W6 -Cellular structure of bone Flashcards

1
Q

What are the bone types and classifications?

A
  • Anatomical bones
    – Flat (like sternum/skull) , long (limbs - allow large movements) , short/cuboid (As long as they are wide - like carpals in wrists and tarsals in feet - allows smaller, precise movements), irregular (specific compound shapes like pelvis protecting reproductive organs or vertebra) , sesamoid (sesame seed like - found embedded in muscles/tendons and acts like a pulley eg. knee cap)
  • Macroscopic structure
    – trabecular/cancellous/spongy
    – cortical/compact
  • Microscopic structure
    – Woven bone (immature)
    – Lamellar bone (mature)
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2
Q

What are cortical bones?

A

Thick bone that makes up shaft of the bone. Outside tube part.
* long bones
* 80% of skeleton
* appendicular
* 80-90% calcified
* mainly structural, mechanical, and protective

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3
Q

What are trabecular bones?

A

Honey comb like bone that cris-crosses throughout the cavity of bones. Highly metabolically active and also adds strength to the bone.
* vertebrae & pelvis
* 20% of skeleton
* axial
* 15-25% calcified
* mainly metabolic
* large surface area

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4
Q

How does bone development work?

A
  • Bones develop throughout growth and into adulthood
    – Growth plate fusion and ossification completes development
    – Clavicles growth plates fuse at ~20 years old
  • Intramembranous ossification
    – Direct differentiation of osteoblasts from connective tissue
    – Flat bones
  • Endochondral ossification
    – Bones form from a cartilage model
    – Long bones
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5
Q

What is endochondral ossification?

A

In early foetal development, a cartilage scaffold of our long bones will form within the limb buds and then at birth. The bones of a new born are still in the cartilage model.

At the scaffold, it would have expanded in size and this would be problematic because it lacks vasculature. This means the centre of the cartilage model becomes hypoxic. To correct this, blood vessels invade the scaffold and they bring precursors for bone cells with them. These then differentiate and convert the centre of that cartilage scaffold into bone. This is what’s called the primary ossification centre - it occurs first in the centre of Diaphysis. You would have bone around the outside cortical bone and the marrow cavity. The ossification then expands out into the ossification in the epiphysis of the bone, which at the moment is cartilage.

In childhood, as the bones continue to expand in size, a secondary ossification centre will form in the prefaces and it will remain separated from the primary one via a cartilage structure called a growth plate. Growth plates allow us to have rapid linear growth and allows us to increase our height.

Development continues as more and more cartilage scaffold becomes ossified into bone in primary and secondary ossification centres and growth finally finishes. The cartilage growth plates finally become ossified fusing the primary and secondary centres together.

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6
Q

How does growth plate allow rapid linear growth?

A

The growth plates contain chondrocytes. Chondro = cartilage and cytes = mature cell.
These are organised into a structure with three distinct zones. Over life time, they will progress through these zones.

1) Reserve zone - contains the stem cell population and proliferate very slowly and they maintain the population - they are very close to the blood supply in the secondary ossification centre.

2) Proliferative zone - they are highly proliferative and they form thick column like structures. Cells get further away from the epiphysis and the blood supply. As this happens, they undergo, hypertrophic differentiation.

3) Hypertrophic zone - They expand in size and start producing a specific collagen called collagen 10. The further into the hypertrophic zone and blood supply, the larger it will be. Eventually, it becomes too much and they undergo apoptosis leaving behind the Cartilage mineral matrix that they’ve been producing. This is then calcified then ossified by the bone cells.

These cells are not moving, the growth plate itself moves up around them.

4) Calcified cartilage zone
5) Ossification zone

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7
Q

What are osteocytes?

A

Osteocytes - mechanosensory network embedded in mature bone.
* Embedded in lacunae in mature bone
* Connected via processes through canalicular channels
* Form a mechanosensory network throughout bone
These are the most popular - makes up over 90% of all cells found in bone tissue.

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8
Q

What is the difference between osteocytes and osteoclasts?

A

Osteocytes - mechanosensory network embedded in mature bone
Osteoclasts - multinuclear cells that resorb/remove bone

Osteo = bone related Clasts = break
They break down or resolve bone tissue.

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9
Q

Why are osteoclasts the bone breaking cells?

A
  • Giant multinuclear cells formed from the fusion of monocyte macrophages precursors.
  • They seal off a portion of bone beneath them
  • They secrete acids and enzymes to ‘resorb’ the sealed off bone

In a culture, can be grown big enough to be seen by the naked eye. They bind to a portion of bone sealing it off to the rest of the environment using an actin ring. The osteoclasts then secrete acids onto that bone tissue and enzyme to remove the organic components - reabsorbing that sealed off portion of the bone.

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10
Q

What are the specialised bone cells?

A

Osteocytes - mechanosensory network embedded in mature bone

Osteoclasts - multinuclear cells that resorb/remove bone

Osteoblasts - produce osteoid to form new bone via the secretion of osteoids.

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11
Q

How do osteoblasts form new bone?

A
  • Secretes osteoid; the organic component of new bone
  • Osteoid is mineralised over time to become mature bone
  • Some osteoblasts are embedded in the new bone and differentiate into osteocytes
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12
Q

What are specialised bone cells?

