1
Q
what are the classifications of bone by shape?
A
- Long bones
- tubular
- hollow shaft
- ends expanded for articulation
- Short bones
- cuboidal
- Flat bones
- plates, often curved
- protective function
- Irregular bones
- Sesamoid bones
- round/oval nodules
2
Q
bone macrostructure types
A
- Cortical
- dense
- only spaces are for vessels and cells
- Trabecular
- Cancellous (i.e. spongey)
- networks of trabeculae - holes filled with marrow
- cells are in the trabeculae and the blood vessels
3
Q
Types of bone microstructure
A
- woven
- no clear structure and disorganises
- lamellar
- organised and layered structure
4
Q
how does a hollow long bone’s structure contribute to its function?
A
- keeps mass away from the neutral axis which minimises deformation
5
Q
how does a trabecular bone’s structure contribute to its function?
A
- gives structural support while minimising mass
6
Q
adult bone composition
A
- 50-70% mineral
- hydroxyapetite which is a crystalline form of calcium phosphate
- 20-40% organic matrix
- mostly collagen
- 5-10% water
collagen stacked in fibrils with the hydroxyapetite crystals stacked like plates between them
7
Q
cells of the bone
A
- osteoclasts
- multinucleated
- break bone down
- osteoblasts
- plump and cuboidal
- build bone up
- osteocytes
- stellate and are entombed in the bone
- in lacunae
8
Q
Osteoblasts
A
- mesenchymal origin just like fibroblasts
- produce type I collagen and mineralise the ECM by depositing hydroxyapetite crystals within fibrils
- secrete factors that regulate osteoclasts
- RANKL
9
Q
Osteoclasts
A
- haematopoietic origin
- they are specialised macrophages
- RANKL causes differentiation into mature osteoclast
- function is to resorb bone
- it dissolves the mineralised matrix with acid called TRAP
- breaks down the collagen with enzyme called cathepsin K
10
Q
what is bone modelling?
A
- gross shape of the bone is altered, bone added or taken away
11
Q
what is bone remodelling
A
- all of the bone is altered, new bone replaces old bone
- on average the entire skeleton is replaced every 20 years
- what happens is
- resorption by osteoclasts creates a hole
- a signal is sent that thats enough resorption
- osteoblasts are sent in to fill the deficit
- this results in new bone where the old bone was
- if remodelling becomes dysregulated we get disease
- the ability to create bone at the same speed it is taken away is diminished with age
- this leads to osteoperosis
12
Q
why remodel bone?
A
- to repair damage
- as a response to weight bearing exercise
- woven bone (bone that has been laid down really quickly) needs to be replaced with lamellar bone
- in order to obtain calcium when there is a deficit
- reorientate fibres into the direction that is best for mechanical strength
13
Q
what percentage of proteins are collagens
A
~30%
14
Q
Type I collagen structure and organisation
A
- 3 chains intertwined and glycosylated forms tropocollagen
- 3 chains are held together in a triple helix by hydrogen bonds between hydroxyproline residues
- this requires vitamin C
- lots of tropocollagen is organised into a fibril
- lots of fibrils are organised into fibers
- fibril and fibers are held together by covalent cross-links between lysine side-chains
- copper needed for these
15
Q
collagen breakdown
A
- uses proteases like collagenases and cathepsin K (in bone)
- these break of the telopeptides at the end of the triple helix
- this gives NTx and CTx
- NTx can be measured in urine and is often used as a marker of collagen breakdown
- CTx is a better marker but must be measured in blood
16
Q
type 1 collagen processing
A
- before collagen can be exported for use in bone or whatever, the end globby bits need to be chopped off
- these bits are referred to as P1NP and P1CP
- for N terminus and C terminus
- these can be measured in the blood as a measure of bone formation
- P1NP is generally used cause it’s not metabolised and is excreted intact in the urine
17
Q
where is type I collagen found?
A
bone, tendons, ligaments and skin
18
Q
where is type II collagen found?
A
articular cartilage and vitreous humour
19
Q
where is type III collagen found?
A
this is reticulate collagen and is commonly found alongside type I
20
Q
where is type IV collagen found?
