1
Q
What are the functions of bone?
A
- calcium regulation
- mechanical support and locomotion
- protection of vital organs
2
Q
What is the macrostructure of bone?
A
CORTICAL BONE:
- higher density
- low surface area
- low remodelling rate
- haversian systems
TRABECULAR BONE:
- lower density
- high surface area
- high remodelling state
- struts and plates
3
Q
What are the three main elements of bone tissue?
A
- a protein matrix, which is largely composed of type 1 collagen which accounts for over 90% of protein, with glycoproteins, proteoglycans and other proteins making up the remainder. Bone matrix is a reservoir of growth factors that are released on resorption
- a mineral component (75%) which accounts for Ca10(PO4)6((OH)2
- cells
4
Q
About the organic (osteoid) protein matrix…
A
- mainly type 1 collagen
- it is flexible, and provides tensile strength
- can be affected by diseases such as osteogenesis imperfect (brittle bone disease)
- the bone stores 99% of the bodys calcium and 85% of its phosphorus. it maintains the narrow serum calcium range.
5
Q
About the bone’s minerals…
A
- hydroxyapatite
- hydrated calcium and phosphate
- it is rigid and brittle, so provides high compressional strength
- vitamin D is converted by the kidney to its active form, which is important for bone mineralisation
6
Q
What types of bone cells are there?
A
Osteoblasts: synthesise bone
Osteoclasts: resorb bone
Osteocytes
7
Q
What are the functions of osteoblasts?
A
- synthesise metric proteins
- formation of bone mineral
- derived from mesenchymal stem cells
8
Q
What are the functions of osteoclasts?
A
- production of acid - dissolution of mineral
- production of proteolytic enzymes - digestion of matrix, cathepsin K, metalloproteinase
- transcellular removal calcium, phosphate, matrix
9
Q
what are the functions of osteocytes?
A
- sense of mechanical stress
- secrete sclerostin
- regulate phosphorus homeostasis
- osteocytes are the most numerous bone cells at 95%
- they live for decades in bone chambers
- signals to osteocytes - PTH, prostaglandin, GC, oestrogen
- osteocytes secrete regulators of phosphorus - FGF23, PHEX, MEPE, DMP1
- sclerostin - inhibition of OB and stimulation of OC
10
Q
How does bone mass change with age?
A
T score - comparing the patient to mean peak bone mass. with age, the average woman bone density will decline further from peak bone mass. therefore, with age more and more women will have a T score below -2.5 SD RR of fracture compared to cohort of younger women (age 30-40) with peak BMD
women reach a lower bone mass in alter life due to having attained a lower peak bone mass and then undergoing accelerated bone loss in 5 years after the menopause.
11
Q
What hormones would increase bone density?
A
- oestrogen/androgens
- growth hormone/IgF1
- calcitonin
12
Q
What hormones would decrease bone density?
A
- thyroxine
- glucocorticoids
- parathyroid hormone
13
Q
What are local regulators of bone?
A
Prostaglandins, PTH, GC, oestrogen affect osteocytes.
Osteocytes produce FGF23, PHEX, MEPE, DMP1 - regulate phosphorus homeostasis
14
Q
About bone fractures…
A
- fractures occur when force exceeds bones strength
- bone has good compressional strength
- bone has good tensile strength
- bone torsional strength is weaker
15
Q
What are the stages of fracture healing?
A
STAGE 1: macrophages remove debris, granulation tissue, fibrous tissue - vascularised
STAGE 2: A.) soft callus formed by osteoblasts B.) woven one (hard callus) formed by mineralisation
STAGE 3: lamellar bone formation and remodelling
16
Q
About parathyroid anatomy…
A
- 2 pairs
- 3-5 mm
- 30-50 mg
- closely related to thyroid
- may be ectopic
- 4 glands on upper and lower poles of each lobe of the thyroid gland
- supernumerary glands not uncommon
- chief cells and oxyphill cells
- supplied by blood from the inferior thyroid arteries (thyroid surgery)
17
Q
How does parathyroid development occur?
A
- from the dorsal part of the third pharyngeal pouch arses parathyroid III which becomes the inferior parathyroid gland
- occasionally parathyroid III or accessory parathyroid tissue formed from either the third or fourth pharyngeal pouches will be carried into the mediastinum by the migrating thymus
- parathyroid IV arises from the dorsal portion of the fourth pharyngeal pouch and migrates caudally, but ultimately becomes the superior parathyroid
18
Q
What are causes of hypercalcaemia?
A
HIGH PTH
- hyperparathyroidism
- cancer
LOW PTH
- cancer
- hypervitaminosis D: exogenous, granulomatous disease, William’s Syndrome
- increased bone turnover: acromegaly, thyrotoxicosis
- primary hyperparathyroidism
- malignancy (PTHrP)
- vitamin D related
- renal failure
19
Q
What is primary hyperparathyroidism?
A
- commonest cause of elevated PTH and calcium levels
- 0.5-5 per 1000
- older than 40 years
- female-to-male ratio of 3:1
- 85% of cases are single adenoma
- ## 15% caused by diffuse hyperplasia
20
Q
What is secondary hyperparathyroidism?
A
compensatory hyper functioning of the parathyroid glands caused by hypocalcaemia or peripheral resistance to PTH
- chronic renal insufficiency
- calcium malabsorption
- vitamin D deficiency
- deranged vitamin D metabolism
21
Q
What is tertiary hyperparathyroidism?
A
occurs following previous secondary HPT in which the glandular hyper function continue despite correction of the underlying abnormality
- renal transplantation
22
Q
What are hormonal causes of the hypercalcaemia of malignancy?
A
- PTH; small cell lung cancer
- PTH-RP; lung, lymphoma, multiple myeloma
- Osteoclast-activating factor; lymphoma, multiple myeloma
- Metastatic solid tumours; breast, lung, kidney, prostate
23
Q
What are granulomatous diseases?
A
Macrophages express 1 alpha hydroxyls and activate vitamin D
- sarcoidosis
- tuberculosis
- berylliosis
- coccidioidomycosis
- histoplasmosis
24
Q
What are signs and symptoms of hypercalcaemia?
A
Stones, bones and psychic moans
25
What investigations might be done for hypercalcaemia?
- calcium
- phosphate
- U&E magnesium
- vitamin D
- PTH
- Urinary calcium excretion
- CXR
- ACE
- Myeloma screen
26
What investigations would be done for increased PTH?
