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MBBS II MSS > L06 - Biochemistry of cartilage and bone > Flashcards

L06 - Biochemistry of cartilage and bone Flashcards

1
Q

What types of macromolecules compose the ECM around a cell?

A

Insoluble fibers
Soluble polymers
Adhesive glycoproteins

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2
Q

Describe the structure of collagen?

A

Gly-X-Y repeats

3 α chains: 2 α1, 1 α2 forms triple helix

Typically staggered ends

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3
Q

Describe the assembly of collagen.

A

1) C-terminal propeptide initiates triple helix formation in rough ER
2) Procollagen is secreted into extracellular space
3) Procollagen peptidase cleaves procollagen to form collagen

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4
Q

How does extra-cellular matrix components dictate tissue function?

A

Function depends on component:

  • Type
  • Organization
  • Relative amount
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5
Q

What is the partition of organic and inorganic molecules in Bone matrix?

A

Dense matrix:
70% inorganic
30% organic (90% collagen)

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6
Q

List the inorganic and organic component of Bone matrix?

A

Inorganic: Calcium phosphate as hydroxyapatite crystals

Organic: Mainly type I collagen in layers, with Proteoglycans, GAGs, Glycoproteins

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7
Q

What type of collagen is Heterotypic?

A

Type V that fits inside layers of Type !

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8
Q

Which collagen types coat the surface of fibrillar collagen ?

A

Type IX, XII, XIV (FACIT)

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9
Q

What is the role of collagen type IV?

A

Abundant in basement membrane

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10
Q

What is the role of collagen type VI?

A

Beaded filament found in desmosomes in muscles

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11
Q

What pathology arises from malfunction of collagen type VII?

A

Anchoring fibril in connecting epidermis and dermis

Malfunction = epidermolysis bullosa

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12
Q

What is the structure of soluble polymers in the ECM?

A

Linear polymers of repeating dissacharide units

1) Amine sugar (N-acetylglucosamine or N-acetlygalactasamine with one or more hydroxyl groups esterified with sulphate)
+
2) Uronic acid

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13
Q

What are the 2 types of Glycosaminoglycans (GAG) in the ECM?

A
  • Unsulphated: Hyaluronic acid

- Sulphated: chondroitin sulphate, heparan sulphate, keratan sulphate, dermatan sulphate

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14
Q

How can hyaluronic acid act as a lubricant in joints?

A

Large and highly negatively charged due to carboxyl group&raquo_space; attracts lots of water &raquo_space; acts as lubricant

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15
Q

List 3 functions of Hyaluronic acid in the MSS?

A
  • Lubricant in synovial joints
  • Resist compressive force in cartilage
  • Fills joint space and maintain structure
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16
Q

Difference between Hyaluronic acid and proteoglycan?

A

Both are GAGs

Hyaluronic acid is unsulphated, much longer, has NO core protein

Proteoglycans are sulphated, much shorter, have core proteins + GAG side chains has site for biological function

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17
Q

What is the structure of proteoglycans?

A

One or more GAG side chains attached to a core protein

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18
Q

List some extracellular Lecticans?

A

aggrecan, brevican, neurocan, versican

19
Q

List some SLRPs?

A

Short leucine repeat proteoglycans (SLRPs): decorin, biglycan, lumican

20
Q

What is the structure of Perlecan?

A

heparan sulphate proteoglycan, up to ~10 GAG side chains

21
Q

What are some membrane- bound proteoglycans?

A

Syndecan, Glypican

22
Q

List 4 functions of proteoglycans?

A

1) Provide hydrated space around cells (e.g. in ‘empty spaces’ of cartilage)
2) Act as selective sieves: regulate traffic of molecules, cells (size, charge)
3) Bind secreted signaling molecules (e.g. growth factors in ECM)
4) Bind and regulate proteases (degrade ECM), protease inhibitors

23
Q

What is the KEY function of adhesive glycoproteins?

A

interact with cells and other macromolecules in ECM

24
Q

How does adhesive glycoproteins interact with ECM?

A

Via Functional peptide domains

> > prescribe interactions with surface receptors, other matrix molecules

25
Q

Apart from interacting with cells and macromolecules in the ECM, give other functions of adhesive glycoprotein?

A

regulate fibril formation

interaction with inorganic phase (e.g. mineralized connective tissues: bone, dentine)

26
Q

There is only one type of Fibronectin. True or False?

A

False

  • Functional form = disulphide-bonded dimer
  • Different isoforms by alternative splicing (increases diversity in function)
27
Q

Function of Fibronectin?

A

Forms fibrillar matrix (further stabilized by extensive disulphide bonding):
1) Promotes cell adhesion

2) Affects cell morphology, migration, differentiation

28
Q

How does Fibronectin interact with cells? Mechanism?

A

Binds to Cell surfaces via integrin receptors, Arg-Gly-Asp (RGD) motif

Also binds to Collagen, heparin/heparan sulphate proteglycans, fibrin

29
Q

What mediates interactions between cell and matrix?

A

Matrix receptors:

Integrins and Discoidin domain receptors (DDRs)

(+Syndecan, Fibronectin receptors…etc)

30
Q

What is the structure of Integrins?

A

Heterodimers (22 known types)

 α chain / subunit (17 types): divalent cation, disulphide bond

 β chain / subunit (8 types): cysteine-rich domain

31
Q

What gives diversity to integrin molecules?

A

Many types of α and β chain

A single β chain can interact with multiple α chains = diversity to bind different ligands

32
Q

How does integrin (matrix receptor) cause intracellular changes? Mechanism?

A

Mediate weak cell-matrix and cell-cell interactions

Bind / interact with ECM (sequence-specific: RGD) and cytoskeleton to signal nucleus to regulate gene expression

33
Q

Explain how cell-matrix interactions can be fine tuned and specific?

A

Multiple interactions through different matrix receptors

34
Q

What is the sequence of ECM homeostasis?

A

Gene expression > matrix assembly > matrix turnover > gene expression

35
Q

What are some enzymes involved in matrix turnover?

A

mostly Matrix metalloproteinases (MMPs)

others: Hyaluronidase, chondroitinase, Serine proteinases, elastase, cathepsins

36
Q

List some subtypes of MMPs?

A

Matrix metalloproteinases

collagenases, gelatinases, stromlysin

37
Q

What acts against the action of MMPs?

A

Activity regulated by tissue inhibitors of matrix metalloproteinases (TIMPs)

38
Q

What are the 2 mechanisms in place to regulate MMP activity?

A

inhibitors of matrix metalloproteinases (TIMPs)

synthesized as inactive proenzymes that only work at specific sites of ECM proteins

39
Q

What are some diseases caused by imbalance of matrix degradation and remodeling?

A

Osteoarthritis
Intervertebral disc degeneration
Rheumatoid arthritis
Osteoporosis

40
Q

What part of the ECM degenerates in Intervertebral disc degeneration?

A

Aggrecan degradation: proteolytic fragmentation of aggrecan structure increases with age

Aggrecan is a proteoglycan that resists compression and acts as a space filler

41
Q

How does the ECM change in RA?

A

Trigger + abnormal immunity&raquo_space; trigger inflammation&raquo_space; abnormally activates MMPs&raquo_space; accelerated breakdown of ECM

42
Q

How is the ECM affected in Osteogenesis imperfecta?

A

mutant type I collagen = Low bone density

43
Q

How is the ECM affected in Marfan syndrome?

A

mutant fibrillin-1 (FBN1) = ECM protein which regulates TGF-β signaling

MBBS II MSS (31 decks)

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