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Phase 1 MSK > MSK Physiology > Flashcards

MSK Physiology Flashcards

1
Q

What can MSK disease be classed as?

A

Degenerative
Inflammatory
Metabolic
Injury

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2
Q

What is the most common joint disease worldwide?

A

Osteoarthiritis

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3
Q

What are some inflammatory arthritis ?

A

Rheumatoid
Spondylitis
Reactive

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4
Q

What is gout?

A

Type of inflammatory arthritis that causes pain and swelling in joints

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5
Q

What is the most common metabolic bone disease?

A

Osteoporosis

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6
Q

What is the purpose of the skeleton?

A
  • raises us from the ground against gravity
  • determine basic body shape
  • transmits body weight
  • forms jointed lever system for movement
  • protects vital structures from damage
  • houses bone marrow
  • mineral storage (calcium, phosphorous and magnesium)
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7
Q

What is the skeleton divided into?

A

Appendicular skeleton - 126 bones
Axial skeleton - 80 bones

= 206 total

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8
Q

What does the appendicular and axial skeleton contain?

A
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9
Q

How many bones do we start of with?

A

350

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10
Q

What are bones classified by?

A

Shape

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11
Q

What are the types of bone?

A

Long - tubular shape with hollow shaft and ends expanded for articulation with other bones
Short- cuboidal in shape
Flat - plates of bone, often curved, protective function
Irregular e.g. ear and spine - various shape
Sesamoid - round oval nodules in a tendon

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12
Q

What are the different types of bone macro structure?(visible by eye)

A

Cortical = compact
And
Trabecular = cancellous, spongy

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13
Q

What is cortical bone like?

A

Dense, solid, only spaces are for cells and blood vessels

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14
Q

What is trabecular bone like?

A

Network of bony struts (trabeculae), looks like sponge, many holes filled with bone marrow. Cells reside in trabeculae and blood vessels in holes

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15
Q

What are the micro types of bone structure?

A

Woven and lamellar bone

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16
Q

What is the difference between woven and lamellar bone?

A

Woven: made quickly, disorganised, no clear structure
Lamellar: made slowly, organised and layered structure

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17
Q

How does bone structure contribute to its function?

A

Hollow long bone - keeps mass away from neutral axis minimises deformation
Trabecular bone - gives structural support while minimising mass
Wide ends - spreads load over weak, low friction surface
Flat bones - protective

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18
Q

What is the composition of bone?

A

Adult bone:
- 50-70% mineral
- 20-40% organic matrix
5-10% water

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19
Q

What is in the organic matrix of bone?

A
  • collagen - type 1 - 90% of all protein in bone
  • non-collagenous proteins - 10% of all protein
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20
Q

What is in the mineral of bone?

A

Hydroxyapatite, a crystalline form of calcium phosphate

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21
Q

Where does collagen in bone assemble?

A

The collagen assembles in fibrils with mineral crystals situated in ‘gap’ regions between them

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22
Q

How does bone microstructure contribute to its function?

A

Mineral provides stiffness
Collagen provides elasticity

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23
Q

What are the cells of bone?

A
  • Osteoclast - multinucleated
  • Osteoblast - plump, cuboidal
  • Osteocyte - Stellate, entombed in bone
  • Bone lining cell - flattened, lining the bone
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24
Q

What do cells of bone do?

A

Osteoclasts - Break down bone (holes)
Osteoblast - repair bone
Osteocyte - organise function of osteoclasts and blasts

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25
Q

What are the origins of osteoblasts?

A

Mesenchymal stem cell
-> progenitor cell -> adipocytes, osteoblasts, chondrocytes, myoblasts and fibroblasts

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26
Q

What are the characteristics of osteoblasts?

A
  • high alkaline phosphatase activity
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27
Q

What is the function of osteoblasts?

A
  • make non-collagenous proteins
  • secrete factors that regulate osteoclasts ie RANKL
  • Form bone in form of osteoid
  • Produce type 1 collagen and mineralise the extracellular matrix by depositing hydroxyapatite crystal within collagen fibrils
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28
Q

What is the origin of osteoclasts?

A

(Blood)Hematopoietic stem cells

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29
Q

What is the function of osteoclasts?

A
  • Resborb bone
  • dissolve the mineralised matrix (acid)
  • breakdown the collagen in bone (enzymatic)
  • high expression of TRAP and cathepsin K
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30
Q

What is bone modelling?

A

Gross shape is altered, bone added or taken away

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31
Q

What is bone remodelling?

A

All of the bone is altered, new bone replaces old bone

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32
Q

When does modeling and remodeling occur?

A

0-20 yrs - development = modeling (formation-> reabsorption)
20-50 yrs - maintenance = remodelling (formation = resorption)

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33
Q

What are the reasons for bone remodelling?

A
  • form bone shape
  • replace woven bone with lamellar bone
  • reorientate fibrils and trabeculae in favourable direction for mechanical strength
  • response to loading (exercise)
  • repair damage
  • obtain calcium
  • dysregulated remodelling = disease
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34
Q

How does osteoporosis show up in old women?

A
  • Back pain
  • heigh difference later in life - shorter (women)
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35
Q

What is brittle bone disease?

A

Osteogenesis imperfecta - genetic defect in kids not enough collagen in bones

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36
Q

What is osteopetrosis?

A

Defect - no osteoclasts - really thick bones - does not fulfill all functions of bone

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37
Q

What is rickets?

A

Caused by vitamin d deficiency - no calcium incorporated ?check!

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38
Q

What is osteomalacia?

A

Mineralisation defect

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39
Q

What is pagets disease?

A

Focal bone turnover

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40
Q

What is pagets disease?

A

Focal bone turnover

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41
Q

What is osteosarcoma?

A

Primary bone cancer

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42
Q

What is secondary bone cancer?

A

Tumour metastasis

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43
Q

What are the treatments ?

A

Anti-catabolic - stop osteoclasts
anabolic - activate osteoblasts

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44
Q

What is a collagen fibre made up of?

A

Collagen fibres - collagen fibrils - collagen molecules (triple helices) (tropocollagen) - amino acid chains

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45
Q

What makes up a collagen molecule?

A

A collagen fibril is made up of 3 collagen chains - made up of recurring triples of amino acids which are glycine X and Y.