- SestaMIBI scan
- Ultrasound of neck
- USS renal tract
- DEXA
27
What investigations would be done for decreased PTH?
- bone scan
| - localisation of primary
28
What are possible treatments for hypercalcaemia?
- saline rehydration
- frusemide
- pamidronate infusion
- calcitonin
- prednisolone
- dialysis
- IV phosphate (not used anymore)
- mithramycin (not used anymore)
29
What is the treatment for hyperthyroidism?
- surgery
| - medical; observation, bisphosphonates
30
What are causes of hypocalcaemia?
- low PTH/action
- hypoparathyroidism
- high PTH
- vitamin D deficiency (renal disease, liver disease)
- pseudo-hypoparathyroidism
- pseudo-pseudo-hypoparathyroidism
- poor dietary Ca
- malabsorption
- chelation; massive blood transfusion
31
What can cause impaired PTH secretion or action?
- primary hypoparathyroidism: congenital, autoimmune
- secondary hypoparathyroidism: after neck surgery or trauma, radio iodine
- neonatal
- hypomagnesemia
- hypermagnesemia
32
What can cause impaired vitamin D synthesis or action?
- poor dietary vitamin D intake
- malabsorption
- liver disease
- renal disease
- hypomagnesemia
33
What can cause calcium chelation or precipitation?
- blood - citrate
- ethylene glycol
- pancreatitis
- rhabdomyolysis
- chemotherapy
34
What are signs and symptoms of hypocalcaemia?
- parenthesis
- laryngospasm
- bronchospasm
- tetany
- seizures/halucinations/confusion
- muscle cramps
- short of breath
- chvostek sign
- trousseau sign
- prolonged Q-T interval on ECG
35
What investigations might be carried out for hypocalcaemia?
- calcium
- phosphate
- U&E
- magnesium
- vitamin D
- PTH
- 1,25, di OH vitamin D
- malabsorption; B12, folate, coeliac screen
- amylase
36
What is the treatment of hypocalcaemia?
- treat underlying cause; discontinue offending drugs, correct other electrolyte disorders
- oral (enteral): up to 2g per day
- vitamin D supplementation
37
What is the treatment and signs of severe hypocalcaemia?
- IV 10ml 10% calcium gluconate diluted in 200ml N saline over 10 minutes
- carpopedal spasm
- fitting
- arrhythmia
- calcium
38
What is the treatment of vitamin D deficiency?
- calcium and vitamin D tablets 800-1000 IU daily
- vitamin D injection 300,000 IU every 6 months
- alpha calcidol (1alpha hydroxyl vitamin D) 0.25-1mg daily
39
What is pseudohypoparathyroidism?
Post receptor defect of PTH receptor; Ca2+, PO4, via D hydroxylation, PTH
- body habits; short stature, obesity, round face
- mental deficit
- brachydactyly
- ectopic calcification
40
What are the functions of calcium?
- bone growth and remodelling
- secretion
- muscle contraction
- blood clotting
- co-enzyme
- stabilisation of membrane potentials
- second messenger/stimulus response coupling
41
What are the functions of phosphate [H2PO4- and HPO42-]?
- element in: high energy commands e.g. ATP, second messengers e.g. cAMP
- constituent of: DNA/RNA, phospholipid membranes, bone
- intracellular anion
- phosphorylation (activation) of enzymes
42
What is the distribution of phosphate in the body?
50% free (controlled by kidneys and effects of PTH and FGF23)
50% bound
skeleton: 90%
intracellular: 9.97%
extracelular:
43
What is the distribution of calcium in the body?
skeleton: 99%
intracellular: 0.01%
extracellular: 0.99% (2.2-2.58mmol/l)
ionised Ca2+ 45% (controlled by PTH and vitamin D)
bound to plasma proteins (45%) and ions e.g. phosphate, lactate, HCO- (10%)
44
What are the basic stages of bone remodelling?
- differentiation of stem cells to osteoclasts
- resorption of bone
- mopping up debris by macrophages/mononuclear cells
- laying down of new osteoid and minerals by osteoblasts
Cycle: -->resorption-->reversal-->formation-->resting-->
45
How is osteoclast differentiation initiated by RANK ligand?
osteoblast stimulates the differentiation of osteoclasts by the production of RANK ligand.
This activates the RNAK receptor on the osteoclast precursor and via activation of nuclear kappa beta stimulates gene transcription and differentiation of osteoclasts.
OPG binding to RANK inhibits differentiation.
46
In what pattern/way is bone laid down?
Along lines of stress
47
How does bone act as an endocrine organ?
- osteocytes produce fibroblast growth factor 23 (FGF23)
- osteoclasts produce uncarbonated osteocalcin (uOCN)
- FGF23 acts on kidney to decrease synthesis of active vitamin D and to increase excretion of inorganic phosphate (Pi)
- uOCN acts on pancreatic beta cells to increase insulin production and secretion, on adipocytes to increase adiponectin and on muscle to increase insulin sensitivity and glucose uptake
48
What is the synthesis of PTH?
- signal sequence - 31 to -6 cleaved in ER
- hexapeptide -6 to 1 removed in golgi apparatus
- 1-84 intact hormone, fragments formed in secretary granules just prior to secretion
- sandwich assay (2 antibodies) detect whole hormone not fragments
- only 1-34 amino acids requires for full biological activity
- long N-terminally truncated PTH also in circulation
- ratio fo fragments to full length PTH increases when plasma Ca2++ is high
- T1/2 2-4 minutes for long fragments
- only 20% of circulating PTH is the full length PTH
49
How does intracellular calcium vary with plasma proteins and pH?
Increased plasma proteins and alkalosis = decreased iCa2+
| decreased plasma proteins and acidosis = increased iCa2+
50
How does the calcium sensing receptor work (CaSR)?
1. circulating calcium levels sense by Ca2+ receptor - when calcium levels are high
2. Gai inhibits constitutive activity of AC cyclase; cAMP and PKa production reduced
3. Gaq increases IP3 pathway. Intracellular concentrations of Ca2+ rise, PKA falls and PTH secretion is inhibited. Low levels of calcium decrease IP3, increase PKA and increase PTH secretion.
51
What are the actions of PTH?
