MSK Flashcards
What is the structure of a collagen fibre?
AA chain
Collagen chain
3 collagen chains form helix
Group to form fibril
Group to form fibre
What is the primary structure of collagen?
Triple repeat of glycine and 2 other AAs
Allows collagen to form chains and crosslinks
What is the structure of type 1 tropocollagen?
3 collagen chains- 2 alpha 1 chains, 1 alpha 2 chains form 3-stranded tropocollagen molecule
What happens in processing of type 1 collagen?
Ends (P1NP, P1CP) are cleaved off and released into circulation
What does tropocollagen go on to form?
tropocollagen modules are assembled into a collagen fibril
What holds tropocollagen molecules and fibrils together?
tropocollagen molecule and the fibril are held together by covalent crosslinks (both intra and intermolecular) derived from lysine/hydroxylysine side-chains
What are the different ways of joining collagen?
Covalent cross links within and between helix and tropocollagen- needs copper
H bonds within triple helix- needs vit c
How is collagen broken down?
collagenases and cathepsin K in bone break down collagen
normal for repair and replacement
can become pathological
What happens when type 1 collagen breaks down?
The telopeptides (NTX and CTX) are removed
What are the types of collagen and what are they for?
Type I – bone, tendon, ligaments, skin
Type II – articular cartilage, vitreous
Type III – alongside Type I – wound healing
Type IV - basal lamina
Type V – cell surfaces
Type X – growth plate
What is the shape of long bones?
tubular shape with hollow shaft and ends
expanded for articulation with other bones
What is the shape of short bones?
cuboidal in shape
What is the shape of flat bones?
plates of bone, often curved, protective function
What shape are sesamoid bones?
round, oval nodules in a tendon
What are cortical bones?
Dense, solid, compact
only spaces are for cells and blood vessels.
What are trabecular bones?
Network of bony trabeculae, looks like
sponge, many holes filled with bone marrow.
Cells reside in trabeculae and blood vessels in holes
How is woven bone made?
Made quickly
Disorganised
No clear structure
How is lamellar bone made?
Made slowly
Organised
Layered structure
What is the adult bone composition?
10% water
50-70% mineral, hydroxyapatite
20-40% organic matrix (90% type 1 collagen)
What is the function of hollow long bone?
keeps mass away from neutral axis
minimizes deformation
What is the function of trabecular bone?
gives structural support while minimizing mass
What is the function of the weak ends of bones?
spreads load over weak, low friction surface
What is the function of flat bones?
Protective
What are the cells of bone and what are they like?
Osteoclast- multinucleated
Osteoblast- plump, cuboidal
Osteocyte- stellate, entombed in bone
Bone lining cell- flattened, lining the bone
What cells do osteoblasts originate from?
Mesenchymal stem cells
What do osteoblasts do?
Form bone (osteoids)
Produce type 1 collagen
Mineralize the extracellular matrix by depositing hydroxyapatite crystal within collagen fibrils
High Alkaline Phosphatase activity
Make non-collagenous proteins
Secrete factors that regulate osteoclasts i.e. RANKL
Where do osteoclasts originate from?
Haemopoietic stem cells
What do osteoclasts do?
Resorb bone
Dissolve the mineralised matrix
Breakdown collagen in bone
High expression of TRAP and Cathepsin K
What are the stages of bone remodelling?
Resting phase
Activation
haemopoietic stem cells become osteoclasts
Reversal phase- osteoclasts leave, influx of mesenchymal stem cells
Formation- osteoblasts
What happens in bone modelling?
Gross shape is altered
Bone added or removed
What happens in remodelling?
All of the bone is altered
New bone replace old bone
Why do bones remodel?
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
What is the average amount of calcium in the body and where is it?
1200g in the skeleton
About 1g in the extracellular space
What is the purpose of calcium in the extracellular space?
Normal blood clotting
Muscle contractility
Nerve function
What are the 3 ways calcium can be in the blood?
Ionised, metabolically active
Protein-bound, not metabolically active (mostly bound to albumin)
Complexed, such as citrate, phosphate
What would happen in alkalosis to Ca?
Lower ionised Ca as more taken up by albumin
Serum calcium stays normally
What is total serum calcium normally?
2.2-2.6mmol/L
What is ionised serum calcium normally?
ionised serum calcium is about 1.1 mmol/L
How can calcium get into the extracellular fluid?