Reoccurring triplet is the reason the three chains cross and twist into a helix.

Three chains made up of 2 alpha 1 chains and 1 alpha 2 chain.

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46
Q

How is type 1 collagen processed?

A

Starts of as a big pro-collagen molecule
- to be incorporated into tissues
- ends chipped off - N-terminals and P-terminals chopped off (P1NP and P1CP)

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47
Q

How is collagen joined together?

A
  • covalent cross-links
  • hydrogen bonds
  • between the tropocollagen molecules
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48
Q

Where are covalent cross-links in collagen?

A
  • within and between the triple helix/tropocollagen molecule
  • “intra/intermolecular crosslinks” - cofactors like OH-lysine x2 Lysol oxidase (needs copper) needed
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49
Q

Where are hydrogen bonds between collagen?

A
  • between hydroxyproline molecules, within tropocollagen
  • Cofactors like OH-proline from proline requires Fe2+
  • Fe3+ to Fe2+ requires vitamin C needed
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50
Q

What bonds are in between the tropocollagen molecules?

A
  • intermolecular crosslinks
  • OH-lysine x 3 = pyridinolines
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51
Q

What is collagen broken down by?

A
  • enzymes called proteinases, especially collagenases and cathepsin K (in bone)

This can be a normal process of repair and replacement (where breakdown is balanced by synthesis), or can be part of a pathological process e.g. arthritis etc

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52
Q

Where are other collagens?

A

Type 1 - bone, tendon, ligaments, skin
Type 2 - articular cartilage, vitreous
Type 3 - alongside Type 1 - wound healing
Type 4 - basal lamina
Type 5 - cell surfaces
Type 6 - growth plate

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53
Q

What is in the bone matrix?

A
  • synthesised by osteoblasts
  • 90% collagen
  • other proteins e.g. contribute to structure, regulate bone cell activity
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54
Q

What occurs in bone mineralisation?

A
  • Alkaline phosphate hydroxylases pyrophosphate
  • inorganic phosphate complexes with calcium to form hydroxyapetite
    -hydroxyapatite crystals propagate along collagen
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55
Q

What occurs in intramembranous ossification?

A

Bone formation
- for skull and clavicles

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56
Q

What enzyme is needed for bone mineralisation?

A

Alkaline phosphatase - hydrolysed pyrophosphate

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57
Q

What is the function of collagen in bone?

A

Allows deformation (toughness)
Creates structure for hydroxyapatite crystals

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58
Q

At what age is peak bone mass reached?

A

About age 25

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59
Q

What does the 2 alpha 1 chains and 1 alpha 2 chain in collagen form?

A
  • 3 collagen chains - 2 x a1 + 1 x a2
    Form the 3-stranded tropocollagen molecule
  • Tropocollagen molecules are assembled into a collagen fibril
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60
Q

What are tropocollagen molecules held together by?

A
  • Tropocollagen molecule and the fibril are held together by covalent crosslinks (both intra and intermolecular) derived from lysine/hydroxylysine side-chains
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61
Q

What type of chain is collagen?

A

Alpha helix

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62
Q

How is P1NP and P1CP also used?

A
  • end chopped of appear in circulation as a byproduct of collagen synthesis
  • can be measured
  • act as a biomarker of how much bone is being made
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63
Q

What is osteogenesis imperfect a caused by?

A

Most common - mutations in collagen A1 or A2

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64
Q

What is scurvy?

A

Caused by vitamin C deficiency
- won’t make iron to make cross links collagen

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65
Q

What are byproducts of type 1 collagen breakdown?

A
  • markers like NTX and CTX
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66
Q

What a re the two types of bone formation?

A

Intramembranous ossification
Endochondral ossficiation

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67
Q

What occurs in endochondral ossification?

A

Starts in chondyctes, become hypertrophic - attracts blood vessels into area of growth which bring with them nutrients and factors which cause cells to differentiate into osteoblasts.

And then they start to form the bone.

Collagen matrix - osteoblasts -> mineralised bone (long bone growth)

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68
Q

What occurs in secondary ossification centres?

A

When do growth plates fuse? - driven by oestrogen

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69
Q

What occurs in appositional growth?

A

Osteoblasts on periosteum surface - adds more and more bone outwards as this happens osteoclasts on the inner cortical surface are resolving themselves so your cortex grows outwards

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70
Q

When does bone mass stop growing?

A

Men - 18 ish
Women - 16 ish

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71
Q

What do all collagens share?

A

A triple helix

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72
Q

What key for collagen function?

A

Folding and cross-linking

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73
Q

What forms on collagen matrix?

A

Hydroxyapatite crystals

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74
Q

What are biomarkers of bone metabolism?

A

Collagen products

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75
Q

What are most bones formed through?

A

Endochondral ossficiation

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76
Q

What are bones like?

A

Continue to change and adapt throughout life

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77
Q

Where is most of the Ca in your body?

A

Most In the skeleton - 1200g
As calcium hydroxyapatite

Also in extracellular space - much smaller amount - 1g
For - muscle contractility
- nerve function
- Normal blood clotting

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78
Q

What is the form of calcium in circulation?

A
  • free and ionised - metabolically active
  • protein bound - not metabolically active
  • complexed - e.g. citrate, phosphate

Serum calcium - 2.4mmol/L - total?
Ionised serum calcium - 1.1mmol/L

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79
Q

What is the form of calcium in circulation?

A
  • free and ionised - metabolically active
  • protein bound - not metabolically active
  • complexed - e.g. citrate, phosphate

Serum calcium - 2.4mmol/L - total?
Ionised serum calcium - 1.1mmol/L

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80
Q

What is the protein binding of Ca dependent on?

A

PH - higher = albumin binds more strongly to calcium - affects amount of ionised calcium and therefore the metabolically active amount

Alkalosis - lower ionised calcium

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81
Q

What is ionised calcium imp for?

A

Nerve functioning
- low ionised calcium causes contraction of small muscles of hands and feet
- depolarisation of long nerves of UL
- tetany - sign

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82
Q

How is extarcellular fluid of Ca regulated?

A
  • absorption via gut and endogenous faecal Ca2+
  • excretion and reabsorption in kidney
  • bone resorption and formation
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83
Q

How is extarcellular fluid of Ca regulated?

