1- The Cellular Structure Of Bone Flashcards
What are the functions of bone?
Structural
- give structure and shape to the body
Mechanical
- site of muscle attachment
Protective
- vital organs and bone marrow
Metabolic
- reserve of calcium and other minerals
- acts an endocrine organ
What is bone composed of?
65% inorganic material
- calcium hydroxyapatite
- store house of 99% of calcium in the body
- 85% of phosphorus, 65% sodium and magnesium
35% organic material
- bone cells and the protein matrix
How are bones classified?
Anatomical bones
Macroscopic structure
Microscopic structure
How are anatomical bones classified?
Flat:
- protective function
- example: sternum/skull
Long:
- movement
- example: limbs
Short/cuboid:
- give stability of joints
- examples: carpal in wrists and feet
Irregular:
- complex shapes allow protection of organs
- examples: pelvis and vertebrae
Sesamoid:
- embedded in tendons/muscles
- act like a pulley to reduce stresses and strains
- found in feet and hands
- example: patella- kneecap
What are the classifications of macroscopic bone structure?
Trabecular
- spongy bone
- inside part
- thin, honey comb like
- highly metabolically active
- gives bone strength
Cortical
- compact
- outside part
- thick
- makes up shaft of the bone
What are the classifications of microscopic bone structure?
Woven bone- immature
Lamellar bone- mature
Describe the differences between cortical and trabecular bone structures
Cortical:
- long bones
- form 80% of the skeleton
- appendicular
- 80-90% calcified
- mainly structural, mechanical and protective
Trabecular:
- vertebrae and pelvis
- forms 20% of the skeleton
- axial
- 15-25% calcified
- mainly metabolic
- has a large surface area due to its crisscross nature
What happens during bone development?
Growth plate fusion and ossification
The clavicles growth plate fuses at 20 years old
What are the two types of ossifications that occur during bone development?
Intramembranous ossification
- direct differentiation of osteoblasts from connective tissue
- flats bones
Endrochondral ossification
- bones form from a cartilage
- long bones
- allows for a rapid growth spurt
Describe the process of endochondral ossification
Early foetal development – scaffold of cartilage forms within the limb buds
Scaffold begins to change by birth but the change itself is not complete - Bones are still mostly in the form of the cartilage model in a new-born
Scaffold expands in size but lacks vasculature within the cartilage
Centre of cartilage model becomes hypoxic
Blood vessels invade the scaffold to offset hypoxia
Precursors for bone cells are present within the vessels
Precursor cells carried by blood vells differentiate
Centre of cartilage scaffold becomes bone
This is the primary ossification centre – first occurs within the diaphysis (of the bone)
Epiphysis of the bone currently remains as cartilage model
Primary medullary cavity forms
Primary ossification centre (POC) expands outwards from the centre, still within the diaphysis
Ossification gradually moves towards the epiphysis of the bone
Bone increases in size during childhood
Secondary ossification centre (SOC) forms within the epiphysis
Growth plates ensure that SOC and POC remain separate
Growth plates allow for linear growth and rapid increase in height
More of the cartilage becomes ossified as development continues
Development will be complete when the cartilage growth plates becomes ossified and fuses the SOC and POC together
How does the growth plate allow for rapid linear growth?
Growth plates are composed of chondrocytes
- Chrondro – related to cartilage
- Cyte – mature cell
Chondrocytes organised into 3 distinct zones – they progress through these zones over their lifetime
- Reserve zone
- Proliferative zone
- Hypertrophic zone
What happens in the reserve zone?
Reserve zone – thought to contain stem cell population of growth plates.
- Cells proliferate very slowly to maintain population
- Close to blood supply in SOC
What happens in the proliferation zone?
Proliferative zone
- Chondrocytes become highly proliferative
- Form distinct column structures as they divide
- Become further away from epiphysis and blood supply
- Undergo hypertrophic differentiation
What happens in the hypertrophic zone?
Hypertrophic zone
- Where chondrocytes undergo hypertrophic differentiation
- Expand in size and begin to produce collagen 10
- A cell will be larger and further away from the blood supply the more the cell is into the hypertrophic zone
- Will become hypoxic as they grow too far from the blood supply. Undergo apoptosis and leave behind a cartilage mineral matrix that has been produced by the cells
- This calcifies (i.e. the calcified cartilage) and is ossified by bone cells
What other two phases are involved in the linear growth of the growth plate?
Two more zones: calcified cartilage zone and ossification zone
Cells remain in place within the growth plate
- The growth plate moves upwards (hence the cells appear to move downwards)
- When the growth plate moves, cells in the hypertrophic zone will undergo apoptosis and will be replaced with bone
- Width of growth plate maintained by the growth plate moves upwards
What are osteocytes?
- They are specialised type of bone cells
- They are mature bone cells
- They are embedded in lacunae in mature bone
- They are connected via processes through canalicular channels
- They form a mechanosensory network throughout bone
What are osteoclasts?
- They are multinuclear cells that resorb/remove bone
- They are known as the bone breaking cells
- They are formed from the fusion of macrophages
- They seal off a portion of bone beneath them
- They secrete acids and enzymes to ‘resorb’ the sealed off bone
What are osteoblasts?