Calcium taken in from diet, 30% absorbed
Remove calcium from bone
Excrete calcium from kidneys
How is calcium lost from the extracellular space?
Faeces
Calcium reabsorption
Bone formation
What are dietary sources of calcium?
Major: dairy (milk, yoghurt, cheese)
Minor: veg, cereals, oily fish
How much calcium from diet is absorbed?
30%
Where is calcium from the diet absorbed?
Duodenum and jejunum for active absorption
Passive absorption in ileum and colon
How can calcium be released from bone?
Rapidly released from exchangeable calcium on bone surface
More slowly by osteoclast during bone resorption
What happens to calcium in the kidney?
Calcium is filtered
98% of filtered calcium is reabsorbed
PTH increases absorption
Sodium decreases
What determines how much calcium is filtered?
The glomerular filtration rate
The ultrafiltrable calcium (Ionised, complexed)
Which hormone regulates serum calcium?
Parathyroid hormone made from PT glands with Ca sensing receptor
How do calcium sensing receptors affect PTH?
Calcium sensing receptor inhibits PTH secretion if calcium too high
Low calcium = more PTH made and released
What does fibroblast growth factor do?
Regulates active form of vitamin D in response to phosphate
Increase phosphate excretion
How does vitamin D influence intestinal calcium absorption?
1,25-dihydroxyitamin D binds to Vit D receptor
3 proteins made for active transport of calcium
TRPV6 on lumen, calcium comes in from food via this
Then goes into blood
What does calcitonin do?
Hormone produced by C cells in thyroid
Secretion stimulated by an increase in serum calcium
Lowers bone resorption
Not that important in humans
What is PTH’s action of the cell?
PTH acts on target cell
One pathway makes cAMP
One makes calcium
What does PTH do?
Reduces phosphate reabsorption
Increases calcium reabsorption
Increases hydroxylation of 25-OH vit D
What happens in a low calcium diet?
Less calcium absorbed
Lower serum ionised calcium
Higher PTH
Exchangeable calcium quickly released form bone
Increased bone resorption and increased fractional absorption by intestine
Serum ionised calcium returns to normal
What is appositional bone growth?
Chondroblasts secrete new matrix on existing surfaces
increases the bone width or diameter
What is interstitial bone growth?
Chondrocytes secrete new matrix within cartilage
lengthening of the bone.
occurs within the lacunae
What is endochondral ossification?
involves the formation of cartilage tissue from aggregated mesenchymal cells and the subsequent replacement of cartilage tissue by bone
What is the axial skeleton?
Vertical axis of body
Skull
Vertebrae
Ribs
Sternum
What is the apendicular skeleton?
Supports limbs
Arms, legs, pelvis, shoulder, hands. feet
Functions of skeletal muscle
Produce movement
Support soft tissues
Maintain posture and position
Communication
Control openings of passageways
Maintain body temperature
Characteristics of muscles
Responsiveness- response to chemical signals, stretch, electrical changes
Conductivity- local electrical changes trigger excitation
Contractility- shortens when stimulated
Extensibility- can stretch
Elasticity- returns to original length
Structure of a muscle
Myocyte (surrounded by endomysium)
Muscle fascicle (bundle of cells, surrounded by perimyosium)
Muscle proper (multiple fascicles surrounded by epimysium
What are T tubules?
Sarcolemma invaginations that help propagating action potential
What is the average size of a myofibre?
Average length: 5cm
Average diameter: 100um
What is the sacroplasm?
Cytoplasm rich in glycogen to fuel contraction
How many sarcomeres per myofibril?
10,000
What is a sarcomere?
basic contractile unit of a myocyte
composed of thin actin and thick myosin
between the 2 Z discs
What does endomyosium surround?
individual muscle fibres
What does perimyosium surround?
a bundle of muscle fibres, forming a fascicle
What does epimyosium surround?
the entire muscle
What is the histology of a skeletal muscle fibre?
cylindrical
long and unbranched
multinucleated
banding pattern with cross-striations of alternating light and dark bands
light bands are divided by a Z disc (dark transverse line)
Describe the process of excitation-contraction coupling
- AP at neuromuscular junction travels down T-tubule to depolarise membrane
- Depolarisation of the sarcolemma triggers opening of voltage-gated L-type Ca2+ channels
- Calcium enters cell
- activation of ryanodine receptors located in the sarcoplasmic reticulum
- allows Ca to flow from the sarcoplasmic reticulum into the cytoplasm and further increases intracellular Ca conc
- Ca binds to troponin-c
- Conformational change reveals a binding site on actin for myosin head
- ATP hydrolysis, providing energy for actin and myosin to slide past each other
- Sarcomere shortens, contraction
What happens at the neuromuscular junction for skeletal muscle contraction?