- stimulate osteoblasts to produce M-CSF and RANK ligand --> increased bone resorption
- increase Ca2+ reabsorption in the distal convoluted tubule
- increase phosphate excretion
- increases 1-alpha hydroxylase in the proximal tubule
52
What are the actions of PTH on bone?
- production of M-CSF and RANKL
- osteoclast differentiation
- bone resorption, increased calcium and phosphate
- release of growth factors to stimulate maturation of osteoblasts and new bone formation
53
What are the actions of PTH in the kidney?
- activity of the cAMP/PKA pathway stimulates inception of epithelial Ca2+ channels in the luminal membrane of the distal convoluted tubule. Entry driven by the steep electrochemical gradient between the filtrate and the cytoplasm.
Calcium is bound and transported to the basolateral surface by calbindin.
PTH also stimulates the sodium calcium exchanger and the calcium ATPase
54
What are symptoms of hypercalcaemia?
NEUROLOGIC: decreased concentration, confusion, fatigue, stupor, coma
RENAL: polyuria, polydipsia, nephrolithiasis, nephrocalcinosis, distal renal tubular acidosis, nephrogenic diabetes insipidus, acute and chronic renal insufficiency
MUSCULOSKELETAL: muscle weakness, bone pain, osteopenia/osteoporosis
CARDIOVASCULAR: shortening of the QT interval, bradycardia, hypertension
GASTROINTESTINAL: anorexia, nausea, vomiting, bowel hypo motility and constipation, pancreatitis, peptic ulcer disease
55
What are the actions of Vitamin D in calcium homeostasis?
- increases Ca2+ absorption in the gut
- requires CaBP's - synthesis stimulated by Vitamin D
- synergises with PTH on bone
- inhibits PTH synthesis
- inhibits 1a-hydroxylase
56
How does paracellular transport of calcium across the epithelial cells of the intestine occur?
diffusion through tight junctions dependent on concentration gradient - does not require energy
57
How does transcellular transport of calcium across the epithelial cells of the intestine occur?
at apical region calcium enters the cell through a selective calcium transporter (TRPV), binds to calbindin, transported across cell and extruded at the basolateral membrane by a sodium-calcium exchanger and a Ca2+/ATPase transporter.
58
What are typical signs and symptoms of vitamin D deficiency?
- aches and pains in bones
- proximal myopathy
- mild hypocalcaemia - secondary hyperparathyroidism
- hypophosphataemia and hyperchloaemic acidosis
- bone deformities - osteomalacia
59
What are pathological conditions associated with abnormalities of the ECM?
- arthritis
- osteoporosis/osteopetrosis
- cancer
- diabetes
- ageing
- various genetic diseases
- scars/fibrosis
60
What is the ECM made up of?
1. ground substance components (e.g. glycoproteins, proteoglycans)
2. fibrous proteins (eg collagen, elastin)
61
How does the 3D organisation of the collagen fibrils determine the mechanical properties of tissues?
tendon/ligaments: parallel bundles
bone: spirals
cartilage: meshwork
62
What is the structure of collagen?
triple helix of 3 alpha chains ("super-helix"). Alpha chains are typically 3 amino acid repeats (GLY-x-y, where X is often proline and Y is often hydroxyproline).
63
How are collagen fibrils formed?
Triple helices cross-link to form a fibril (diameter 10-300nm)
Most common fibrillar collagens: I, II, III, V, IX
64
About Collagen IV (vs fibrillar collagens)...
- lack regular glycine = 'loose' helix; increased flexibility, sensitivity to digestion with proteases
- terminal peptides are to cleaved
- assemble Nehad to head and ultimately form a sheet
65
What affects synthesis of the extracellular matrix?
- increased TGFbeta (transforming growth factor beta)
- increased PDGF (platelet derived growth factor)
- decreased glucocorticoids
- decreased age
66
What affected degradation of the extracellular matrix?
- increased MMPs, matrix metalloproteinases
| - decreased TIMPs, tissue inhibitors of MMPs
67
What are examples of the matrix in normal health?
- embryo implantation, throughout development
- tissue homeostasis = constant remodelling
- pregnancy
68
What are examples in the imbalance of extracellular matrix in disease?
- arthritis/osteoporosis/osteopetrosis
- tumour invasion and metastasis
- scurvy
- ageing
- scarring/fibrosis
- many genetic diseases
69
What is the function of MMP1 (collagenase)?
MMPs are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Specifically, MMP-1 breaks down the interstitial collagens, types I, II, and III.
70
What are symptoms of scurvy?
- pale skin
- loss of teeth
- sunken eyes
71
What are examples of diseases caused by mutations in collagen genes?
- osteogenesis imperfecta (type I collagen mutation)
- achondrogenesis (type II collagen mutation)
- ehlers-danlos syndromes (type III or V collagen mutation)
72
About elastin...
- imparts elastic properties to tissues
- like collagen, is proline and glycine rich
- synthesised as a precursor --> troop-elastin (~72 kDa)
- after secretion, cross-linked to form elastic fibres
73
About elastic fibres...
- elastic fibres are more than just elastin
- elastin 'core' covered by a sheath of microfibrils
- microfibrils composed of glycoproteins, namely fibrillar
- microfibrils essential for integrate of elastic fibres (and contribute to assembly and organisation)
74
What is elastin degradation influenced by?
- elastase
| - alpha1-anti-trypsin (inhibits elastase)
75
What is the relationship between elastin synthesis and hypertension?
There is increased elastin synthesis in hypertension.
- 50% of the mass of large vessel walls consists of elastin (80% elastin and collagen)
- in hypertension, there is increased synthesis and deposition of elastin and collagen in vessel walls
- vessel walls are thickened
- diameter of vessel is reduced
- turnover of elastin (and collagen) is slow, so it is difficult to treat/recover
76
Why is there increased degradation of elastin in pulmonary emphysema?
- loss of elastin = reduced elasticity of the lungs
- sometimes due to deficiency in alpha1-anti-trypsin, which normally inhibits elastase.
- too much elastase = excessive degradation
77
What are problems caused by mutations in elastin?
- cutis laxa
| - marfan syndrome (can be caused by mutations in the fibrillin gene)
78
What is cartilage?
- avascular tissue, lacking innervation
- low metabolic activity and proliferation capacity (displaying both interstitial and appositional growth)
- chondrocytes embedded in extravascular matrix of collagen and proteoglycan (may be seen in lacunae, a histological artefact)
79
What types of cartilage are there?