A
it is found at the basal lamina
21
Q
where is type V collagen found?
A
it is commonly found at the cell surface
22
Q
where is type X collagen found
A
at the growth plate
23
Q
what is appositional growth?
A
- growth at the periphery of bone
- growth in the perichondrium causes an increase in diameter
- cell division takes place
24
Q
what is interstitial growth?
A
- increase in length
- it happens in the middle of the bone at the growth plate
- chondrocytes become chondroblasts
- matrix becomes more dense
25
targeted resorption
for long bones to develop they need to model bone (build) but also resorb bone in targeted areas so that they have the proper structure - see picture
inability to resorb bone leads to metaphyseal flare where the bone remains wide for much of its length
in picture: needs to grow into green outline and resorb red outline in order to preserve proper structure
26
how much calcium is held in the skeleton?
1200g
27
how much calcium is held in the extra cellular space
and for what?
1g
for normal cell function e.g. blood clotting, muscle contraction, nerve function
28
how much calcium is in the serum
2.4 mmol/L
it's wither complexes with citrate or phosphate, ionised (and therefore metabolically active) or bound to protein and therefore not metabolically active
29
why are ionised calcium levels important
* at higher pH, albumin binds to calcium strongly
* this reduces ionised calcium (metabolically active) in the blood
* low ionised calcium leads to depolarisation of the long nerves of the upper limb
* this is associated with contraction of the small muscles of the hands and feet
* this is tetany
30
calcium kinetics: resoption, absorption and reabsorption
31
calcium absorption
* we absorb 30% of dietary calcium
* active absorption
* this is the majority
* duodenum and jejunum
* mediatedx by calcitriol (1,25-dihydroxyvitaminD3)
* calcitriol is upregulated in a low calcium diet to ensure a greater fraction is absorbed
* passive absorption
* happens in the ileum and the colon
32
calcium release from bone
* quickly from exchangable calcium on the bone surface
* more slowly from osteoclasts during bone resorption
33
calcium and the kidney
* 98% of calcium filtred through the glomerulus is reabsorbed
* reabsorption is increased when PTH level is high
* reabsorption is decreased when filtered sodium is high
* most of the reabsorption happens in the proximal conveluted tubule
34
1,25 (OH)2-D effect on parathyroid cells
* 1,25 (OH)2-D enters nucleus
* binds Vitamin D receptor on DNA
* reduces the synthesis of PTH
35
effect of calcium on PTH secretion
* very small changes in ionised clacium produce a big effect on the amount of PTH
* the parathyroid glands have calcium sensing receptors
* a narrow normal range of calcium must be maintained
36
actions of parathyroid hormone
* kidney
* increased Ca2+ reabsorption
* this is by decreasing phosphate reabsorption
* hydroxylation of 25,OH vit D (activation)
* Bone
* resorption at a faster rate than formation
* Gut
* increased Ca2+ absorption because of increased 1,25(OH)VitD
37
what is calcitriol
it is the active form of vitamin D
1,25(OH)2VitD
it is activated by 1a-hydroxylase and PTH causes this to happen
38
calcitriol action
* binds vitamin D receptor
* this mediatews the transcellular calcium absorption in the gut
* in a high calcium diet this is unecessary as it can move into the blood paracellularly
39
what is calcitonin
* a hormone produced by C cells in the thryroid
* its secretion is stimulated by an increase in serum calcium
* the effect is to lower bone resorption
40
fast and slow actions of PTH
* Fast:
* exchangable calcium is released from the surface of the bone
* excretion of calcium from the kidney is decreased
* Slow:
* increased bone resorption
* increased fractional absorption by the intestine (by activating 1a-hydroxylase which activates vitamin D)
41
what is normal serum ionised calcium?