A
  • absorption via gut and endogenous faecal Ca2+
  • excretion and reabsorption in kidney
  • bone resorption and formation
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84
Q

What is the major source of calcium?

A
  • dairy products - 2/3 - milk, yoghurt cheese
  • minor sources - veg (broccoli), cereals (white bread) and oily fish (sardines)
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85
Q

What occurs in calcium absorption?

A
  • we absorb 30% of dietary calcium
  • active absorption in duodenum and jejunum
  • passive absorption in ileum and colon
  • higher fractional excretion when low availability of Ca2+
  • more active transport - becomes more important
  • mediated by calcitrol, the active form of vitamin d
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86
Q

How is calcium released from bone?

A
  • can be released rapidly form exchangeable caclcium on the bone surface
  • can be released more slowly by osteoclasts during bone resorption
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87
Q

What does the amount of Ca2+ filtered by the glomerulus depend on?

A
  • GFR
  • ultrafiltrable calcium
    ionised
    complexed

Protein bound calcium not filtered

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88
Q

What affects reabsorption of Ca?

A
  • 98% of this filtered calcium is usually reabsorbed
  • reabsorption increased by PTH
  • reabsorption decreased if the filtered sodium is high
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89
Q

Where in the kidney is calcium absorbed and how?

A
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90
Q

What do PTH do?

A
  • Four parathyroid glands situated next to your thyroid.
  • they express a calcium sensing receptor
  • when your serum calcium decreases this is sensed
    by the parathyroid.
  • And in response they secrete parathyroid hormone.

classic negative feedback endocrine loop

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91
Q

What happens to PTH when serum calcium is low?

A

Increase PTH secretion

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92
Q

How does Ca regulate PTH secretion?

A
  • Ca sensing receptor is a cell surface receptor
  • G-protein coupled receptor
  • signal transduced through cyclic AMP
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93
Q

What is the relationship between serum calcium and PTH?

A

Small changes in serum ionised calcium causes big changes in pTH

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94
Q

What is the hormone action of PTH in the kidney?

A

When PTH acts on kidney calcium and phosphate go in opposite directions

In kidney - increases serum calcium decreases serum phosphate

  • also increases expression of 1- a hydroxylation of 25-OH vit D - final step in activation of vit D
    So PTH creates more active vit D
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95
Q

What is the affects of PTH hormone action on the bone?

A

Acts on bones - increases bone remodelling
- drives osteoclasts to resorb more bone - releases calcium from bone matrix

Net loss cal chum of bone into circulation

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96
Q

What is the affect of pTH hormone action on the gut?

A

PTH no direct effect on gut
Increases active vit D - increases gut absorption of calcium

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97
Q

What is the affect of PTH action on phosphate in the kidney?

A
  • decreases phosphate reabsorption
  • decreases serum phosphate
  • decreases FGF-23
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98
Q

What is the response of PTH to decreased serum calcium?

A
  • decreases in serum calcium
  • detected by Ca receptor in PTH
  • increases PTH secretion
  • increases calcium resorption in the kidney
  • increases active vit D
  • more AT of calcium in the gut
  • increases bone resorption
  • releases calcium from bone
  • increases bone resorption to maintain ExtraCellular calcium
99
Q

What is the response to low calcium diet?

A

Low dietary calcium ->
Low serum calcium ->
Increased PTH -

Fast actions: exchangeable calcium released from the surface of bone - decreased excretion of calcium from kidney

Slow actions: increased bone resorption
- increased fractional absorption by the intestine

Serum calcium returns to normal = PTH returns to normal

100
Q

What occurs in a Vit D overdose?

A

Increased gut absorption
- higher serum calcium
- decreased PTH
- decreased renal absorption of calcium
- decreased bone resorption
- serum calcium returns to normal
- PTH returns to normal

101
Q

What is calcitonin?

A
  • hormone produced by thyroid c cells (parafollicular cells)
  • secretion stimulated by increased serum calcium
  • its effect is to lower bone resorption
  • significance in humans uncertain
  • much more imp in animals living in high calcium environment e.g. fish
102
Q

What occurs in vit D synthesis?

A
  • synthesis in skin
  • substrate - cholesterol
  • vit D = steroid hormone
  • made by action of UVB light on 70 hydroxy cholesterol in your skin

Into circulation - goes to liver
- first activation step - 25 hydroxylase- 25hydroxy vit D
- active from - now can absorb calcium from glute

Main job to absorb calcium and pohsophate in gut

103
Q

How much exposure to sunshine do you need/

A

Exposed skin for 20 min a day - for sunshine May - Aug

104
Q

What is the active form of vit D?

A

Calcitrol - hydroxylated at positions 1 and 25
- stimulates intestinal calcium absorption

105
Q

What is the UK recommended daily dietary calcium intake?

A

700mg

106
Q

What is the UK recommended daily dietary calcium intake?

A

700mg

107
Q

How does increased blood pH affect serum ionised calcium?

A
  • decreased ionised calcium (because increased protein binding)
108
Q

What are the three actions of PTH on the kidney?

A
  • increased calcium reabsorption
  • decreased phosphate reabsorption
  • increased 1-hydroxylation of vitamin D
109
Q

What is the function of calcitrol?

A

Active gut absorption of dietary calcium

110
Q

What is calcium essential for?

A

Nerve and muscle function and bone integrity

111
Q

What is the role of phosphate in physiology?

A
  • ATP
    -cAMP
  • cell membrane - phospholipid bilayer
  • post-translational protein modification -
    kinases - phosphorylate
    Phosphatases- dephosphorylate
  • change structure and so function of proteins
  • On/Off switch

Bone mineral - calcium hydroxyapatite

112
Q

What is the phosphate storage in the body?

A

Whole body phosphate 500-800g
- 1% total body weight
- 90% in bone mineral

  • serum phosphate 0.8-1.5mmol/L
113
Q

What occurs in low phosphate levels?

A
  • poor mineralisation e.g. rickets or osteomalacia, pain, fractures
114
Q

What occurs in high phosphate levels?

A
  • excessive formation of hydroxyapatite
  • deposition in tissues other than bone
  • femoral artery calcification/tumoral calcinosis
115
Q

What are the dietary sources of phosphate?