- AP arrives
- Calcium channels open, intracellular calcium increases
- Triggers release of ACh from vesicles
- ACh activates nicotinic ACh receptors on muscle fibre membrane
- Depolarisation
- ACh broken down by acetylcholinesterase
What does acetylcholinesterase do?
Breaks down ACh in synaptic cleft to allow membrane repolarisation
What is the Z line of the sarcomere?
where the actin filaments are anchored.
What is the M line of the sarcomere?
where the myosin filaments are anchored.
What makes up the I band of sarcomeres?
actin filaments
What is the A band of sarcomeres?
the length of a myosin filament, may contain overlapping actin filaments
What is in the H zone of a sarcomere?
myosin filaments
What is nebulin?
an actin-binding protein which is localized to the thin filament of the sarcomeres in skeletal muscle
What are the functions of ligaments?
Attach bone to bone.
Augment mechanical stability of joints.
Guide joint motion.
Prevent excessive motion
What do ligaments attach?
Bone to bone
What do tendons attach?
Muscle to bone
What are the functions of tendons?
Connect muscle to bone
Aid joint stability
Provide joint torque, motion and restraint
What is the exception to tendon?
Patellar tendon connects bone to bone and is a ligament
What is the general structure or tendons and ligaments?
Dense connective tissues consisting of mainly parallel fibres
Extracellular matrix
Fibroblasts which synthesise & remodel extracellular matrix
Sparsely vascularised
How much of the tissue volume of tendons and ligaments is made up by extracellular matrix?
80%
What makes up the extracellular matrix in ligaments and tendons?
70% of tissue wet weight is water
30% solids [collagen, ground substance (proteoglycans and glycoproteins)]
Has a hierarchical structure
What does the sparce vascularisation of tendons and ligaments mean?
Poor capacity for healing
What does the dense connective tissue of ligaments and tendons enable?
Enables the tissue to sustain high tensile strains
What is the major component of the tendon and ligament fibres?
Type 1 collagen (90-95%)
Some type 3
What do proteoglycans do in tendons and ligaments?
Make up 1-5% of dry weight
Regulate fibre diameter during fibrillogenesis
Aid in keeping fibrils together
Act as lubricant to aid collagen fibres gliding over each other
How is collagen synthesised and processed?
synthesized within fibroblasts as procollagen
3 individual polypeptide chains each coiled in L hand helix, then combine to form R hand helix
Cross linking increases strength
Secreted outside the cell
Processed to remove terminal peptides (for tropocollagen) and self assembles into collagen fibrils
Describe process of fibrillogenesis
Collagen molecules group together to form microfibrils
Microfibrils combine to form subfibrils
Subfibrils combine to form fibrils (50-200nm diameter)
Fibrils combine together to form fibres (3-7µm diameter)
Fibres combine to form fascicles
Fascicles group together to form tendon fibres
Order of fibrillogenesis
Collagen molecules
Microfibrils
Subfibrils
Fibrils
Fibres
Fascicles
Tendon fibres
What does elastin do?
Influences elastic properties of tendons and
ligaments (↑ elastin =↑ elasticity)
Where would you find elastin?
Little in tendons and extremity ligaments
More present in ligamentum flavum (between laminae of
vertabrae)
What is the role of elastin in the spine?
protect spinal nerve roots
provide intrinsic stability to spine
What are the differences between tendons and ligaments?
Tendons muscle to bone, ligaments bone to bone
Tendons have higher collagen I (95-99% dry weight), ligaments 90%
Tendons have very little elastin, ligaments have more
Fibres highly organised in tendons, more random in ligaments
What does enthesis mean?
Place of insertion of a tendon or ligament into bone
What is a fibrous insertion?
formed through intramembranous ossification
Calcified anchorage is by calcified collagen fibres (Sharpey’s fibres) into bone
E.g. distal medial collateral ligament
What is a fibrocartilage insertion?
formed through endochondral ossification.