1mmol/L
42
name some roles of phosphate in physiology
* Membranes
* ATP - energy source
* In DNA
* In activating/inactivating proteins via kinases
* As a bone mineral: calcium hydroxyapatite
43
what should total body phosphate be
* 500-800g
* 1% of total body weight
* 90% in bones
* serum phosphate --\> 0.8-1.5mmol/L
* 50% free ions
* 35% complexed with Ca, Mg or Na
* 10% protein bound
44
High phosphate
* excessive production of hydroxyapetite
* deposition in tissues other than bone
* e.g. artery calcification
45
low phosphate
* poor bone mineralisation
* rickets of osteomalicia
* pain and fractures
46
dietary sources of phosphate
dairy
soy
seeds adn nuts
meat
recommended daily intake is 700mg
47
gut absorption of phosphate
* in the small intestine
* passive diffusion at high concentrations
* active transport (Na dependent) at lower concentrations
* fractional absorption increases at lower concentrations
48
renal phosphate handling
* 90% of unbound phosphate is filtered
* 80% of this is reabsorbed in the proximal tubule
* 10% of this is reabsorbed in the distal tubule
* there is a maximum rate of reabsorption so excess is excreted
49
which factors regulate phosphate metabolism
* Parathyroid hormone
* 1,25 dihydroxyvitamin D
* FGF-23
* fibroblast growth factor 23
50
FGF-23
* major regulator of phosphate metabolism
* the abnormality in a rare form of rickets
* it causes hypophosphataemia
* produced by osteocytes in response to:
* high phosphate levels
* dietary phosphate loading
* PTH
* 1,25 vitamin D
51
FGF-23 actions
* increases expression of Na+ cotransporter in the tubules
* increases renal excretion of phosphate
* decreases 1a hydroxylation of vitami D
* decreases gut absorption of phosphate
52
two reasons that osteoclasts and osteoblasts must be able to communicate
* coupling
* bone formation must occur at sites of previous bone resorption
* Balance
* the amount of bone removed by osteoclasts should be replaced by osteoblastic activity
53
pleiotropism
a single cytokine, for example, has many different functional effects on many different cell types or even the same cell
54
RANK and OPG
* Rank ligand is secreted by osteoblasts or stromal cells and binds RANK on the osteoclast surface
* this is essential for osteoclast formation, function and survival
* OPG works by binding RANKL and blocking it so that it can't bind RANK
* this decreases resorption by osteoclasts
* inhibits differentiation of osteoclast precursors
* OPG knockout mice have osteoperosis (osteoclasts are uninhibited)
* mice with OPG overexpressed have increased bone density
* osteoclastic bone resorption is controlled by the balance between RANKL and OPG
* in this way osteoblasts regulate osteoclasts
55
3 broad classifications of joints - give a brief description and an example of each
* Synovial
* *capsule* encloses a joint *cavity*
* capsule has outer fibrous layer and inner serous synovial membrane
* bones covered by articular cartilage
* e.g. most of limb joints
* Fibrous joints
* no joint cavity and bones united by fibrous tissue
* e.g. sutures of cranium
* Cartilaginous
* bones united by cartilage
* in a *primary* cartilagenous joint hey are uited by *hyaline*
* in a *secondary* they're covered with *hyaline* but united by *fibrocartilage*
* e.g. joints between limb bodies
56
Subdivisions of synovial joints - just give name
1. Plane
2. Hinge
3. Condyloid
4. Saddle
5. Ball and Socket
6. Pivot
57
Briefly describe a plane joint and give an example
58
Briefly describe a hinge joint and give an example
59
Briefly describe a saddle joint and give an example
60
Briefly describe condyloid joints and give an example
61
Briefly describe a ball and socket joint and
62
Briefly describe a pivot joint and give an example
63
what are these muscles? give their nerve supply, blood supply and function
64
what is the nerve supply and the arterial supply of the sternocleidomastoid? What is its function
* Nerve supply:
* CN XI Spinal accessory nerve
* Arterial supply
* Superior thyroid artery
* Function
* Unilaterally: rotation to opposite side
* Bilaterally: cervical flexion
* Raises sternum to assist with forced inspiration
65
nerve and blood supply to rectus abdominus
* Nerve: T7 - T11
* Blood supply is superior epigastric
66
Blood supply to external and internal obliques
* It's the same for both
* Nerve T7-T12
* Blood: subcostal arteries
67
Nerve and bloos supply to pec major. What is its function?