A
  • protein - dairy, animal, soy, seeds and nuts

Adult recommended daily intake =700mg

116
Q

What occurs in renal phosphate handling?

A

Unbound phosphate - 90% is filtered
80% reabsorbed in proximal tubule
Na co-transporter
10% reabsorbed in distal tube

Max rate of reabsorption is limited so excess is excreted

117
Q

What also affects phosphate?

A

PTH

118
Q

Act of pTH on phosphate?

A
  • increases 1,25 Vit D
  • increases gut absorption
  • of phosphate
  • decreases tubular reabsorption of phosphate
  • increases renal excretion
119
Q

What is the main regulator of phosphate?

A

FGF-23 - fibroblast growth factor 23

120
Q

What causes inherited rickets?

A
  • presents in child hood or adulthood
    -bone pain, deformity, fractures
  • low bone density
  • low serum phosphate
  • high urine phosphate
  • X-linked hypophosphataemic rickets (XLH)
  • autosomal dominant rickets (ADR)
121
Q

How was inherited rickets founds?

A

Genetic investigation - linkage analysis and sequencing

122
Q

What is tumour induced osteomalacia?

A
  • Rare form with low phosphate
  • seen in patients with small benign mesodermal tumours
  • osteomalacia heals when tumour removed
123
Q

What is FGF-23 produced by?

A

Produced by osteocytes
- in response to:
- rise in phosphate levels
- dietary phosphate loading
- PTH
-1,25 Vit D

124
Q

What is the action of FGF 23?

A
  • decreases expression of Na transporter in the renal tubule
  • increases renal excretion of phosphate
  • decreases 1a-hydroxylation of Vit D
  • decreases gut absorption of phosphate
  • decreases whole body phosphate
125
Q

What are some common pathways with calcium regulation?

A
  • calcium mostly regulated by hormones that increase serum calcium
  • PTH, Vit D
  • phosphate mostly regulated by hormones that decreases serum phosphate
  • FGF 23, PTH
126
Q

What does low and high phosphate lead to?

A

Low - osteomalacia
High - excess calcification

127
Q

What is PTH a secondary regulator of?

A

Phosphate

128
Q

What occurs in the regulation of bone turnover (remodelling)

A

• Osteoblasts and osteoclasts must be able to communicate with each other.
• Coupling
o Bone formation occurs at sites of previous bone resorption
• Balance
o Amount of bone removed by osteoclasts should be replaced by osteoblastic activity

129
Q

What are osetoclasts derived from?

A

Macrophages
- Involved in chronic inflammation
- Phagocytose (ingest) pathogens

Osteoclasts are specialised macrophages

130
Q

What occurs in inflammation and bone loss?

A
  • soft tissue swallowing
  • joint narrowing
  • erosions
  • destruction of ulnar styloid
131
Q

What are the inflammatory mediators of bone?

A

• Cytokines
o A group of proteins and peptides that are used to allow one cell to communicate with another.
o Released by many types of cells (both haemopoietic and non-haemopoietic)
o Particularly important in immune responses (immunological, inflammatory and infectious diseases).
o Sometimes these effects are strongly dependent on the presence of other chemicals and cytokines.

132
Q

What are the attributes of the cytokine system?

A

Redundancy and pleiotropism

133
Q

Define redundancy

A

Redundancy means that most functions of cytokines can be performed
by many different cytokines.
o Blocking or genetically ablating (“knockout” transgenic technology) a particular
cytokine rarely has widespread or dramatic effects.

134
Q

Define Pleiotropism

A

• Pleiotropism means that a single cytokine has many different functional
effects, on many different cell types or even on the same cell.
o Overexpression or exogenous administration of a single cytokine frequently has
several diverse effects.

135
Q

What are the endocrine mediators of osteoclasts differentiation and activity?

A

Hormones (endocrine) including
o 1,25 dihydroxyvitamin D
o PTH/PTHrP
o Oestrogen
o Leptin

136
Q

What’s re the paracrine mediators of osteoclast differentiation?

A

Paracrine/autocrine including
o Prostaglandins
o Interleukin-1 (IL-1)
o Interleukin-6 (IL-6)
o Tumour necrosis factor (TNF)

137
Q

Why are mediators of osteoclasts odd?

A

• They didn’t work in pure osteoclast cultures
• They only worked in the presence of osteoblasts or other bone marrow
stromal cells (mesenchymal lineage)

138
Q

What is OPG?

A

Osteoprotegerin (OPG)
• Also known as osteoclastogenesis inhibitory factor (OCIF)
• A member of the tumour necrosis factor (TNF) receptor superfamily.
• Inhibits the differentiation of myeloid precursors into osteoclasts
• Decreases resorption by osteoclasts in vitro and in vivo.
• Works by binding to RANK-ligand, thus blocking the RANK-RANK ligand interaction between Osteoblast/Stromal cells and Osteoclast precursors

139
Q

What is the function of RANK ligand?

A

RANK ligand stimulates osteoclasts formation, function and survival

Receptor Activator of Nuclear factor K B (RANK)

140
Q

What is osteoclastic bone resorption driven by?

A

Balance between RANK ligand and OPG

141
Q

What is osteoclastic bone resorption driven by?

A

Balance between RANK ligand and OPG

142
Q

How does bone resorption interact with bone formation and osteoblasts?

A
143
Q

What do mesenchymal stem cells give rise to?

A

Can give rise to
o Osteoblasts
o Adipocytes
o Chondrocytes
o Myocytes

• As we age, more mesenchymal
progenitors are directed down
the adipocyte pathway

144
Q

What are the functions of skeletal muscles?

A

• Produce movement of body parts: simple motion or
coordinated movement.
• Support soft tissues: support the weight and shield
visceral organs.
• Maintain posture and body position: allows standing
position.
• Communication: speech, expression & writing
• Control of openings and passageways: voluntary control
of movements of digestive and urinary tracts.
• Maintain body temperature: heat released through muscle
contraction participates in control of body temperature.

145
Q

What’s are the characteristics of muscles?

A

Responsiveness (excitability)
–capable of response to chemical signals, stretch or other signals & responding with electrical changes across the plasma membrane
•Conductivity
–local electrical change triggers a wave of excitation that travels along the muscle fiber
•Contractility – shortens when stimulated
•Extensibility – capable of being stretched
•Elasticity – returns to its original resting length after being stretched

146
Q

What is the muscle structure?