- HYALINE CARTILAGE: type II collagen: embryonic skeleton, articularjoints, costal cartilage, respiratory passages
- ELASTIC CARTILAGE: elastin: ears, larynx, epiglottis
- FIBROCARTILAGE: type I collagen: annulus fibrosus, pubic symphysis, sites of repair or articular cartilage
80
By what process is the cartilage of the neonatal skeleton replaced with bone?
endochondral ossification
81
What is the basic structure of proteoglycans?
protein core with carbohydrate side chains
82
What are the stages of proteoglycan biosynthesis?
- translation in the RER
- GAG synthesis by glycosyl transferases in the golgi
- sulfotransferases in the golgi
- secretion and matrix assembly
83
How is sulphate taken in in the diet?
- methionine and cysteine
- inorganic sulphate
- including glucosamine sulphate and chondroitin sulphate
84
What is assimilated in sulphate metabolism?
- proteins (incorporation of methionine and cysteine)
- glutathione, S-adenysl methionine, taurine, CoA etc
- sulphated macromolecules e.g. proteoglycans (via PAPS, activated sulphate)
85
what is excreted in sulphate metabolism?
- inorganic sulphate, sulphated xenobiotics (e.g. paracetamol)
86
What are the stages of the assembly of the cartilage proteoglycan aggregate?
- hyaluronan
- aggrecan
- link glycoprotein
87
What is TGF-beta?
- abundant in bone and cartilage where it is store bound to decorin and biglycan
- stimulates mesenchymal cell growth and matrix production (during development and in fibrosis)
- decreases metalloproteinase and increases TIMP production
- predominantly growth inhibitory for most cell types; anti-inflammatory and immunosuppressive
88
What is interleukin-1?
- major pro-inflammatory cytokine produced by activated macrophages
- promotes matrix turnover by stimulating metalloproteinase release
- stimulates fibroblast growth and bone resorption by osteoclasts
- released in rheumatoid arthritis
89
What is the pathogenesis of osteoarthritis?
--> chondrocyte activation in response to cartilage damage: increased multiplication and metabolic activity with increase in matrix production
--> disruption normal matrix structure: collagen fibre size and arrangement, proteoglycan structure
--> gross cartilage damage - fibrillations (cracking of cartilage surface), erosion (subchondral bone exposure), fragmentation (cartilage fragments released into joint space)
--> other effects: joint space narrowing, eburnation of subchondral bone, stimulation of cartilage and bone formation at edge of joint (osteophytes)
90
What are proteoglycan functions?
- swelling pressure (resistance to comprehensive loads)
- lubrication, hydration
- matrix permeability
- collagen fibrillogenesis - determination of distance and adhesion between collagen fibres
- bone calcification
- cell adhesion
- growth factor binding
91
What are the basic functions of joints?
- transmit loads
- allow movement
- yet provide stability
92
What are the main classes of joint?
- FIBROUS JOINT (synarthrosis), immobile e.g. skull sutures, tooth socket
- CARTILAGINOUS JOINT (amphiarthrosis), slightly mobile e.g. intervertebral disk
- SYNOVIAL JOINT (diarthrosis), freely mobile e.g. limb joints
93
What types of movement are allowed by synovial joints?
- planar (sliding) joints eg inter tarsal joints (foot)
- simple hinge joint eg interphalangeal joint (fingers), humeri-ulnar (elbow)
- pivot ie rotational joints
- saddle joints e.g. carbo-metacarpal, base of thumb
- complex hinge with sliding and rotation e.g. the knee
- ball-and-socket e.g. hip, shoulder; maximum mobility, but least stability
94
What are the ways to achieve stability of joints?
- congruity (matching the shapes of the bone ends)
- fibrous capsule and its thickenings into extra articular ligaments
- intra-articular ligaments
- packing to improve congruity by menisci, fat pads
- muscles acting across the joint
95
How does cartilage work?
Smooth articulating surface: collagen parallel to surface
Type II collagen fibrils - hold it together - resist gel swelling tendency
Aggrecan - huge osmotic pressure inflates cartilage with water (gel swelling pressure)
Chondrocytes - secrete the collagen, proteoglycans and hyaluronan
Hyaluronan - tethers the aggrecan
96
What is a model of how collagen works?
Balls in a string bag can support a load but neither can alone.
Network of string (collagen) enclosing balloons (water drawn in osmotically by proteoglycans - 'gel swelling pressure')
97
What are the key features of synovial fluid?
- an ultra filtrate of plasma generated by fenestrated capillaries just below synovial surface
- electrolyte and plasma protein content similar to other interstitial fluids
- actively secreted molecules lubricant and hyaluronan are added by the synoviocytes
- lubricin, a glycoprotein, lubricates cartilage under conditions of high load and low velocity (boundary lubrication)
- hyaluronan is a gigantic non sulphated GAG, Mw 6 million, hydrated radius 100-200nm (bigger than viruses!). Makes synovial fluid very viscous (syn-ovium = like egg white). Lubricates synovial surface and cartilage under conditions of low load and high velocity (hydrodynamic lubrication - like oil in a car engine)
- volume of fluid is tiny - thickness of fluid film is normally only 10-100mm
- volume increases 10-100 times in arthritis - called joint effusion
- pressure varies with joint angle; sub atmospheric in extension, rising about atmospheric on flexion. So fluid enters joint in extension and is driven out of it on flexion
- in arthritic joint effusion, pressure is above atmospheric even in extension and pressure-angle relation is extremely steep. A minimum pressure at a certain angle determines the affected joints 'angle of cease'.
98
What types of arthritis are there?
- ACUTE: monoarticular (1 joint), polyarticular (>1 joint), caused by infection or injury
- CHRONIC: monoarticular (1 joint), caused by immune-mediated, degenerative e.g. OA or other reasons
99
What is osteoarthritis?
- primarily a mechanical breakdown of articular cartilage
- 'fibrillation' and denudation (erosion, sometimes to bone)
- due to collagen fibril rupture and aggrecan loss
- associated with ageing, mechanical dysfunction, obesity
- inflammation of synovium (synovitis)
100
What is inflammatory arthritis?
eg rheumatoid arthritis
- primarily an inflammation of synovium by mediators such as prostaglandin E2, bradykinin, histamine, NO cytokines
- mediator release triggered, in case of rheumatoid, by an autoimmune mechanism
- secondary erosion of cartilage by invading hypertrophic synovium ('pannus'), which releases metalloproteinases
101
What are features of postnatal muscle development?