* Nerve: lateral and medial pectoral nerves
* C5-8, T1
* Blood: pectoral branch of thoracocromial trunk
* Function:
* medially rotate and adduct shoulder
68
Nerve and blood supply to trapezius. What is its function?
* Nerve: C3-C4 and the spinal accessory
* Blood: superficial cervical artery
* Function: shrug shoulders
69
Nerve supply, blood supply and and function of lattisimus dorsii
* Nerve
* Thoracodorsal nerve
* Blood
* Subscapular artery
* Function
* Adducts, extends and internally rotates arm
70
Nerve and blood supply to rhomboid major and minor. What is their function?
* Nerve: C4-C5 Dorsal scapular nerve
* Blood:
* Dorsal scapular artery to the major
* Deep branch of transverse cervical artery to the minor
* Function: Retracts scapular
71
Nerve supply to the Deltoid. What is its function?
* Nerve: C4 the axillary nerve
* Function: shoulder abduction, flexion and extension
72
How many muscles are there in the anterior forearm - how many in each compartment
* Superficial compartment (5)
* Flexor carpi ulnaris
* Palmaris longus
* Flexor carpi radialis
* Pronator terres
* Flexor digitorum superficialis
* this is slightly deeper
* Deep compartment
* Flexor digitorum profundus
* Flexor pollicis longus
* Pronator quadratus
73
What are the muscles of the superficial compartment of the anterior forearm - go from ulnar side to the radial side. What do they all come off?
1. flexor carpi ulnaris
2. palmaris longus
3. flexor carpi radialis
4. pronator teres
5. deeper is flexor digitorum superficialis
they all originate from the medial epicondyle
Remember - your carpis and your palmaris are superficial
* waving is superficial
Also - the palmaris doesn't go through the carpal cunnel - it attaches to the flexor retinaculum
74
label this
75
which nerve supplies the muscles of the anterior compartment of the forearm
all supplied by the median nerve (C5-T1)
EXCEPT for the flexor carpi ulnaris and the medial half of flexor digitorum profundus which are supplied by the ulnar nerve
so medial two fingers are supplied by ulnar and the middle finger and the index finger are supplied by the median nerve
76
label this
77
What are the muscles in the deep compartment of the anterior forearm
Flexor digitorum profundus
Flexor pollicus longus
Pronator quadratus
78
Label this
79
innervation of the muscles of the deep compartment of the anterior forearm
* Flexor digitorum profundus
* medial half is innovated by the ulnar nerve
* the lateral half is innovated by the median nerve
* Flexor pollicus longus and pronator quadratus
* median nerve
80
Fill in this table
81
Label these - what are they?
82
Label this. What happens in the hand?
In the hand the radial and ulnar arteries anastomose to form the deep and superficial palmar arches
83
what does FGF 23 do?
* decreases the expression of the Na+/PO4- cotransporter in the proximal tubule
* this decreases phosphate reabsorption
* decreases 1 alpha hydroxylation of 23, dihidroxy vitamin D (calcidiol) in the kidney
* decreases gut absorption of phosphate
* decreases bone resorption
84
what is the major regulator of phosphate metabolism?
what is it produced by and in response to what?
FGF-23 (fibroblast growth factor 23)
produced by osteocytes in response to a rise in phosphate levels, PTH, calcitriol or dietary phosphate loading
85
what factor does FGF 23 need to work
klotho
86
what factor inhibits FGF 23 and what is this factor produced in response to?
PHEX which is produced in response to low phosphate
PHEX mutations lead to very high FGF23 which causes X linked hypophosphataemic rickets
87
what will result from low phosphate and what will result from high phosphate
* Hypophosphatemia: osteomalicia
* Hyperphosphatemia: calcification
88
difference between osteoporosis and osteomalicia
* Osteoporosis: Decrease in bone mass with normal ratio of mineral to matrix
* so bones are brittle and break easily
* Osteomalicia: The ratio of mineral to matrix is decreased
* so bones are softened
89
osteoclasts are derived from what?
macrophages
90
what is OPG and what does it do?