Gradual change from collagenous ligament into fibrocartilage into mineralised cartilage into bone.
E.g. proximal medial collateral ligament
What do tensile load result in?
Elongation of tissue between ends
What do compressive loads result in?
Contraction between tissue ends
What does the ligamentum flavum do?
Substantial proportion of elastin (60-70%)
Connect laminae of adjacent vertebrae
Function to protect spinal nerve roots
Provide intrinsic stability to spine
What is the golgi tendon organ?
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
How does the inverse myotatic reflex work?
(a protective reflex)
Stimulation of golgi tendon organ
nerve impulse travels to spinal chord
(afferent 1b neurones)
synapse on interneurone
α motor neurone innervating the muscle
muscle relaxation (prevention of muscle
and tendon damage)
How does aging affect the mechanical properties of tendons and ligaments?
Collagen content of tendon and ligaments decreases
decreased tensile strength
How does pregnancy and postpartum affect the mechanical properties of tendons and ligaments?
tensile strength & stiffness in tendons decreases due to hormonal influences
How does physical training affect the mechanical properties of tendons and ligaments?
increase in tendon tensile strength and ligament-bone interface strength.
ligaments become stronger and stiffer, collagen fibers increase in diameter
How does immobilization affect the mechanical properties of tendons and ligaments?
decrease in tensile strength of ligaments, more elongation, less stiff.
decrease in cross-links.
after 8 weeks of immobilization → 12 months to recover strength & stiffness
What can affect the mechanical properties of tendons and ligaments?
Physical training
Aging
Immobilization
Pregnancy
What happens in ligaments and tendons up to 20 years of age?
number and quality of cross-links in collagen molecules increases
increased tensile strength
Collagen fibril diameter increased so increased tensile strength
What is the general pathway for tendon and ligament healing?
Short inflammatory phase (time course of days).
Proliferative phase (time course of weeks).
Remodelling and maturation phase (time course of months)
What is capacity of a tendon or ligament to heal dependent on?
Location and magnitude of injury
What takes place in the reparative phase of tendon and ligament repair? (3-6 weeks)
Formation of granulation tissue
deposition of disordered collagen
neovascularisation
fibroblast proliferation.
Extracellular matrix production including collagen III and glycosaminoglycans
What happens in the remodelling phase of tendon/ligament repair?
Decrease in cellular and vascular content of the repairing tissue.
Increase in collagen I content.
Collagen becomes more organised, properly oriented.
Cross-linking with healthy matrix outside the injury occurs
What the functions of joints?
To allow movement in 3-dimensions
To bear weight
To transfer the load evenly to the musculoskeletal system
What tissues are associated with joints?
Bone
Muscle
Cartilage
Synovium
Synovial fluid
Dense fibrous tissue/ capsule, tendons and ligaments
What are the 3 types of joints?
Fibrous e.g. teeth sockets
Cartilaginous e.g. intervertebral discs
Synovial e.g. metacarpophalangeal
What are the 3 functional ways to classify joints?
Synarthroses
Amphiarthroses
Diarthroses
What are synarthroses joints?
immovable joints, mostly fibrous (e.g. skull sutures)
What are amphiarthroses joints?
slightly moveable joints, most cartilaginous (e.g. intervertebral discs)
What are diarthroses joints?
freely moveable joints, mostly synovial (e.g. hip)
What are suture joints?
Occur only between bones of the skull (allow skull growth in development)
Adjacent bones interdigitate
Junction filled with very short tissue fibres
Fibrous
What are syndesmoses joints?
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
What are gomphoses joints?
A peg-in-socket fibrous joint found only in tooth articulation
Fibrous
What are synchondroses joints?
The bones are directly connected by hyaline cartilage. These are usually amphiarthroses ie. slightly moveable eg. costal cartilage of the ribs
Cartilage
What are symphyses joints?
connecting cartilage is a pad or plate of fibrocartilage eg. Intervertebral discs
Cartilage
How are intervertebral discs designed to take load?
water-binding proteoglycan-rich nucleus pulposus surrounded by tough fibrous annulus fibrosus – a shock absorber
What are synovial joints?
Articulating bones are separated by a fluid-filled cavity
Most joints of the body fit into this category
What are the components of synovial joints?
Articular cartilage
Joint capsule - inner layer is synovial membrane
Joint (synovial) cavity - a space filled with synovial fluid
Synovial fluid
Reinforcing ligaments
What are bursa?