- no increase in muscle fibre number - it is genetically determines
- growth involves an increase in several muscle fibre parameters which is reflected in increased strength
- growth is accompanied by changes in myosin isoforms
- growth involves activation of satellite cells in a fashion akin to the muscle fibre regeneration process - effect of micro-damage
- growth is under systemic and local control by the growth factor endocrine axis
102
What does normal growth and development of the limb require?
- normal cell numbers
- normal locomotor elements e.g. bone, joint, muscle
- normal blood and nerve supply
103
In what parameter does muscle grow by?
by increasing muscle fibre diameter not number
104
What does music size and function increase in proportion to?
Body mass
105
What are type 2B muscle fibres?
MHC2B containing muscle fibres (Type 2B) are fastest, gain energy solely from glycolysis, do not contain myoglobin, hence are 'white' and are the largest and strongest fibres.
106
What are type 2a muscle fibres?
contain MHC2A and are intermediate in velocity and fatigue resistant but may use glycolysis and the Krebs cycle for energy
107
What are type 1 muscle fibres?
The slowest contracting, contain MHC1, gain energy aerobically via the krebs cycle and oxidative phosphorylation (many mitochondria). They are 'red' in appearance due to a high myoglobin content. They produce less power then 2B fibres but are much more resistant to fatigue
108
What are the types of myosin?
There are at least 6 kinds of MHC in skeletal muscle, 2B, 2A, 2X, 1, embryonic and neonatal.
These proteins are coded for by separate genes as are the various isoforms of MLCs. Each muscle fibre in the adult will contain one of either 2B, 2A, 2X or 1.
This is a stain for the catalytic activity of the MHC ATPase. Very useful for the diagnosis of a myopathy.
109
What factors affect muscle fibre type/muscle properties?
- cell lineage
- hormones
- load/stretch
- motor neurones; neurotrophic substances, electrical activity
110
How does muscle grow in response to intense exercise?
When the muscle in subjected to intense exercise/injury activation postnatal growth occurs.
A satellite cell will undergo asymmetric division, the produced myoblast will mature and then fuse to the muscle.
111
What is muscle fibre hypertrophy?
increased diameter and hence contractile force
112
What is the cycle of muscle fibre hypertrophy?
1 - resting myofiber
2 - intense exercise and micro trauma
3 - progenitor cell activation and proliferation (can undergo self-renewal to stage 1)
4 - chemotaxis to injured fibre
5 - fusion to damaged myofibril (hypertrophy) OR fusion to produce new myofibers (hyperplasia)
6 - regenerated myofibril with central nuclei
113
What are motor units of muscle cells?
MOTOR UNIT: a group of muscle cells sharing one motor nerve.
- muscle cells in the motor units
- neuromuscular junctions: one for each cell in the motor unit
One nerve contacts many muscle fibres but one muscle fibre is supplied by only one nerve
114
What is motor unit recruitment?
A measure of how many motor neurones are activated in a particular muscle, and therefore is a measure of how many muscle fibres of that muscle are activated. The higher the recruitment the stronger the muscle contraction will be.
115
How has a marathon runner adapted to their environment?
- muscles small but fatigue resistant
- muscle dense and strong for their size
- high oxidative capacity of muscles
- work over very long periods of time
- not explosive strength
116
How has the sprinter adapted to their environment?
- rapid powerful contractions
- easily fatigued at maximum effort
- low oxidative capacity via mitochondria
- high force per cross-sectional area of muscle
117
How has the powerlifter adapted to their environment?
- muscles are hypertrophied
- highly glycolytic
- fatigue easily
- high muscle to total body mass ratio
- muscle size beginning to interfere with locomotion
Thus, the powerlifter is moving along the same path of adaptation as the sprinter but is more extreme. His power to weight ratio is moving to a point where he is less able to move his body through a distance and hence would be less fast at running.
118
What is strength training?
high impact resistance training with maximum weights - increases type 2 myosin, increases IGF-1 release and induces muscle fibre hypertrophy. It also increases glycolytic pathway capability
119
What is endurance training?
low impact cardiovascular training - induces mitochondrial replication and increases in size and complexity, increased myoglobin content giving rise to increased oxidative metabolic capability and hence fatigue resistance. Also induces type 1 slow myosin to generate low force over long periods of time.
120
What happen when muscle gets smaller?
- adaptive reduction in fibre diameter
| - pathological atrophy due to disuse or disease
121
What happens in ageing muscle?
- muscle fibres die
- muscle atrophy
- muscles get weaker
- nerves remodel (lose and rearrange connections with muscles)
- muscles contract more slowly
122
Why is Alzheimers important to study?
- common
- relevant for GPs
- economic burden
- 2nd commonest cause of working days lost
- cost to nation £5.7 billion annually
123
What are cardinal signs of inflammation?
- swelling
- redness
- heat
- pain/tenderness
124
What are important tests for septic arthritis?
- joint aspiration and blood cultures
| - essential to consider it before treatment
125
What type of arthritis can be life threatening?
SLE
| Septic arthritis
126
Is raised serum rate level diagnostic of gout?
hyperuricaemia --> acute gout --> chronic tophaceous gout
127
What is the drug treatment for gout?
- 2 step drug treatment
STEP 1: treat acute attack - aim is to reduce inflammatory response to crystals: NSAID, colchicine, (steroids)
STEP 2: prevent further attack - to reduce serum uric acid level (xanthine oxidase inhibitors, allopurinol, febuxostat... other: urocosuric drugs e.g. benbromarone, pegloticase (synthetic uricase))
128
What are the treatments of gout?
- LIFESTYLE - reduce risk factors:diuretics, weight loss, dietary purine reduction - red meat/shellfish, alcohol reduction, less sugary/fructose drinks
- INCREASE INTAKE OF: cherries, vitamin C, coffee
129
What are risk factors for gout?
- high BMI
- hypertension
- high triglycerides
- loop/thiazide diuretics
- spouse with gout!
130
What is the damage process of inflammatory arthritis?
inflammation --> joint damage and deformity --> disability
RA synovitis leads to deformity
RA deformity leads to disability
131
What are the aims of RA drug treatment?
- to switch off joint inflammation EARLY
- prevent bone erosions and joint deformity
- prevent disability
132
What are disease modifying drugs (DMARDs)?