A

Myofiber size: average length: 5cm, diameter: 100um.
Sarcomeres: 10000 sarcomeres per myofibril.
T-tubules: sarcolemma invaginations that help propagating action potential.
Sarcoplasm: cytoplasm rich in glycogen to fuel contraction.

147
Q

What is the structure of myofibrils?

A

Thin filament contains F-actin capped by α-actinin and CapZ, and Tropomodulin. Nebulin consists of
35aA actin binding motifs and acts as a molecular ruler.
Thick filament contains Myosin filaments maintained by Titin, which acts as a molecular spring. Titin
is the largest protein in our genome with > 34000aA.

148
Q

What are the thick and thin filaments like?

A

• Each thick filament contains approx. 300 Myosin heads
• Each head cycles 5 times/second

149
Q

How is contraction initiated?

A
  1. Nerve impulse reaches the nerve terminal, the neuromuscular junction. Ca2+ is released and causes release of Acetylcholine by exocytosis.
    2.Binding of Ach to its receptor causes entry of Na+ into the sarcoplasm, which produces an action potential.
    3.Ca2+ is released and binds to troponin, provoking a
    conformation change that unmasks myosin binding sites.
    4.Myosin heads slide along the actin filament, a process that require energy (ATP).
    5.The process terminates when nerve impulse stops. Ach is then degraded by Acetylcholinesterase, and Ca2+ is reabsorbed by the sarcoplasmic reticulum. Ca2+ detached from troponin, which returns to its initial position, masking myosin binding sites.
150
Q

What is teh structure and function of troponin?

A

Troponin C - binds to Ca2+
Troponin T binds to tropomyosine
Troponin I is an inhibitory subunit

  • unmasking of myosin binding site on the thin filament
151
Q

What is key to muscle contraction?

A

Neuromuscular junctions

152
Q

What drugs affect the neuromuscular junction?

A

Na+ channel - tetrodotoxin
Ca2+ channel - conotoxin
AChR channel - d-tubocurarine (curare)
Ach Release - tetanus toxin (lockjaw), botulinum toxin (botulism)
K+ channel - dendrotoxin (mamba snake)

153
Q

What is botulinum toxin?

A

Botulinum toxin (botulism)
• most common cause of food poisoning
• Clostridium botulinum (Botulus:sausage)
• muscle weakness, paralysis leading to death
• endoproteinase that cleave proteins required
for exocytosis of Ach in autonomic nervous system
• 1st symptoms: dry mouth, double vision
• 2nd symptoms: gastrointestinal (diarrhea, vomiting)
• 3rd symptoms: paralysis of limbs, respiratory muscles

154
Q

What is the clinical use of botulinum toxin?

A

Clinical use of botulinum toxin
• Treatment of strabismus (cross eyedness)
by injection into peri-ocular muscles

• Blepharospasm (uncontrolled eyelid
movements)

• Cosmetic treatments (Botox: Toxin A)

155
Q

Are all muscles the same?

A

No
- Slow fibers are metabolically economical
• Fast fibers are metabolically expensive

156
Q

What’s re the different classes of muscle fibers?

A
157
Q

What is the difference between slow and fast fibers?

A
  • Slow fibers are half the diameter of fast fibers
  • take longer to contract after nerve stimulation

• Fast fibers take 10msec or less to contract

158
Q

What are the conditions of muscle metabolism?

A

• Cells generate ATP through aerobic metabolism in mitochondria or
through glycolysis (anaerobic) in the cytoplasm.

• Aerobic/oxidative metabolism (moderate activity, slow fibers)

  • results in production of 38 molecules of ATP
159
Q

How does anaerobic conditions affect muscle metabolism?

A

• Anaerobic/Glycolytic metabolism (peak activity, fast fibers)
- Advantage: produces ATP in the absence of O2
- Disadvantage: ATP yield is low and toxic products are generated.

  • results in production of 2 molecules of ATP + lactic acid
160
Q

What is an essential shittele of ATP?

A

Phosphocreatinine

  • Creatine is ingested from the diet and transported to muscles via bloodstream.
    •95% of creatine is present in muscles as P-creatine (60%) or creatine (40%).
    •The enzyme catalysing the synthesis and degradation of P-creatine is creatine kinase (CK). CK has cytoplasmic and mitochondrial isoforms.
    •Provides a readily source of energy in the first minutes of intense exercise.
    •Creatine is recycled into P-creatine in mitochondria at rest.
161
Q

What is muscle fatigue?

A

Muscle fatigue is the progressive weakness of muscle contraction until
no response.

162
Q

When does muscle fatigue occur?

A

It strikes when:

• ATP synthesis decreases due to shortage of glycogen (aerobic
conditions).

• Lactic acid levels rise and lower the pH of sarcoplasm, which
prevents normal functioning of muscles (anaerobic conditions).

• Failure from motorneurons (production of Ach due to reduced
availability of Ca2+.)

163
Q

Key points about muscle metabolism

A

The neuromuscular junction is critical to muscle contraction.
Toxins can block its function, but can also be used as drugs to
treat neuromuscular disorders.

2.Slow fibers use aerobic metabolism, which results in the net
production of 38 ATP. They are fatigue resistant.

3.Fast fibers use anaerobic metabolism, which results in the net
production of 2 ATP and lactic acid. Fatigue strikes rapidly.
However, if ATP production occurs through P-creatine
hydrolysis, there is reduced fatigue.

164
Q

What is the function of joints?

A

To allow movement in 3-dimensions
• To be weight-bearing
• To transfer the load evenly to the
musculoskeletal system

165
Q

How are joints classified?

A
  1. Structural classification
    • by the components/tissues
    which hold the joint together
  2. Functional classification
    • by the degree of movement
166
Q

What are the types of joints?

A

Fibrous
e.g. teeth sockets
Cartilaginous
e.g. intervertebral discs
Synovial
e.g. metacarpophalangeal

167
Q

What are the functional classifications of joints?

A
  1. Synarthroses - immovable joints, mostly fibrous
    (eg. skull sutures)
  2. Amphiarthroses - slightly moveable joints,
    most cartilaginous (eg. intervertebral discs)
  3. Diarthroses - freely moveable joints, mostly
    synovial (eg. hip)
168
Q

What are the fibrous joints?