A

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
– Your whole skeleton has been replaced after 7 years
* This is done by the specialised bone cells via the bone remodelling cycle

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13
Q

What is the bone remodelling cycle?

A

Microfracture
Resorption
Formation
Repaired Bone

As we move around and get exposed to stress and strain, microfractures can form (tiny cracks typically in older bones). This is then detected by our osteocyte mechanosensory network. They signal for osteoclast to come in to differentiate at the site of damage and resolve away the old damaged bone. Once finished, they undergo fission, differentiating back into individual mononuclear cells. The osteoblasts then arrive and secrete the osteoids to produce an amount of new bone equal to that removed by the osteoclast. The bone become mineralised and the bone has been repaired becoming mature bone.

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14
Q

How does bone loss work?

A

That remodelling cycle can go wrong when the balance between reabsorption by the osteoclasts and the formation by osteoblasts.
You would either get insufficient formation at the end of the cycle, or a net loss of bone mass. Conversely, if you have insufficient bone reabsorption or excess osteoblastic bone formation, you will end up with a net gain in bone mass.

Osteoporosis = excess resorption means loss of bone, particularly in more metabolically active trabecular bone with higher sufficient surface area, they become thinner and many trabecular vanish entirely. Porous bones.

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15
Q

How does bone gain work?

A

Osteosclerosis - where you gain bone mass, More trabeculae and thicker. Far less common - can be seen in various genetic conditions and focally around metasteses from prostate cancers. Continuous increase in bone mass can be painful and debilitating.

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16
Q

What controls bone remodelling?

A
  • Endocrine
  • Estrogen, Thyroid hormone, PTH
  • Paracrine
  • RANKL, Wnt signalling
17
Q

What is Osteoclast differentiation and RANKL?

A
  • RANK receptor – Activation required for osteoclast differentiation and survival.
  • RANK Ligand – produced by
    osteocytes and osteoblasts
  • OPG (osteoprotegerin) – decoy
    receptor for RANKL also produced by
    osteocytes and osteoblasts.

With osteoclasts, RANK receptors are the master regulators. Absence would mean no differentiation of osteoclasts at all. When removed with undergo apoptosis or fission. RANK is found on osteoblasts and their precursors . This causes a signalling pathway through NF KEppa beta pathway results in differentiation, fusion, maturation and activation of osteoblasts.

OPG inhibits the differentiation of osteoclasts by binding up the available RANK ligand before it can interact with the RANK receptor on the osteoclast precursors. Proteger means to protect = bone protecting molecule.

Osteoblast Lineage cells produce OPG and RANKL

By controlling the rates, you can control osteoclast differentiation. Drug: Denusomab - a synthetic OPG. With this treatment, you can inhibit osteoclast differentiation and prevent osteoclast bone loss.

18
Q

What is Wnt signalling and bone formation?

A
  • Highly complex pathway involved in many different organ systems
  • Stimulates osteoblast differentiation
  • Inhibited by Sclerostin and Dkk-1. These bind to LRP5/6 and prevent them from interacting with the frizzled receptor.

It occurs via the canonical signalling pathway.
Wnt ligand binds onto a cell membrane receptor, this is the frizzled receptor is 7 transmembrane span protein with similarities to G protein coupled receptor. Before it can be activated, frizzled must be in complex with a CO receptor in bone (LRP5/6). This sets off a signalling cascade that results in the translocation of beta catenin into the cell nucleus causing a change in gene expression and leading to osteoblast differentiation.

19
Q

How do Osteocytes act as key regulators of remodelling?

A

Osteocytes are the key regulators of the other bone cell types via paracrine signalling.
- produce RANK ligand
- Inhibits it with OPG production
- Balance controls rate of osteoclast differentiation and activity.
- Also produces Sclerostin and DKK1
- Regulates differentiation of osteoblasts

20
Q

What is osteopetrosis?

A

This can occur locally at sites of prostate metastasis, but systemically quite rare.

Causes:
* LRP5 activating mutations.
Someone walked away unscathed from a high impact car crash - 8 times denser than normal. The reason was activated LRP5 mutations in the family. The canonical wnt signalling pathway is continuously activated within the osteoblasts. Unusual facial features and an extreme difficulty swimming. Very thick cortical bone.

  • van Buchem’s and SOST
    Systemic increase in bone mass. Patients have a loss of function in the SOST gene that encodes sclerosten. No inhibition of wnt signalling within the osteoblasts. This means increased osteoblast differentiation and bone formation throughout life. Patients have distinctively large mandible and the skull, as well as generalised bone overgrowth throughout the body. This is progressive and results in trapped nerves, palsy, headaches due to increased intracranial pressure.
21
Q

What is osteoporosis?

A
  • Defined as having a bone mass greater than 2.5 SD below average peak bone mass
  • Estimated that it will effect 1:2 women and 1:5 men.
    – Causes 500,000 low impact bone fractures every year in the UK
  • Can be primary (menopause, aging), or secondary (drugs, disease, lifestyle eg. smoking/alcohol)

Risk increases with age. Will reach peak bone mass in late 20s, early 30s, then it goes downhill. It’s more common in women because of bone loss due to menopause. Loss of oestrogen causes temporary increase in osteoclast activity resulting in sudden loss of bone that lasts until the body adapts to the new oestrogen levels.