Cellular structure of bone Flashcards
What are the functions of bone?
- Support and movement as it is the attachment site for muscles
- Protection for internal organs
- Provides home for bone marrow
- Acts as a mineral reservoir
- Endocrine: source of some “non-classical” hormones
How does the bone support movement?
System of joints and levers together with the muscle system
What does the bone marrow do?
Produces blood cells and other types of stem cells
What part of the bone acts as a mineral reservoir?
Serum calcium (extracellular calcium) that is tightly regulated as an important mineral source for calcium and phosphate
How does bone act as a endocrine organ?
It secretes signalling molecules and some of which reach the circulatory and act in the classical sense
Describe the two structures in bone
- Cortical (compact) bone
- Trabecular (spongy, cancellous) bone
What is cortical bone?
- Organised in a highly organised manner
- Forms the outer surface of long bones and flat bones
- Organised in repeating units called osteons around central canals called haversian canals
- Minute network of canals called lacunae that permeate throughout the structure
What are osteons?
Osteons are circular sheets or lamellae of bone matrix/tissue around central canals called Haversian canals
What do Haversian canals contain?
They contain blood vessels, nerves etc
What is trabecular bone?
- Located inside the bone - underneath the cortical bone
- Located in the head of long bones
- Like a meshwork of the bone matrix with spaces inbetween
- Mostly has the same composition as cortical bone
What are the two typical types of bones?
- Long bone
- Flat bone
What is the structure of long bones?
Composed of the head and the shaft
What is in the middle of the long bone?
Bone marrow filled cavity
Describe the normal composition of bone
- Protein: organic osteoid matrix (25%)
- Mineral (75%) - mixed with the osteoid matrix and is mainly calcium and phosphate
- Cells
What is the composition of the organic protein matrix?
Mainly type 1 collagen
What is the purpose of the organic protein matrix (osteoid)?
- For flexibility and tensile strength
- the strength of the bone resides here
What is tensile strength of bone?
The ability of bone to bend slightly to resistance the perpendicular forces (right angles).
What is the major component of bone mineral?
Hydroxyapatite
What are the other components of bone mineral?
Calcium and phosphate
What is the function of bone mineral?
Rigid, brittle and gives high compressive strength (longitudinally) which is important for the ability of the bone to bear load
What are the major bone cells?
Osteoblasts
Osteoclasts
Osteocytes
What do the mesenchymal (stromal) stem cells differentiate into?
They give rise to osteoblasts
What is the function of osteoblasts?
Responsible for forming the organic matrix of bone and promoting the mineralisation
How are osteocytes formed?
The osteoblasts terminally differentiate and become osteocytes found within the bone matrix.
What do osteoblasts secrete?
The bone matrix and intune themselves encased inside the bone matrix
What do cells of the haematopoietic stem cell lineage become?
Red blood cells (erythrocytes) and white blood cells
Osteoclasts
Where are osteoclasts found?
Found lining the inside of the cortical bone on the marrow cavity, large multi-nucleated cells and derive from the blood cell lineage
Summarise function of osteoblasts
- Bone forming cells
- Derived from mesenchymal stem cells
- Secrete osteoid, collagen matrix of bone
- Promote mineralisation of osteoid
What do the osteoclasts do?
Bone reabsorbing cells
What do bone reabsorbing cells do?
Essential digesting of the bone organic matrix and combined with release of the mineral content - hydroxyapatite - releasing calcium and phosphate.
What is unique about osteoclasts?
Large, multinucleate and in the final differentiation, they involve fusion of several precursor cells
How do osteoclasts work?
- Attach to the surface of bone, either inside the Haversian canals or along the struts in trabecula bone or the inner surface of bone facing bone marrow forming a tight seal.
- Secrete acid to dissolve bone mineral and enzymes to digest organic matrix and secrete proteolytic enzymes.
What is the most important proteolytic enzymes released by osteoclasts?
Cathepsin K that has a high affinity for type 1 collagen to dissolve bone and cartilage.
What controls the life cycle of osteoclasts?
Apoptosis
What are osteocytes?
Terminally differentiated osteoblasts
What is osteocytes encased in?
In bone mineral matrix (lacunae)
What do the dendrites on the osteocytes do?
They extend multiple dendrites via minute canals in bone matrix (canaliculi) connecting one lacuni to the other and lacunae to the surface. This forms the lacunocanalicular system.
What is the lacunocanalicular system?
It maintains communication with bone surface and blood vessels.
What do the osteocytes coordinate?
They coordinate osteoblast (cells forming new bone) and osteoclast (cells that reabsorb old bone) activity
Define bone remodelling
The opposing processes of bone formation and bone reabsorption
What is the remodelling unit?
It is on the surface or within the Haversian canal of cortical bone. It involves osteoclasts dissolving and reabsorbing old bone and osteoblasts replacing with new bone.
What do the osteoblasts secrete and do?
They secrete osteoid which will mineralise and form new bone. This is bone recycling.
Why is bone recycling important?
It is essential for normal skeletal health
Is bone inert dead tissue?
Not
Why is the bone remodelling process important?
It is critical to the differentiation and life cycle of bone.
When do osteoclasts differentiate?
They differentiate in response to appropriate signals and then undergo apoptosis within a certain timeframe.
When do osteoblasts differentiate and what happens to them?