A

Fibrous joints 1 - sutures
- Occur only between bones of the skull (allow skull growth in development)
- Adjacent bones interdigitate
- Junction filled with very short tissue fibres

To allow growth after birth a baby has
fibrous tissue between skull bones which
develops into sutures

Fibrous joints 2 - Syndesmoses
Bones are connected by a cord (ligament) or sheet
(interosseous membrane) of fibrous tissue.
Amount of movement permitted is proportional to
length of fibre.

Fibrous joints 3 - Gomphoses
A peg-in-socket fibrous joint found only in tooth
articulation

169
Q

What are cartilaginous joints like?

A

Cartilaginous joints - Synchondroses
The bones are directly connected by hyaline
cartilage. These are usually amphiarthroses ie.
slightly moveable eg. costal cartilage of the ribs

Cartilaginous joints - Symphyses
Here the connecting cartilage is a pad or plate
of fibrocartilage

170
Q

What are intervertebral discs like?

A

Designed to take load; water-binding proteoglycan-rich nucleus pulposus surrounded by tough fibrous annulus fibrosus – a shock absorber

171
Q

Summarise joints?

A

Fibrous -> Synarthrosis -> 1. Suture, 2. Syndesmosis, 3. Gomphosis

Cartilaginous -> Amphiarthrosis -> 1. Synchondrosis, 2. Symphysis

Synovial -> Diarthrosis

172
Q

What are articulating joints separated by?

A

Articulating bones are separated by a fluid-filled
cavity

173
Q

What are articulating joints separated by?

A

Articulating bones are separated by a fluid-filled
cavity

174
Q

What are teh five characteristics of synovial joints?

A
  1. Articular cartilage
  2. Joint capsule -the
    inner layer is the synovial
    membrane,
  3. Joint (synovial) cavity
    - a space filled with
    synovial fluid.
  4. Synovial fluid
  5. Reinforcing ligaments
175
Q

What additional components are associated with some synovial joints?

A
  1. Bursae – fluid filled sacs lined by synovial
    membrane
  2. Menisci – Discs of fibrocartilage
176
Q

What is articulate hyaline cartilage like?

A

Almost frictionless surface
Resists compressive loads
High water content
Low cell content
No blood supply

177
Q

What is the structure of articulate cartilage?

A
178
Q

What is synovial fluid like?

A

Also known as joint lubricant

• Covers articulating surfaces with thin film (e.g. healthy knee just 0.5 ml fluid)
• Modified from plasma by synovial membrane (synoviocytes)
• Fluid, proteins, charged sugars that bind water eg. hyaluronate
• Result: slimy fluid (like egg white)
• Reduces friction during articulation

179
Q

What is the synovial membrane like?

A

Sits on the joint capsule
and encloses synovial
cavity
• Only a few cells thick
• Can have villi and
projections to increase
surface area
• Secretes synovial fluid
components eg.
hyaluronate

180
Q

What are ligaments like?

A

Ligaments: connect bone to bone
• Stabilise joints
• Similar to a tendon but with less regularly arranged
fibres
• Can stretch up to 6% before breaking and may
contain more elastic fibres than tendon
(generalisation)

181
Q

What are tendons like?

A

Tendons: connect bone to muscle
• Stabilise joints
• Made of dense regular connective tissue, rich in
type I collagen
• Allow muscles to be accommodated at a distance
from their insertion, e.g. muscles of the forearm
move the fingers. Provides a solid base (insertion to
bone) on which muscles can pull
• Muscles also stabilise joints

182
Q

What are the movements for synovial joints?

A
183
Q

What are the main stabilising ligaments of the hip joint?

A

Main stabilising ligaments:
Iliofemoral
Pubofemoral
Ischiofemoral

184
Q

What is the shoulder joint like?

A

A ball and socket joint
Stability sacrificed for range of movement. Joint capsule is loose.
Dislocation of the shoulder quite common. The rotator cuff muscles
help in stabilisation but are prone to injury, especially at tendon
insertion sites

185
Q

What is the knee joint like?

A

Not a hinge joint, femur/tibia is
condyloid (ovoid head of one bone
moves in an elliptical cavity of
another) and femur and patella
gliding. Joint capsule thin but
strengthened by many tendons
and ligaments

186
Q

What are the ligaments of the knee joint?

A
187
Q

What is the elbow joint like?

A

Classic hinge joint between
humerus and ulna and
gliding joint between
humerus and radius
Single joint cavity but synovial
membrane partly divides ulnar
and radial portions

188
Q

What are the ligaments and tendons at the elbow

A
189
Q

What joints have the most range of movement?

A

Synovial> cartilaginous> fibrous

190
Q

How are synovial joints different?

A

In synovial joints the bone ends are covered by cartilage to aid friction-free
movement and absorb compressive stresses
Synovial fluid in the joint cavity increases lubrication of the joint

191
Q

What is the main function of ligaments and tendons?

A

Ligaments and tendons, dense connective tissue, stabilise the joints

192
Q

What is the function of ligaments?

A

• Attach bone to bone.
• Augment mechanical stability
of joints.
• Guide joint motion.
• Prevent excessive motion.

193
Q

What are the functions of tendons?

A

Connect muscle to bone
– Provides a solid base (insertion to
bone) on which muscles can pull.

• Transmit tensile loads from
muscle to bone to:
– produce joint torque
– stabilize joint during isometric contractions and in opposition to other torques
– enable joint motion during isotonic contractions
– act as a dynamic joint restraint
– interact with ligaments and joint capsule to mitigate loads that they receive

• Aid joint stability

194
Q

What is the compositions of tendons and ligaments?

A

Tendons and ligaments, in general, have similar
structure:

• Dense connective tissues consisting of mainly parallel fibres.
– Enables the tissue to sustain high tensile strains
• Cells (fibroblasts also called tenocytes/ ligamentocytes) which synthesise & remodel the ECM
– 20% of the tissue volume
– Relatively low cell number leads to a low tissue turnover rate and generally poor capacity for healing
• Extracellular matrix (ECM)-80% of the tissue volume.
– 70% of tissue wet weight is water
– 30% solids [collagen, ground substance (proteoglycans and glycoproteins)]
– Has a hierarchical structure
• Sparsely vascularised
– Generally a poor capacity for healing

195
Q

What is the structure of tendons and ligaments?