* osteoclastogenesis inhibitory factor
* it works by blocking the RANK - RANKL interaction
* it binds RANKL
* this RANK-RANKL interaction is essential for osteoclast formation, function and survival
* Therefore opg knockouts have very very low bone density because there is unregulated osteoclast activity
in health OPG secretion is regulated by cytokines and hormones (like PTH) and these are the master regulators of osteoclast activity. these factors may also have an effect on RANKL expression
91
osteoblasts are derived from what?
mesenchymal progenitors
92
functions of ligaments
* to attach to bones and:
* guide joint motion
* augment mechanical stability of joints
* prevent excessive motion
93
functions of tendons
* to bind muscle and bone
* transmit tensile load from muscle to bone
* provide solid base on which muscle can pull
94
what is the composition of tendons and ligaments
* dense connective tissue with mainly parallel fibres
* fibroblasts are 20% of tissue volume
* low cell number = generally poor healing
* ECM 80% of volume
* 70% of tissue wet weight is water
* poorly vascularised
* another reason it's bad at healing
95
label the layers of this tendon
96
what is the main type of collagen in tendons and what % of the dry weight of tendons is this?
Mainly type I and this is 90-95% of the dry weight
the rest is generally proteoglycan
97
collagen formation
* molecules synthesised within fibroblasts as procollagen
* three individual chains coiled round each other
* secreted out of the cell into EC space
* the terminal ends are cleaved and then there's covalent linkage to form microfibrils
1. microfibrils combine to form subfibrils
2. subfibrils combine to form fibrils
3. fibrils combine together to form fibres
4. fibres combine to form fascicles
5. fascicles group together to form tendons
98
In tendons: each fascicle is surrounded by a _______ and the fascicles are grouped together with \_\_\_\_\_\_\_
In tendons: each fascicle is surrounded by a **endotenon** and the fascicles are grouped together with **epitenon**
99
what are some differences between ligaments and tendons?
* ligaments connect to bone, tendons to muscle and bone
* ligaments have lower collagen
* ligaments have higher elastin content
* the fibre organisation is more random in ligaments
100
tendon and ligament healing
* some are good at healing and some are incapable - it depends on the location and the magnitude of the injury
* general course of healing:
1. short inflammatory phase (days)
2. proliferative phase (weeks)
* fibroblast proliferation and ECM formation
3. remodelling and maturation phase (months)
* decrease in cellular and vascular component
* increase in collagen I content
101
functional classification of joints and an example of each
1. synarthroses
* immovable, mainly fibrous
* e.g. skull sutures
2. amphiarthroses
* slightly movable, mainly cartilaginous
* e.g. IV discs
3. diarthroses
* freely movable joints, mainly synovial
* e.g. hip
102
types of fibrous joints
1. **sutures** - bones interdigitate and are connected with very short fibres
2. **syndesmoses** - bones connected by a cord or ligament i.e. the interosseus membrane
* amount of movement is proportional to length of fibre
3. **gomphoses**
* ****peg in socket fibrous joint found only in tooth articulation
103
types of cartilagenous joints
1. synchondroses
* hyaline connects the bone - e.g. costal cartilages
2. symphyses
* theres a pad or plate of connective cartilage
* e.g. pubis symphysis and IV disks
104
different parts of the IV disc and their properties
* nucleus pulposus
* proteoglycans bind water making it gel like
* annulus fibrosus
* tough shock absorber
105
joint classification summary - can you draw the diagram
106
what are the 5 characteristic features of synovial joints?