- start EARLY - within 3 months
- oral; methotrexate, sulfasalazine, HCQ
- injections; biologics eg antiTNF drugs
133
What are the signs of inflammatory arthritis?
- pain worse with rest
- early morning stiffness (EMS) > 30 mins
- systemic symptoms
- tenderness
- soft swelling
- joint may be hot or red
- pathogenic autoantibodies
134
What are signs of degenerative arthritis?
- pain worse with exercise
- minimal EMS
- no systemic symptoms
- tenderness
- hard (bony) swelling and pain on weight bearing or after use
- no autoantibodies
135
What are different patterns of arthritis?
- rheumatoid arthritis
- osteoarthritis
- MCP/PIP/wrist joints
- DIP/1st CMC joint
136
What is the aetiology of osteoarthritis?
- genetic - e.g. nodal OA affecting DIPJs
- age
- trauma
- obesity
- malalignment
- other
137
What are the treatments of osteoarthritis?
- aim to reduce symptoms
- no disease modifying treatment available yet
- analgesia/NSAIDS
- lifestyle; weight loss, exercise
- surgery; joint replacement - arthroplasty
138
What is the treatment of inflammatory arthritis?
- disease modifying drugs
- analgesia/NSAIDs
- lifestyle e.g. smoking
- surgery (synovectomy, arthroplasty)
139
What is the treatment of degenerative arthritis?
- no disease modifying drugs available yet
- analgesia/NSAIDs
- lifestyle (weight loss)
- surgery (arthroplasty)
140
What is ankylosing spondylitis aetiology?
- genetic: HLA B27
- immunological: role of CD8 cytotoxic T cells
- environmental: infection
141
What are the treatments of ankylosing spondylitis?
- NSAIDs
- analgesia
- aTNF treatment
- daily exercises - to prevent kyphosis
142
What are the aims of the treatment for ankylosing spondylitis?
- reduce inflammation
- reduce spine damage
- reduce disability
143
About peripheral nerves...
- bundles of axons, schwann cells, myelin and supporting cellular tissues
- communicate neural information between CNS and peripheral sensory or effector structures (muscle, sweat glands, blood vessels etc)
- action potential --> saltatory conduction
- speed of signal sent along the nerve = conduction velocity
- dependent on 2 main factors (myelination and fibre diameter)
144
What is conduction velocity dependent on?
myelination and fibre diameter
145
About sensory nerves...
- afferent pathways providing both conscious and non-conscious sensation
- touch
- nociception
- temperature
- joint position
- vibration sense
- enteroception
146
Where are cell bodies?
dorsal root ganglia
147
What is a motor unit?
- a functional structure consisting of a motor neurone and the muscle fibres it innervates
- cell body is in spinal cord
- important parts: motor neurone, neuromuscular junction, muscle
148
What is peripheral neuropathy?
pathology of the peripheral nerve
149
What is plexopathy?
pathology of the plexus
150
What is radiculopathy?
pathology of the nerve root
151
What is myelopathy?
pathology of the spinal cord
152
What is myopathy?
pathology of muscle
153
What are the various types of peripheral neuropathies?
- mononeuropathy: one nerve is affected
- mononeuritis multiplex: several separate nerves are affected
- polyneuropathy: several nerves are affected
154
What is charcot-marie-tooth disease?
- the most common inherited neuropathy
- 1/2500 caucasian population
- usually presents with length-dependent sensory motor neuropathy
- clinically and genetically heterogeneous
- very complicated and evolving classification system
- demyelination
- majority are autosomal dominant
- present in 1st 2 decades with lower limb motor symptoms
- 70% of european cases due to duplication of the peripheral myelin protein 22 gene (PMP22)
155
What are the symptoms of charcot-marie-tooth disease?
- distal wasting/sensory loss
- weakness
- hyporeflexia (lower limbs > upper limbs)
156
What possible neuropathies could be caused by trauma/compression?
- carpal tunnel
- ulnar neuropathy at the elbow
- post-surgical
157
What toxic substances could cause neuropathies?
- alcohol
- chemotherapy (especially platinum based)
- metronidazole/nitrofurantoin/phenytoin
158
What infections could cause neuropathies?
- HIV
| - only poliomyelitis
159
What inflammations could cause neuropathies?
- Guillain-Barre syndrome
| - Vasculitis
160
What are common causes of mono neuritis multiplex?
- vasculitis
- diabetes
Can become confluence over time, giving the appearance of a polyneuropathy
161
What is the most common cause of polyneuropathy?
diabetes
162
What is small fibre neuropathy?
- small unmyelinated peripheral nerve fibre
- distribution of polyneuropathy
- most common cause = diabetes
- paraesthesia = burning/electrical
- hyperalgesia
163
What is Guillain-Barre Syndrome?
- most common cause of acute neuromuscular weakness
- inflammatory
- post-infective (most common cause Campylobacter jejuni)
- incidence = 1-2/100,000
- present with progressive ascending sensorimotor paralysis with arefelxia
- nadir in less than 4 weeks
- medical emergency --> some patients will develop tetra paresis and require ventilation within 48 hours
- require respiratory monitoring (if rapidly progressive --> elective intubation)
- Rx - IVIG
- outcome - 5-8% mortality, 1/3 left with significant disability
164
What is motor neurone disease?
- progressive neuronal degenerative disease
- prevalence 4-8/100,000
- leads to severe disability and death
- amyotrophic lateral sclerosis is the most common (ALS)
- upper and lower motor neurone (bulbar/upper limb/lower limb)
- wasting, fasciculations, weakness, dysphagia, dysphonia, dysarthria, brisk reflexes)
- supportive management
165
What is plexopathy?
a disorder affecting a network of nerves, blood vessels, or lymph vessels. The region of nerves it affects are at the brachial or lumbosacral plexus. Symptoms include pain, loss of motor control, and sensory deficits
- usually post-infective/post-traumatic
- constellation of symptoms dependent on location and extent of plexopathy
166
What is radiculopathy?
a set of conditions in which one or more nerves are affected and do not work properly. The location of the injury is at the level of the nerve root.
Common causes:
- arthritis
- prolapsed disc
- radicular pain
- if severe: weakness and wasting
167
About myelopathy...