A

Major component of the tendon and
ligament fibres is collagen
– Mainly type I (90-95% of dry weight).
– Some collagen type III, small amounts of
other collagens (V, VI, IX which function to
control fibril diameter).
• 1-5% of dry weight are proteoglycan
– Act as lubricant to aid collagen fibres gliding
over each other.

196
Q

What else do tendons and ligaments contain?

A

• Tendons and ligaments also contain elastin
• Influences elastic properties of tendons and
ligaments (↑ elastin  ↑ elasticity)
• Proportion varies by function
– Little in tendons and extremity ligaments
– More present in ligamentum flavum (between laminae
of vertabrae)
• protect spinal nerve roots
• provide intrinsic stability to spine

197
Q

What is the diff between tendons and ligaments?

A

Ligament
• Connect bone to bone.
• Lower collagen I (90% dry
weight).
• Higher elastin content.
• Fibre organisation more random.
- blood supply from insertion points

Tendon
• Connect muscle to bone.
• Higher collagen I (95-99% dry weight).
• Very little elastin.
• Fibres highly organised.
• Blood supply from paratenon,
mesotenon and insertion points

198
Q

What are insertion sites of tendons and ligaments?

A

• Place of insertion of a tendon or ligament into bone:-
enthesis.
– Innervated with proprioceptive and pain receptors.
• Important later on as site for disease
• Common examples
– Achilles tendon joins calcaneum (back of ankle)
– Epicondyles of elbow
– Patellar tendon into anterior surface of tibia

199
Q

How do tendons and ligaments load bear?

A

• Encounter load bearing in everyday activities
– Transmitting forces from muscles or bone to the skeleton
• Tendons are viscoelastic
– Exhibit both elastic and viscous behaviour
– Can regain original shape following deformation (once load
removed)
• Tensile loads result in elongation between the original
ends of the tissues.
• Compressive loads result in contraction between the
tissue ends

200
Q

What is a typical load elongation curve?

A
  1. ‘Toe’ region. Small increase in load as the crimped
    collagen fibres straighten.
  2. ‘Linear’ region fibres straightened and stiffness increases rapidly with loading.
  3. Maximum deformation and tensile strength of tissue
    (Pmax). Beyond this, there is progressive failure of the
    collagen fibres.
  4. Yield point, after which, there is complete failure of tissue to support loads
201
Q

When is Pmax elongation achieved?

A

• Maximum degree of tissue elongation Pmax
of ligaments and tendons is not achieved
during normal activities.
• normally 30% of Pmax achieved

202
Q

What is the ligamentum flavum?

A

Ligamentum flavum:
• Substantial proportion of elastin (60-
70%)
• Connect laminae of adjacent vertebrae
• Function to protect spinal nerve roots
• Provide intrinsic stability to spine

  • high levels of elastin
  • most tendons and extremity ligaments contain little elastin
203
Q

What is the Golgi tendon organ?

A

• Encapsulated sensory receptors proprioceptors
activated by stretch or active muscle contraction.
• Located in tendons near the junction with the muscle
(also in joint capsules).
• Consist of thin capsule enclosing collagen fibres
penetrated by terminal branches of sensory
neurones.-senses muscle tension.

204
Q

What is the inverse myotonic reflex-protective reflex?

A

Streatch of Golgi tendon organ causes reflex inhibition (relaxation)

  • stimulation of GTO -> nerve impulses travels to spinal cord (afferent 1b neurones) -> synapses on interneurone -> alpha motor neurone innervating the muscle -> muscle relaxation -> prevention of muscle and tendon damage
205
Q

What factors affect the mechanical properties of ligaments and tendons?

A

Factors Affecting the Mechanical Properties of
Ligaments and Tendons
• Maturation and aging
– Up to 20 years of age,
• number and quality of cross-links in collagen molecules
increases  increased tensile strength
• Collagen fibril diameter increased  increased tensile
strength
– Aging
• Collagen content of tendon and ligaments decreases 
decreased tensile strength
• Pregnancy and postpartum
– tensile strength & stiffness in tendons  due to hormonal
influences.

206
Q

What factors affects the mechanical properties of ligaments and tendons?

A

• Physical Training
– increase tendon tensile strength and ligament-bone interface strength.
– ligaments become stronger and stiffer, collagen fibers
increase in diameter.
• Immobilization
– decrease tensile strength of ligaments, more elongation, less stiff.
– decrease in cross-links.
– after 8 weeks of immobilization → 12 months to recover
strength & stiffness

207
Q

What causes gout?

A

High uric acid levels in the blood cause urate/uric acid crystals to deposit in the joints.
•The crystals cause inflammation, which then causes the swelling, pain & redness.

208
Q

What is Uric acid like?

A
  • poorly soluble in plasma
  • the lower pH less less soluble it becomes
209
Q

What joints are commonly affected in gout?

A

Toe
Ankle
Knee
Elbow

210
Q

Where does uric acid come from?

A

Purines - like adenine and guanine, hypoxanthine and xanthine

From diet, breakdown of nucleotides in tissue and synthesis in body

211
Q

How does uric acid leave the body?

A

Excreted in urine
Breakdown in gut

212
Q

What occurs in purine metabolism?

A

Body purine nucleotides (tissue nucleotides, purine synthesis and dietary purines)-> purines -> uric acid -> excretion

213
Q

Who is gout more common in?

A

Men - predisposed to having higher levels of uric acid - less oestrogen which promotes excretion of uric acid

214
Q

What are some food sources of purines?

A
  • meat
  • offal - heart, liver and kidney
  • seafood - muscles
  • fish - herring and sardines
  • also oatmeal, soya and yeast extracts
  • fructose - found in soft drinks
215
Q

What are some food sources of purines?

A
  • meat
  • offal - heart, liver and kidney
  • seafood - muscles
  • fish - herring and sardines
  • also oatmeal, soya and yeast extracts
  • fructose - found in soft drinks
216
Q

What are risk factors for gout?