Fluid filled sacs lined by synovial membrane
In some synovial joints
What are the 3 types of cartilage?
Elastic
Hyaline
Fibrocartilage
What are menisci?
Discs of fibrocartilage
In some synovial joints
What is hyaline cartilage like?
Almost frictionless surface
Resists compressive loads
High water content
Low cell content
No blood supply
What composes cartilage?
Water
Proteoglycans
Collagen (type 2)
What is the purpose of synovial fluid?
Covers articulating surfaces with thin film
Reduces friction during articulation
What is and makes up synovial fluid?
A joint lubricant
Fluid, proteins, charged sugars that bind water eg. hyaluronate
Modified from plasma by synovial membrane (synoviocytes)
What does the synovial membrane do?
Secretes synovial fluid components eg. Hyaluronate, and a source of inflammatory cells in rheumatoid arthritis
Sits on the joint capsule
Encloses synovial cavity
What is a fulcrum?
A synovial joint is the fulcrum of a lever system
What is a first class lever in joints? (elbow example)
the fulcrum is in the middle (the elbow joint) the force is at one end (the triceps muscle) and the resistance is at the other end (the weight being pulled)
How does a second class lever work? E.g. chewing
the fulcrum is at one end (eg. Temperomandibular joint) the force is at the other end (the muscles of the chin) and the resistance is in the centre (the muscles attached to the coronoid process).
How does a third class lever work?
the fulcrum is at one end (eg. elbow joint), the force is in the middle (the biceps muscle) and the resistance is at the other end (the weight being pulled).
What are the types of synovial joint?
Ball and socket- hip, shoulder
Condyloid- knee
Gliding- Carpals
Hinge- elbow
Pivot- vertebral
Saddle- carpometacarpal
What in secondary bone contains the blood vessels?
Haversian canal
What forms via intramembranous ossification?
Flat bones of skull
Some cortical bones
What is intramembranous ossification?
Formation of bone from membrane prescursor
Bone deposited in primitive embryonic mesoderm without cartilagenous proformer
Begins in 2nd trimester
Process of intramembranous ossification
Small clusters of progenitor cells within a primitive mesenchyme transform into osteoblasts
Osteoblasts deposit isolated bone islands
Islands gradually form open meshwork
Osteoblasts continue to deposit until holes fill creating primary plate
Over time woven bone remodelled to lamellar
What does endochondral ossification do?
Converts hyaline cartilagenous template into bone
When do cartilageneous proformers form?
2nd trimester
What is the process of endochondral ossification?
Shaft calcified and blood vessels grow into bone
Osteoprogenitor cells differentiate into osteoblasts
Osteoblasts lay down bone to form primary centre of ossification
Proformer cartilage eroded away as new bone forms
Secondary centres form in heads of bones
By birth most bones have primary, some have secondary
Cartilage remains on articular surface and epiphyseal growth plates
What layers form from endochondrial ossification?
Chondrocytes in resting cartilage divide creating columns of new cells in the zone of hyperplasia
These cells enlarge and give rise to zone of hypertrophy, eroding extracellular matrix
Remaining strands of matrix become calcified and osteoblasts can attach
What do type A and B synovial cells do?
Type A- phagocytic action
Type B- rich in rER and secret synovial fluid
What is the histology of synovium?
Lines the inside of the joint capsule
1-4 layers of synovial cells
Type A – phagocytes
Type B – rich in rER
Variable shapes – squamous to cuboidal
Richly vascular, highly innervated
What are the functions of bones?
Support
Protection
Anchorage
Mineral storage (most important calcium and phosphate)
Blood cell formation (in red marrow), Triglyceride storage (yellow marrow of long bones)
Hormone production (osteocalcin)
What are osteoprogenitor cells?
mitotically active stem cells in membranous periosteum and endosteum
differentiate into osteoblasts when activated
What are epiphyses?
bone ends, covered by thin layer of hyaline cartilage
What is a diaphysis?
shaft, forms long axis of bone
What is the epiphyseal line?
between diaphysis and epiphyses, remnant of growth plate
What is spongy bone?
internal
aka trabecular
honeycomb of trabeculae, filled with red or yellow marrow
What is compact bone?
external layer, dense, smooth and looks solid
What is an osteon?
structural unit of compact bone
What is the inorganic component of bone?
hydroxyapatites (mineral salts), largely calcium phosphates
What makes up the organic component of bone?