(disease of the spinal cord)
- signs dependent on the level of the cord pathology
- common cause = disc herniation, trauma, neoplastic
- upper motor neurone signs
- sensory levels
- upper cervical = diaphragmatic paralysis
To the side of damage on the spinal cord, you will get ipsilateral loss of tactile sensation and proprioception, and contralateral loss of pain and temperature sensation.
168
What are neuromuscular transmission disorders?
- most common is myasthenia gravis
- autoimmune disorder
- antibodies directed against the AchR in the muscle membrane
- fatiguable weakness, blurred vision, diplopia, ptosis
- symptoms worse by the end of the day or following exertion
169
What would be the treatment for neuromuscular transmission disorders?
- SYMPTOMATIC: anticholinesterases
- DISEASE MODIFYING: immunosuppression (steroids, immunosuppressant drugs, immunoglobins, plasma exchange)
- thymectomy
170
What are symptoms of myopathy?
- weakness
- wasting
- pain
- cramps
- stiffness
- fatigue
- pigmenturia
- acquired: inclusion body myositis, dermatomyositis, polymyositis, steroid-induced
- inherited: muscular dystrophy
171
What is inclusion body myositis?
- most common acquired myopathy
- disease of alter life
- uncertain aetiology
- wasting/weakness of quadriceps and deep finger flexors
- foot drop/dysphagia in some
- no effective treatment
172
What investigations might be done for inclusion body myositis?
- CK
- EMG
- muscle biopsy
173
What is Duchenne muscular dystrophy?
- most common inherited muscle disease
- x-linked recessive
- 1/3600 boys
- disability in early childhood
- death in 20s
- mutation of the dystrophin
174
What is growers sign?
using hands to push on legs to stand up - sign of duchenne muscular dystrophy
175
What are signs and symptoms of duchenne muscular dystrophy?
- shoulders and arms are held back awkwardly when walking
- swayback
- weak butt muscles (hip straighteners)
- knees may bend back to take weight
- thick lower leg muscles (but the 'muscle' is mostly fat and not strong)
- tight heel cord (contracture); child may walk on toes
- weak muscles in the front of the leg cause 'foot drop' and tip toe contractures
- belly sticks out due to weak belly muscles
- thin, weak thighs (especially front part)
- poor balance and falls often
- awkward, clumsy if walking
176
What are the investigations that might be done for duchenne muscular dystrophy?
- most important thing is the history and examination
- bloods: exclude metabolic/toxic
- MRI: structural
- NCS/EMG: functional
- nerve biopsy
- muscle biopsy
177
What parts of our body comes from SOMITES?
- axial skeleton; vertebrae, ribs (sternum)
- axial muscles; vertebral, thoracic, abdominal
- appendicular muscles; flexors, extensors
178
What parts of our body comes from LIMB BUDS?
- appendicular skeleton; limbs, digits, girdles
179
In what kind of pattern are somites produced in?
They are produced one at a time in a sequential process, starting from the front end (PSM) and are then pushed along in a way.
The development of the somite is very much dependent on the surrounding tissues and vice versa. The somites develop in little balls of cells, and at this stage they are relatively undifferentiated. As the somite matures, and as more and more are added behind it, it differentiates.
180
What controls the regular production of somites?
Cycles of notch and Wnt gene expression in pre-somatic mesoderm.
This is controlled, and kept symmetrical, by Wnt, FGF and retinoid acid gradients.
At the same time as their formation, each somite develops an 'identity' e.g. cervical or thoracic or lumbar.
181
What are the various populations of cells the somite produces as it matures and differentiates?
- sclerotome
- dermatome
- myotome
[sometimes dermatome and myotome called dermamyotome as they lie closely together]
(- syndetome)
182
What is the sclerotome?
will migrate individually away from the somite. This population is going to become BONE.
Ultimately the sclerotome migrates and surrounds the neural tube, and becomes the precursors for the bone of the back - becomes vertebrae.
183
What is the dermatome?
going to become skin
184
What is the myotome?
going to become MUSCLE
185
What is the syndetome?
becomes tendons - it lies between the sclerotome and the myotome (i.e. between muscles and bones) and so joins them together.
186
How is an individual vertebra formed?
from the sclerotome from two half somites - the caudal part of one somite and the cranial part of another. This is to do with the relationship with the surrounding structures - the growth of the spinal nerve from the neural tube growing out splits the sclerotome part of the somite into cranial and caudal parts. At the most cranial end, the first 5 will come tighter and form the occipital bone.
187
What is the fate of the sclerotome?
most bones develop as a cartilaginous precursor which is then slowly ossified, with continued growth postnatally at growth plates. This is called endochondrial. In contrast, bones of the face and skull ossify directly without a cartilage stage.
- most cranial 5 somites = occipital bone
- centrum, surrounds the notochord
- neural arches (spina bifida occulta if fail to fuse)
- costal process
- sternum
- continues interaction with adjacent tissues
the notochord persists only in intervertebral disks as nucleus pulposus
188
What are possible abnormalities of the sclerotome?
- abnormal segmentation - hemivertebre or fused vertebra, scoliosis, congenital, kyphosis
- klippel-feil syndrome (brevicollis) - short neck, reduced number of cervical vertebra
- failed fusion or non-union of arches; spina bifida occulta
- non union of sternum; split xiphoid process
189
In what way does the limb bud develop?
The limb develops in a progressive way, not a segmental way. The limb buds elongate and will eventually become a limb.
190
What are the steps of limb bud development?
1. ) INITIATION - the deciding of where the limb is going to develop, the particular somite region triggers the development of the limbs
2. ) LIMB BUD PATTERNING - the limb bud grows like a kind of paddle. As it develops it becomes patterned along the proximal to distal axis (cranial to caudal) which will distinguish what is the ventral and dorsal side of the limb bud
3. ) DIGIT PATTERNING AND SCULPTING - for digits, they are sculpted away rather than being grown. There is an ectodermal ridge along the leading edge of the developing digits.
191
About limb buds...
Limb buds grow from lateral mesoderm and overlying epidermis (ectoderm). They form all appendicular skeletal and connective tissues (tendons, ligaments, cartilage) but not muscles (from somites).
They are induced to develop (FGF10 is key signal) by particular somites (hox controlled). Fore and hind differences controlled by Tbx5 (Holt-Oram gene) and Tbx4 transcription factors. Muscle cells are attracted from somites by HGF (aka scatter factor; c-met receptor in myotomes).
192
What three axes is the limb patterned in?
