human body

30

Collagen is the major structural protein of ?

connective tissues such as bone, tendon, and skin.

Structure of collagen

Triple helix

Repeating Gly–X–Y sequence (often proline and hydroxyproline)

Collagen has a ?

High tensile strength

What is collagen synthesised as?

procollagen with N- and C-terminal propeptides. folding into a triple helix is essential and time-dependent.

The maturation of collagen

After secretion, procollagen is processed by specific enzymes:

• C-proteinase (BMP1/tolloid family) removes C-terminal propeptides

• N-proteinase (ADAMTS family) removes N-terminal propeptides

Removal of propeptides allows collagen molecules to self-assemble.

Collagen fibril assembly

• Processed collagen molecules align and assemble into collagen fibrils.

• Fibrils provide tensile strength and structural integrity to tissues.

• Fibril formation is tightly regulated:

  • Influenced by circadian rhythm

  • Daily deposition of collagen occurs, particularly in tendon tissue

Collagen turnover in adults

very low in healthy tissues

What protects long lived collagen?

pool of newly synthesised collagen that absorbs daily wear and tear

What do many collagen mutations involve?

Glycine residues which are critical for tight triple helix packing

What does the severity of collagen disease depend on?

Type of mutation and its effect on collagen folding, secretion and function

what are milder collagen diseases?

Reduced collagen quantity e.g Osteogenesis Imperfecta Type 1

Type 1 osteogenesis imperfecta

• Caused by null mutations in COL1A1 or COL1A2

• Lead to reduced collagen production

• Results in milder phenotype: early osteoporosis, few fractures

What do severe collagen diseases involve?

Dominant-negative structural defects which leads to more severe or lethal forms of disease. e.g. autosomal dominant osteogenesis imperfecta

effect of mutated collagen chains

• Delay folding

• Undergo excessive modification

• Are secreted and incorporated into fibrils, weakening them

Which forms of OI occur without collagen gene mutations?

Some recessive e.g. SERPINH1 (HSP47) mutations

SERPINH1 (HSP47) mutations

• HSP47 is a collagen chaperone

• Mutations cause delayed collagen secretion

• Result in severe connective tissue pathology