Osteo cells and osteoid (containing collagen fibres and ground substance)
What is the normal range for uric acid in the blood?
Men 200-430 umol/l
women: 140-360 umol/l
How soluble is uric acid?
Poorly soluble in plasma so easily forms crystals
Lower pH = less soluble
Where does uric acid come from?
Metabolism of purines
What are 4 purines?
Adenine
Guanine
Hypoxanthine
Xanthine
What are the sources of purines?
Diet
Breakdown of nucleotides from tissues
Synthesis in the body
How does uric acid leave the body?
Excreted in urine
Breakdown in gut
What is the end substance of purines?
Uric acid
What foods contain purines?
Meat
Offal – heart, liver & kidney
Seafood - muscles
Fish – herring and sardines
Oatmeal, soya & yeast extracts
Fructose – found in soft drinks
Alcohol
What are some risk factors for gout?
Obesity
Raised BP
Raised triglycerides
Male as oestrogen protective
Diuretic
Reduced kidney function as this reduced uric acid excretion
What is the pathway for uric acid formation?
Purines to xanthine to uric acid
All converted by xanthine oxidase
What is the rate limiting step in uric acid synthesis?
Phosphoribose 1 pyrophosphate (PRPP) to 5’ phosphoribosylamine
Enzyme: PRPP amido transferase
How does bone respond to exercise?
When you exercise regularly, your bone adapts by building more bone and becoming denser
Mechanical stress stimulates remodeling
What is bone resorption?
Removing calcium from bone
What is a fracture?
breach in continuity of bone
When do fractures occur?
non-physiological loads applied to normal bone
Physiological loads applied to abnormal bone
When are fractures more common?
Early years (0-24) or older years
Post-menopausal women
What are some metabolic bone diseases?
Osteoporosis
Paget’s Disease
Osteogenesis Imperfecta
What would you use to describe fractures?
Site
Pattern
Displacement / angulation
Joint involvement
Skin involvement
What fractures are high energy?
Comminuted
Segmental
What does displacement mean in fractures?
the abnormal position of the distal fracture fragment in relation to the proximal bone
What are the stages of fracture healing?
1: inflammatory
2: soft callus formation
3: hard callus formation
4: remodelling
What happens in the haematoma formation of fracture healing?
Haematoma forms within hours
Inflammatory exudation
Bleeding
Decreased blood flow
Periosteal stripping
Osteocyte death
How does the soft callus form in fracture healing?
Soft callus forms in 2-3 weeks
Progenitor cells in periosteum and endosteum develop into osteoblasts (intramembranous ossification)
Ingrowth of capilliaries
Proliferation of mesenchymal cells
What happens as the hard callus forms in fracture healing?
Hard callus forms weeks to 5 months
Intramembranous ossification continues
Callus undergoes endochondral ossification
How do you manage fractures?
Reduce
Immobilise
Rehabilitate
What happens in inflammation of fracture healing?
- Haematoma
- Fibrin clot organisation
- Neovascularisation
- Cellular invasion: Haematopoietic cells (clear debris and express repair cytokines), Osteoclasts (resorb dead bone), Mesenchymal stem cells (building cells for repair)
What happens during the repair stage of fractures?
- Callus’ formation:
Fibroblasts produce fibrous tissue (high strain)
Chondroblasts form cartilage (strain <10%)
Osteoblasts form osteoid (strain <1%) - Progressive matrix mineralisation
- High vascularity
What happens in the remodelling stage of fracture healing?
Woven bone structure replaced by lamellar bone (osteonal remodelling)
Increased bone strength
Vascularity returns to normal
Healing without scar - unique
How long does the repair stage of fracture healing last?
Weeks
How long does the remodelling stage of fracture healing last?
Months-years
How long does the inflammatory stage of fracture healing last?
Days (0-7 of fracture)
How can you fix fractures?
Slings
Casts and splints
Extra-medullary devices: plates and screws
Intra-medullary devices: nails
External Fixation
What patient factors influence fracture healing?
Age
Nutrition
Smoking
Drugs – NSAIDs, steroids
What bone factors influence fracture healing?
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
What are some early local complications of fractures?
Vessel damage
Nerve damage
Compartment syndrome
infection
What are some general early complications of fractures?