- proximal to distal (shoulder to finger)
- posterior to anterior (little finger to thumb)
- dorsal to ventral (e.g. back to palm of hand)
193
What is sonic hedgehog?
The signal from the caudal part of the limb bud. There is also a signal that comes from the apical ectoderm ridge.
194
What controls digit pattern?
a morphogen gradient
195
What controls the growth and patterning of the limb?
reciprocal interactions between the apical ectodermal ridge (AER) and the underlying mesoderm (progress zone) and the zone of polarising activity (ZPA).
196
In what order do the bones of the limb develop?
proximal to distal
All other limb tissues are patterned by this bone template - the AER maintains the 'progress zone'
197
What is the progress zone?
The progress zone is maintained as proliferative by FGF8 from the AER. Removal of the AER results in distal truncation.
The theory is that as cells leave the progress zone they have a proximo-distal identity. The first cells to leave are proximal.
The hot genes (master transcription factors) are involved, both in patterning in the long bones, and the digits. The same gives somites their identity.
198
About the separation of digits...
- digital rays of condensed mesenchyme in hand plate and foot plate
- notches between rays as mesenchyme breaks down
- breakdown is due to programmed cell death (apoptosis)
- blocking apoptosis leads to syndactyly
Separate digits are produced by programmed cell death of the interdict areas. Before they die, these areas are the source of signals reinforcing digit identity. BMPs (bone morphogenic proteins) are important signals here.
199
What is fibrodysplasia ossificans progressive (FOP)?
missense mutation in action receptor IA (ACVR1), a BMP type I receptor, leading to promiscuous activity.
There are characteristic big toe malformations which are one clue to BMP pathway, allowing it to be picked up clinically.
In FOP, fibrous soft tissue is converted into bone. This is caused by a subtle abnormality in one of the receptors of BMP (ALK2) - it remains at bit active even when there is no BMP around - so their soft tissues are receiving signals as if there was BMP around - meaning as adults bone would be developed (which is only meant to happen in embryos), so their soft tissue ends up being turned into bone.
200
What are possible clinical defects of the limb bud?
- loss of elements: amelia, meromelia, phocomelia (micromelia - all small)
- digits: loss: extrodactyly, Extra: polydactyly, fused: syndactyly (polysyndactyly; hoxd13)
- club hand or foot
- club foot most common defect to be found in humans, the mechanism is largely unknown but it is not a patterning defect
- congenital hip dislocation (acetabulum roof flat)
- amniotic bands: constriction/amputation of limbs or digits
Most abnormalities in the limbs are caused by abnormalities in the 3 axis patterning process or digit sculpting process e.g. thalidomide - long bone snot developed properly but goes straight on to develop the digits straight away.
201
What does the spinal nerve do in relation to the myotome and dermatome?
They are not split, but rather the nerve establishes a contact with these tissues that persists as segmental innervation throughout life, for example giving motor control for any particular muscle. This also has implications for the patterning of dermatomes.
202
How are nerves spaced in dermatomes?
The dermis is segmentally innervated by spinal nerves, in 'dermatomes'. On this basis in clinical exams you can test the function of spinal nerves by testing the sensory function on different parts of the body.
Limbs rotate so that even spacing of dermatomes are changed by adulthood - the plantar surface of the foot started out as a ventral surface for example. The abdominal and thoracic areas remain quite regularly striped however.
You can sometimes see the dermatome stripes under disease conditions, for example in shingles which is a viral infection caused by varicella zoster.
203
What are other consequences of somite segmental relationships?
- cranial and caudal halves of adjacent somites make centrum
- intersegmental arteries between somites come to lie midway over bodies
- myotomes bridge intervertebral disks, so can move vertebrae
- spinal nerves pass through somites, but come to run through intervertebral foramina.
204
In what way does the myotome migrate?
The myotome migrates along way, like the sclerotome. The population that is towards the back of the embryo is the EPIMERE and toward the ventral surface is the HYPOMERE.
The epicure lies dorsal to the transverse process, and the hypomere lies ventral.
205
What happens in the migration of the myotome and formation of muscle groups?
- epaxial muscles are the muscles of the back and hey develop from the epicure
- hypaxial muscles develop from the hypo mere
- muscle patterns are dictated by connective tissue
- limb muscles migrate from hypo mere in two streams, forming the extensor and flexor compartments of the limb. The early bone precursors pattern muscle development.
- molecular signals from adjacent tissues regulate the differentiation of the somite into its. pairs
206
What signals is somite development regulated by?
Somite development is regulated by soluble signals secreted from adjacent tissues...
- notochord and floor plate to sclerotomes - Shh, noggin
- dorsal neural tube to epaxial myotome - Wnt
- dorsal (surface) ectoderm to hypaxial myotome - BMP4
- dorsal neural tube to dermatome - NT3
- reciprocal sclerotome/dermomyotome interactions
207
What do myogenic factors do in relation to the myotome?
Cells in the myotome are myogenic precursors that will differentiate and fuse together to produce muscle fibres. This sequential process is controlled by transcription factors called 'myogenic factors'.
The so called myogenic factors drive skeletal muscle specific cellular differentiation. PAX7, MyoD, myogenic, Myf5, MRF4. The myogenic factors are transcription factors expressed only in myoblasts and muscle fibres and drive the differentiation of muscle cells in the embryo.
208
What does muscle fibre regeneration involve?
satellite cells (muscle stem cells) and recapitulates embryogenesis. Regeneration is a recapitulation of embryogenesis i.e. satellite cell division and differentiation is again controlled by Pamrf4.x7, Myf5, MyoD, Myogenic and MRF4
209
What is the development of a functional muscoxluskeletal system dependent on?
- mechanical regulation of cartilage morphogenesis
- joint formation
- bone morphogenesis and tendon
- mechanical load controls skeleton and tendon development
210
What is the mature neuromuscular circuit made up from?
spinal cord --> motor neurones --> neuromuscular junction --> muscle fibres (cells)
211
How does the neuromuscular junction develop?
- growth cone of axon approaches muscle fibre
- growth cone forms contact with muscle fibre surface
- terminal differentiates, basal lamina appears in cleft, specialised extracellular matrix, 'defines' the NMJ
- multiple axons converge, AChR laid down on muscle surface and competition of axons - one wins!
- all axons bar one are eliminated, axon develops myelin sheath
- increase in AChR density and elaboration of the post-synaptic membrane
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