- They produce osteoid to form new bone
- Osteoid is mineralised over time to become mature bone
What is osteoid?
- the organic component of new bone
How are osteocytes network maintained in newly forming bones?
Some osteoblasts are embedded in the new bone and differentiate into osteocytes
What is the bone remodelling cycle?
- The skeleton is not a fixed or stagnant organ, it is dynamically regulated to maintain health
- Small portions of bone are constantly being removed and replaced
- It is composed of 4 main steps
Describe the steps involved in the bone remodelling cycle
- Microfracture is detected by osteocyte mechanosensory network
- Osteoclasts are recruited at the site of damage to differentiate and to resorb the damaged bone, fusion occurs to allow the osteoclasts to differentiate into mononucleated cells
- Osteoblasts arrive and secrete osteoid, the amount secreted = amount resorbed
- Bone is mineralised and repaired
When does bone loss happen in the bone remodelling cycle?
- balance between resorption by osteoclasts and formation by osteoblast is lost
- excess osteoclast resorption
- insufficient osteoblast formation
- net loss of bone mass
When does bone gain happen in the bone remodelling cycle?
- balance between resorption by osteoclasts and formation by osteoblast is lost
- insufficient bone resorption by osteoclast
- excess bone formation by osteoblast
- net gain of bone mass
What is osteosclerosis/osteopetrosis?
- gain in bone mass
- more trabeculae
- net gain
- excess formation
- LRP5 (relates to osteoblast differentiation) activating mutations
- mutation in the SOST gene, no production of sclerostin, no Wnt signalling inhibition
- increase osteoblast differentiation and increase bone formation
What is osteoporosis?
- decrease in bone mass
- increased resorption
- net loss
- trabeculae are thinner
- can be primary (menopause, aging)
- can be secondary (drugs, disease, lifestyle)
What is the endocrine control of bone remodelling?
- oestrogen
- thyroid hormone
- PTH
What is the paracrine control of bone remodelling?
- RANKL
- Wnt signalling
What is RANKL?
- master regulator of osteoclasts
- produced by osteocytes and osteoblasts
- no RANKL means no differentiation of osteoclasts
Describe the induction of osteoclast differentiation by RANK ligand
RANK receptor - activation of the receptor is required for osteoclast differentiation and survival
Binding of RANKL to the RANK receptor causes:
- Signalling cascade via RANK pathway
- Results in differentiation, fusion, maturation, and activation of premature osteoclast precursors to mature, active osteoclasts
What is OPG?
OPG (osteoprotegerin) – decoy receptor for RANKL also produced by osteocytes and osteoblasts.
OPG is a protein produced cells of the osteoblast lineage – the function of this is to inhibit the differentiation of osteoclasts by binding to RANKL before RANKL can bind with RANKr on osteoclast precursors
What is osteoclast differentiation controlled by?
- the ratio between RANKL and OPG
Describe the Wnt signalling pathway in bone formation?
- its a highly complex pathway
- it stimulates osteoblast differentiation
Occurs via canonical signalling pathway:
1) Wnt ligand bids to frizzled receptor (7 transmembrane protein – has similarities to G-protein coupled receptors)
2) Frizzled must be in complex with a co-receptor in bone
- Coreceptor is composed of LRP5 and LRP6 in humans
- LRP = low density lipoprotein related protein
3)Wnt binds to Frizzled receptor (in complex with LRP5 and LRP6)
4)Canonically sets of signalling cascade
- Causes translocation of b-catenin into the cell nucleus
- Results in a change in gene expression – results in differentiation of osteoblasts
What inhibits the Wnt signalling pathway and how?
- Inhibited by Sclerostin and Dkk-1 – these are antagonists
- Both bind to LRP5 and LRP5 – prevent both proteins from forming a complex/interacting with Frizzled receptor
- Wnt has no effect on Frizzled receptor
- b-catenin cannot enter cell nucleus = inhibition of osteoblast differentiation
Osteocytes are key regulators in bone remodelling, what do they regulate?
- Differentiation of osteoclasts by RANKL production
- Inhibition of osteoclast production by OPG production
- Regulate differentiation of osteoblasts by production of Sclerostin and Dkk-1
- Osteocytes
What is the importance of osteocytes in bone remodelling?
- Osteocytes detect microfractures within bone
- Induce differentiation of osteoclasts during resorption; done by producing RANKL and ceasing production of OPG
- Local ratio of RANKL:OPG will be changed by the osteocytes when the osteoclast has resorbed the bone to a sufficient depth
- Osteoclasts can no longer be sustained
- Osteocytes control the level of expression of Dkk-1 and Sclerotin in order to regulate the differentiation of the osteoblasts
Note that osteocytes are formed when osteoblasts become embedded within the osteoid that they secrete
What cell produces sclerostin?
osteocytes
Why is osteoporosis more common in females?
- menopause
- loss of oestrogen
- causes temporary increase in osteoclast activity
- sudden loss in bone mass