1. articular cartilage
2. joint capsule (inner layer of which is the synovial capsule)
3. synovial cavity (fluid filled)
4. synovial fluid
5. reinforcing ligaments
107
Hyaline cartilage
* Almost frictionless surface
* the key to painless articulation
* Resists compressive loads
* High water content
* Low cell content
* No blood supply
108
Ligaments stabilising the shoulder
* 3 glenohumoral ligaments
* the transverse humeral ligament
* coracohumeral ligament
* glenoidal labrum - fibrocartilage
109
what happems if you don't get rid of uric acid properly?
it may lead to gout
high uric acid levels in the blood lead to urate/uric acid crystals depositing in joints
the crystals then cause inflammation which causes the swelling pain and redness
110
where does uric acid come from?
purines like guanine and adenine
others include xanthine and hypoxanthine
these can come from diet, breakdown of nucleotides or they can be synthesised in the body
111
is uric acid soluble
it is poorly soluble and the lower the blood pH the less soluble it becomes
112
dietary source of purines?
meat and offal
113
why is gout less common in pre-menopausal women?
oestrogen promotes uric acid excretion
114
purine metabolism - can you draw the (very simple) diagram
115
what is the metabolic end product of purine metabolism in humans?
uric acid
116
HPRT is what
its an enzyme that converts purines back into nucleotides
so theyre recycled not turned into uric acid
so if you don't have enough HPTR it can cause uric acid excess
117
fill in this table
118
stages of fracture healing
1. Haematoma (hours)
2. Inflammation (days)
* Neovascularisation
* Invasion of:
* haemopoietic cells --\> express repair cytokines
* osteoclasts --\> resorb dead bone
* mesenchymal stem cells
3. Repair (weeks)
* Callus formation
* fibroblasts form fibrous tissue
* chondrocytes form cartilage
* osteocytes form osteoid
4. Remodelling (months to years)
* woven bone replaced by lamellar bone
* the only healing in the body without a scar
* increased bone strength
* vacularity returns to normal
119
what is the undividual functional units of bone?
an osteon
120
what is the canal in the middle of an osteon and what does it transmit?
the haversian canal and it transmits neurovascular and lymphatics
121
what are type 1 muscle fibres and where are they in their highest proportions
* these are slow teitch
* oxidative in terms of energy
* fatigue resistant and are found in their highest numbers in the postural muscles
* stain dark brown due to large amounts of fibrillar ATPase
* fibres contain large mitochondria that lie in rows between the myofibrils alongside fat droplets
122
what is one important enzyme to remmeber in purine degradation?
* xanthine oxidase
* purines are converted to xanthine to be degraded
* xanthine oxidase produces uric acid from xanthine
* gout medications inhibit xanthine oxidase to reduce the quantity of uric acid
123
what are type 2A muscle fibres and where are they in their highest proportions
* fast twitch muscle fibres
* use oxidative **and** glycolytic processes to obtain energy
* are moderately fatigue resistant
* stain pale due to low amounts of fibrillar ATPase
* large reserves of glycogen
124
what are type 2B muscle fibres and where are they in their highest proportions
* Fast twitch muscle fibres
* depend on glycolytic processes for energy
* are fatigue sensitive
* highest proportion of these is in sprint muscles
* large reserves of glycogen
125
what are sharpey's fibres
they are numerous collagen bundles that attach muscles to periosteum bone
unlike more discrete tendons they spread the attachment over a wide area
* Rotator cuff muscles have a wide origin of sharpey's fibres on the blade of the scapula
* They have a discrete tendonous insertion on the head of the humerus
126
difference between primary and secondary bone
* Primary
* collagen of the osteoid is randomly woven and calcium is amorphous rather than crystalline
* Secondary
* collagen organised into regular laminae
* calcium deposited as crystaline hydroxyapetite parallel to collagen fibrils
* this is lighter but stronger bone
* at birth most bone is still primary but eventually will be broken down and replaced with secondary
127
describe endochondrial ossification
128
explain what this is and what is happening in this picture
129
describe intermembranous bone development
* formation of flat bones of the skull
* no cartilagenous proformer
* process begins in the 2nd trimester of embryonic life
* small clusters of progenitor cells in primitive mesenchyme differentiate into osteoblasts
* these begin to lay down isolated islands of bone
* islands enlarge and form a meshwork
* bone is deposited by osteoblasts until the holes are filled
* this forms a plate of primary bone
* later primary bone is eroded and replaced with denser, lamellar secondary bone
130
how much calcium hydroxyapetite does mature bone normally contain?
5%
131
what are the two layers of periosteum
outer fibrous
inner more cellular layer
EM:
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