A
  • metabolic syndrome
  • obesity - raised BMI
  • raised triglycerides
  • raised blood pressure
  • coronary heart disease
  • diabetes
217
Q

What cab cause a patient to develop high uric acid levels?

A

Reduced kidney function can lead to reduced excretion of uric acid

218
Q

How can some medication counter high uric acid levels?

A
  • e.g. monoclonal antibody that inhibits pro-inflammatory cytokine IL-1

Or allopurinol - works in metabolic pathway from purines -> uric acid

e.g. Purines —(xanthine oxidase)—> xanthine —(XO)-> uric acid

Allopurinol inhibits XO

219
Q

What are complications of high uric acid?

A
  • kidney stones - irate crystals can from in kidneys
  • causes damage to kidneys and reduces kidney function
  • gouty tophi - irate crystals deposited in the soft tissues
220
Q

What are some complications for gout?

A
  • damage to the joint (degenerative arthritis)
  • secondary infections
  • Nerve damage
221
Q

What are normal uric acid levels?

A

Too high for men?
Too high for women?

222
Q

What are some causes of increased turnover of cells?

A
  • rapidly growing malignant tissue
  • leukaemia
  • lymphoma
  • polycythaemia rubra vera
  • increased tissue breakdown
  • tumour lysis syndrome
  • trauma
  • starvation
    -psoriasis
223
Q

How does rasburicase work?

A
  • U-O is not present in humans
  • present in other mammals
  • rasburicase is a recombinant form of urate-oxidase

Uric acid —(urate- oxidase enzyme)—> allantoin

  • allatonin is more water soluble more easily excreted by kidney In urine
224
Q

What occurs during reduced salvage of purines?

A

Purines turned back into body purine nucleotides:

Hypoxanthine and guanine are recycled back to precursors by enzyme HPRT

If enzyme missing leads to increased production of uric acid - HPRT (hypoxanthine-guanine phosphoribosyl transferase)

225
Q

What is hyperuricemia?

A

Over production or under excretion of uric acid

226
Q

What are the clinical consequences of high uric acid?

A

Deposition of uric crystals in joints, soft tissue and kidneys

227
Q

Define a fracture

A

Breach in continuity of bone

Occurs when - non-physiological loads applied to normal bone or when physiological loads applied to abnormal bone

228
Q

How do you calculate load being applied?

A

KE = 1/2MV^2
OR
F= MA

229
Q

What causes fractures In abnormal bone?

A

E.g. Tumour
Metabolic bone disease

230
Q

How do you describe fractures?

A

Site
Pattern
Displacement/angulation
Joint involvement
Skin involvement - infection?

231
Q

How do you describe fractures?

A

Site
Pattern
Displacement/angulation
Joint involvement
Skin involvement - infection?

232
Q

What fracture patterns are unique to children?

A

Epiphyses open and bone more ‘plastic’
- change in fracture types?

Heal quickly
- deformity remodelling

233
Q

What are the stages of fracture healing?

A

Phase 1 - inflammation (days)
Phase 2 - soft callus formation
Phase 3 - Hard callus formation -
Phase 4 - remodelling (months to years)

234
Q

What occurs in inflammation?

A

0-7 days
- haematoma and inflammatory exudation from blood vessels
- bone necrosis
- soft tissue injury and platelet degranulation precipitate inflammatory cellular response to clear debris
- replacement by granulation tissue

235
Q

What occurs in repair - soft callus formation?

A

Callus formation

Soft callus - 2-3 weeks
- progenitor cells in periosteum and endosteum develop into osteoblasts
- intramembranous ossification
- in growth of capillaries
- proliferation of mesenchymal cells
- fibroblasts and chondrocytes

236
Q

What occurs in repair - hard callus formation

A

Hard callus - weeks - 5 months
- intramembranous ossification continues
- callus undergoes endochondral ossification
- woven bone
- peripherally inwards

237
Q

What occurs in remodelling?

A
  • woven bone replaced by lamellar bone
  • surface erosion
  • osteonal remodelling
  • restoration of normal morphology
  • medullary canal

(Osteoblasts?)

238
Q

What are the principles of fracture management ?

A

Reduce (the fracture)
Immobilise (/stabilise the part)
Rehabilitate (the patient)

239
Q

What are the types of fracture fixation?

A

Slings
•Casts and splints
•Extra-medullary devices
–plates and screws
•Intra-medullary devices
–nails
•External Fixation

240
Q

What are the modes of fracture healing?

A

Primary (strain<2%)
- intramembranous
- Haversian remodelling
- occurs within rigid fixation - plates and screws

Secondary (strain 2-10%)
- responses in the periosteum and external soft tissues
- endochondral healing
- occurs within non-rigid fixation - cast

Combined
- semi-rigid fixation - I.m nail

Fibrous response
- results in non-union

241
Q

What factors influence fracture healing?

A

•Patient
–Age
–Nutrition
–Smoking
–Drugs – NSAIDs, steroids
•Tissue
–Bone type: cancellous vs. cortical
–Bone site: upper limb vs. lower limb
–Vascularity / soft tissue damage
–Bone pathology - # in metastatic deposit does not heal
–infection
•Treatment
–Apposition of fragments
–Stability (ability to resist force without deforming)
–Micromotion (<1mm)

242
Q

What factors influence fracture healing?

A

•Patient
–Age
–Nutrition
–Smoking
–Drugs – NSAIDs, steroids
•Tissue
–Bone type: cancellous vs. cortical
–Bone site: upper limb vs. lower limb
–Vascularity / soft tissue damage
–Bone pathology - # in metastatic deposit does not heal
–infection
•Treatment
–Apposition of fragments
–Stability (ability to resist force without deforming)
–Micromotion (<1mm)

243
Q

What are early local and general complications of fractures?

A

Local
–Vessel damage
–Nerve damage
–Compartment syndrome
–infection

General
–Hypovolaemic shock
–ARDS
–VTE
–Fat embolism

244
Q

What are late local and general complications of fractures?

A

Local
–Malunion
–Non-union
–Avascular necrosis
–Ischaemic contractures
–Joint stiffness
–Myositis ossificans
–Complex regional pain syndrome
–Osteoarthritis

General
–Poor mobility
–Functional disability and social isolation
–Pressure sores
–Disuse osteoporosis
–Loss of income / job

Phase 1 MSK (11 decks)

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