Osteoblasts will terminally differentiate into osteocytes and remain embedded in the matrix or remain inert along the bone surface
What are the four stages of bone remodelling?
- Activation
- Reabsorption
- Reversal
- Formation
What is the activation step in bone remodelling?
Involves stimulation of osteoclast differentiation
What is the reabsorption step in bone remodelling?
Phase governed by the lifecycle of the osteoclast - it’s duration of action.
What is the reversal step in bone remodelling?
Involves the signals of termination of the osteoclast activity and promote further osteoblast differentiation and the apoptosis of osteoclast.
What is the formation step in bone remodelling?
The formation of new bone
What do the bone cells form?
They form the basic multicellular unit that moves along the surface of the bone recycling (reabsorbing old bone and laying down new bone).
What controls remodelling?
- Load-bearing exercise
- Cytokines and other local signals
- Endocrine signals
How does load-bearing exercise affect bone remodelling?
There is bone loss, as seen in bedbound pts, as it is thought that by doing load-bearing exercise such as walking, this leads to micro-stress fractures, detected by osteocytes, that then coordinate remodelling itself. However, bedbound patients, there is noticeable loss of the density of the skeleton.
How do cytokines and other local signals affect the bone remodelling process?
At the cellular level, the control is via a network of signalling molecules promoting differentiation or apoptosis of osteoclasts and osteoblasts.
How does the endocrine system affect the bone remodelling process?
Oestrogen inhibits osteocyte apoptosis and promtes osteoclast apoptosis. It favours formation rather than reabsorption - promoting bone health - essential in both sexes. It is produced by aromatase and is essential for bone health.
What induces osteoclast differentiation?
RANK ligand?
What does RANK stand for?
Receptor activator of nuclear factor kappa-B
What is RANK?
A transcription factor that when activated will promote osteoclast differentiation.
Where is RANK located?
It is surface receptor on pre-osteoclasts that stimulates differentiation.
How is the RANK receptor activated?
It is activated by RANK-ligand that is expressed by pre-osteoblasts, osteoblasts and osteocytes. It binds to the RANK receptor and stimulates osteoclast differentiation. This stimulates the activation stage in the remodelling process.
What do the osteocytes secrete?
They secrete OPG (osteoprotogerin)
What is OPG?
It is a decoy receptor released by the osteocytes and competes with RANK-ligand for the RANK receptor, preventing activation of RANK(-L).
What is demunosab?
It is one of the more recent drugs used for the treatment of osteoporosis.
What is osteoporosis?
Common disease with the loss of bone mineral density
What is demunosab?
It is a human monoclonal antibody against RANK-L.
What is the Wnt signalling pathway?
It is a complex signal pathway that is highly conserved in the animal kingdom involved in animal development.
What is the Wnt signalling pathway needed for?
It is required for osteoblast differentiation.
What is the Wnt pathway negatively regulated by?
It is negatively regulated by various factors including DKK (dickkopf) and sclerostin (SOST).
What is WNT?
It is a signal protein that activates the WNT receptor, Frizzled.
What is the WNT receptor and what is needed for it to work?
The WNT receptor is Frizzled and it needs the co-receptor, LRP5 to work.
What happens when the WNT receptor is activated?
The receptor is activated and beta-catenin is released and acts as a transcription factor and promotes other particular differentiation pathways.
What prevents full activation of WNT?
When DKK and SOST bind to the co-factor, LRP5. This will no longer activate the intracellular cascade. It acts as a brake - negative regulation.
Why is OPG released by osteocytes?
It acts to inhibit osteoclast differentiation whereas RANK-L acts to enhance it.
What do sclerostin and DDK do?
They are produced by osteocytes and act as a brake on osteoblast differentiation.
What happens if sclerostin is decreased?
It results in an increase in osteoblast differentiation.
What can sclerostin and RANK- L be used in?
Be used in drugs and developed in new drugs
What are some very rare diseases of the bone?
Mutations affecting key signals - important and serious disease
What is the less rare disease of the bone?
Osteomalacia
What is osteomalacia?
The failure of bone mineralisation.
What is ricketts?
Soft bones like cartilage in children, due to vitamin D deficiency. It can occur in the elderly.
What is vitamin D required for?
It is an endocrine factor required for bone mineralisation.
What is a common bone disease?
Osteoporosis
What is osteoporosis?
Accelerated loss of bone mineral density/organic component by two standard deviations or more below the average peak of bone density of sex and ethnic group
What is the downfall of osteoporosis?
More prone to fractures, suffered by the elderly, can be attributed to the weakening of the bone.
What are some bone diseases caused by mutations?
- Osteoporosis pseudoglioma
- Sclerosteosis
- van Buchem disease
- Osteopetrosis
What causes osteoporosis pseudoglioma?
Inactivation of LRP-5, WNT Co-receptor
What causes sclerosteosis and van Buchem disease?
Mutation of SOST gene, inactivating sclerostin protein so there is excess bone mass.
What causes osteopetrosis?
Mutation inactivates RANK-L protein. This prevents the reabsorption of bone.
Describe the loss of bone density correlation with ageing
There is an overview of bone density loss with ageing through different ages and sexes. Peak bone density is 25-30 and there after it is a slow downhill process with somewhat accelerated in women due to reduced oestrogen levels in menopause