Hypovolaemic shock
ARDS
VTE
Fat embolism
What are some late local complications of fractures?
Malunion
Non-union
Avascular necrosis
Ischaemic contractures
Joint stiffness
Myositis ossificans
Complex regional pain syndrome
Osteoarthritis
What are some late general complications of fracture?
Poor mobility
Functional disability and social isolation
Pressure sores
Disuse osteoporosis
Loss of income / job
What is angulation in a fracture?
Specific type of fracture displacement where the normal axis of the bone has been altered such that the distal portion of the bone points off in a different direction
Why do bones remodel?
Repair microdamage
Respond to mechanical stimuli
Store and release mineral
What is bone modelling?
Gross shape is altered
Bone added or taken away
What is bone remodelling?
All of the bone is altered
New bone replaces old bone
What happens in bone remodelling?
Signal sent out
Osteoclasts arrive and attach to bone surface
Secrete glycogen ions and absorb bone
Signal to osteoblasts and they arrive
Restore bone
What does coupling mean in bone turnover?
Bone formation occurs at sites of previous bone resorption
Osteoblasts know where clasts have been
What does balance mean in bone turnover?
Amount of bone removed by osteoclasts should be replaced by osteoblastic activity
What hormones regulate bone turnover?
PTH
Oestrogen and testosterone
Active vit D
Cortisol
GH, IGF-1
Leptin and adiponection
What is the paracrine regulation of bone turnover?
Prostaglandins
Interleukin-1
Tumour necrosis factor
What is the RANK Ligand pathway?
RANK Ligand signals to osteoclasts (secreted by osteoblasts, a key coupling pathway)
OC precursors express receptor
RANKL binds and precursor differentiates into osteoclast
Binds to osteoclast
Increases osteoclast activity and bone resorption
What does the OPG pathway do?
Decoy receptor for RANKL
Secreted by osteoblasts
Inhibits osteoclast differentiation and activity
What secretes RANK ligand?
Osteoblasts
What is sclerostin?
Osteocyte secreted protein
Loss of function can increase bone density
What does sclerostin do?
Signals to osteoblast
Inhibits bone formation
Secreted with decreased oestradiol or PTH
What is phosphate involved in in physiology?
Phospholipid bilayers and maintains integrity
Nucleotides and ATP
Bones
Kinases
What is normal serum phosphate?
0.8 – 1.5 mmol/l
What is the total amount of phosphate in the body?
500 - 800g
90% in bone
What happens in high phosphate?
Excess formation of hydroxyapatite
Deposited in tissues other than bone
What is the recommended daily intake of phosphate?
700mg
What are the dietary sources of phosphate?
Protein: meat, dairy, soy, seeds and nuts
How is phosphate excreted?
Unbound phosphate is filtered (about 90%)
80% reabsorbed in proximal tubule
10% reabsorbed in distal tubule
Maximum rate of reabsorption is limited, so excess is excreted
What regulates phosphate metabolism?
PTH
1,25 dihydroxyvitamin D
FGF-23 (fibroblast growth factor)
What is the effect of PTH on phosphate?
Increases phosphate loss in kidney (via decreased tubular reabsorption)
Increases active gut absorption via vitD
What produces FGF-23?
Osteocytes
What is FGF-23 produced in response to?
Rise in phosphate levels
Dietary phosphate loading
PTH
1,25 vitamin D
What does FGF-23 do?
Increases renal excretion of phosphate (by decreasing expression of Na transported in tubule)
Decreases gut absorption of phosphate (by decreasing 1α-hydroxylation of vitamin D)
Decreases whole body phosphate
What happens when serum phosphate rises?
Increase in FGF - decreases absorption
Increase of PTH, feeds into FGF - decreased reabsorption
Serum phosphate falls - FGF falls
How are calcium and phosphate generally regulated?
Calcium mostly regulated by hormones that increase serum calcium
- PTH, vitamin D
Phosphate mostly regulated by hormones that decrease serum phosphate
- FGF-23, PTH
When does intramembranous ossification happen?
begins in-utero and continues into adolescence
What are slow twitch fibres?
ATPase hydrolyses ATP slowly
Small
Weakest contractions
Myoglobin binds and stores oxygen
Extensive blood vessels
Red
Mitochondria
What does more RANKL than OPG mean?
Bone resorption increased
What happens when there is more OPG than RANKL?
Osteoclast activity decreased
