Cellular structure of bone

Question 1

What are some functions of bone?

Answer 1

• Support and movement: 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

Question 2

What is cortical bone?

Answer 2

Cortical bone is highly organised, and it forms the outer surface of long bones and flat bones.

It is organised in repeating units called osteons. These are circular, wrapped sheets of bone matrix (bone tissue) organised around little central canals called Haversian canals, which can contain blood vessels.

Within the Cortical bones there is a very intricate network of little canals, called Lacunae. These would permeate throughout the structure of cortical bone, and they are where the masterclass of bone cell (osteocytes) reside.

Question 3

What is trabecular bone?

Answer 3

It is located inside the bone, underneath the cortical bone.

In the case of long bones it tends to be located in the head at either end of the bone, where it expands. It consists of the same sort of structure, but like a mesh work of the bone matrix with spaces in-between.

Question 4

What is the composition of bone?

Answer 4

It is 25% protein (mainly collagen), and 75% minerals (mixed osteoid, mainly calcium and phosphate)

It is also made up of cells, but they don’t count for a significant weight percentage.

Question 5

Describe the organic (osteoid) protein matrix

Answer 5

It is made up of mainly type 1 collagen, and the mineral component.

It gives the bone flexibility and tensile strength (the resistance of the bone to snapping)

Question 6

Describe the bone mineral

Answer 6

It is mainly hydroxy apatite, which is hydrated calcium and phosphate (Ca10(PO4)6(OH)2).

It makes the bone rigid, brittle and gives it a high compressive strength (the ability to resist shortening).

Question 7

What are the different types of bone cells/

Answer 7

The three main types of bone cells are:

• osteoblasts
• osteoclasts
• osteocytes

Mesenchymal (stromal) stem cells give rise to osteoblasts and osteocytes.

Haematopoietic stem cells give rise to all blood cells, and osteoclasts (which are the same lineage as macrophages).

Question 8

Describe osteoblasts

Answer 8

• Bone forming cells
• Derived from mesenchymal stem cells
• Secrete osteoid, collagen matrix of bone
• Promote mineralisation of bone

Question 9

Describe osteoclasts

Answer 9

• Bone reabsorbing cells
• Derived from haematopoietic stem cells
• Large, multinucleate
• They attach to the surface of the bone either inside the Haversian canals or along the bone, or on the inner surface of the bone facing the bone marrow, forming a tight seal, and they secrete acid to dissolve the bone mineral and enzymes to digest organic matrix
• Life cycle controlled by apoptosis

Question 10

Define osteocytes

Answer 10

• Terminally differentiated osteoblasts
• They may last for years/decades, encased within the bone mineral matrix (they live in small holes called lacunae)
• The lacunocanalicular system maintains communication with bone surface and blood vessels
• Important, the osteocytes are increasingly considered as the co-ordinator bone cells: they are involved in co-ordinating the activity of osteoblasts and osteoclasts

Question 11

What are Canaliculi?

Answer 11

Tiny canals in the matrix connecting one lacuna to another, and various lacunae to the surface in contact with blood vessels, and the osteocytes themselves extend cellular processes (dendrite like processes) along these tiny little canaliculi

Question 12

What is bone remodelling?

Answer 12

The term used to refer to the opposing processes of bone formation and bone reabsorption.

It involves osteocytes dissolving and re-absorbing old bone, and osteoblasts replacing it with new bone. In this case we would have a moving edge of bone being reabsorbed, followed by new bone being laid down. New osteoid will become mineralised, forming new bone.

Question 13

How are osteoclasts and osteoblasts involved in bone remodelling?

Answer 13

The balance is controlled by the differentiation and then the lifecycle of these cells.

Osteoclasts will differentiate in response to appropriate signals and then undergo apoptosis in response to other signals.

Osteoblasts may terminally differentiate into osteocytes, remaining embedded within the matrix. If they remain inert along the bone surface, they become lining cells.

Question 14

Describe the stages of bone remodelling

Answer 14

1) Activation
Involves stimulation of osteoclast differentiation

2) Reabsorption
Phase governed by the lifecycle of the osteoclast

3) Reversal
Involves signals to terminate osteoclast activity and promote further osteoblast differentiation, coupled with osteoclast apoptosis

Question 15

What some ways in which we can control bone remodelling?

Answer 15

1) ordinary load-bearing exercise. That is simply being up and about and mobile.
2) various cytokines and other local signals.
3) the endocrine system. The sex steroids in general, androgens in males and oestrogen in females are important. Oestrogen inhibits osteocyte apoptosis, and promotes osteoclast apoptosis, meaning oestrogen favours formation over reabsorption.

Question 16

Describe the induction of osteoclast differentiation by RANK ligand

Answer 16

RANK is a transcription factor that when activated will promote osteoclast differentiation.

RANK is the cell surface receptor, when activated, it activates this transcription factor, promoting differentiation of precursors into osteoclasts.

RANK ligand activates the receptor. It is expressed by osteoblasts and osteoclasts. When RANK ligand binds to the receptor, you promote osteoclast differentiation. This promotes the activation phase of the remodelling. Osteoblasts and osteocytes themselves can promote this.

However, the osteocytes also secrete OPG (osteoprotogerin), which will compete with RANK ligand for the RANK receptor. OPG is opposing activation of RANK, and hence is acting as a break on osteoclast differentiation.

Question 17

Describe the Wnt signalling pathway

Answer 17

Wnt is a gene family that encodes for Wnt proteins, which are involved in developmental signalling throughout the animal kingdom. Thus, they are highly conserved genes.

So, wnt is a protein signalling molecule, which will activate a receptor. The wnt receptor is called Frizzled. Frizzled requires a co-receptor to function, which is called LRP5. When the co-receptor and Frizzled are both present, wnt can bind, activating the Frizzled receptor. B-catenin becomes released following wnt binding and Frizzled activation, allowing it to act as a transcription factor and promoting whatever differentiation pathways are involved in this particular case.

Question 18

What is osteoporosis?

Answer 18

Very common disease of the bone. Defined as an accelerated loss in bone density, that is two standard deviations or more below the average for peak bone density for your sex and ethnic group. Makes you more susceptible to fractures.

Question 19

What is osteomalacia?

Answer 19

Less common disease of the bone. Specifically a loss of the bone mineral component, or a failure of mineralisation, rather than loss of the organic component. Largely environmental. In children, it went by the name of Rickets, essentially due to vitamin D deficiency. Vitamin D is one of the endocrine factors required for bone mineralisation. A failure of that will result in Rickets, so your bones are soft and flexible, like cartilage, rather than hard and brittle.

Question 20

What is Osteoporosis pseudoglioma?

Answer 20

A bone disease caused by mutation.

In children, it means very poor bone development, which becomes severe osteoporosis, and children become very fracture prone. Genetic analysis of these rare individuals tracked down the LRP-5 molecule. LRP-5 is the co-receptor with Frizzled for the wnt signalling pathway. Mutations which lead to this disease are inactivating mutations of LRP-5, which means the wnt signalling pathway is unable to function properly. The gene called SOST, which is one that makes a protein called sclerostin, was also discovered by linkage analysis.

Question 21

What happens during osteoporosis?

Answer 21

Another bone disease caused by mutation.

Bone becomes more ridged and brittle. This is an inactivating mutation of the RANKL protein. This will impact bone reabsorption by preventing it. If you really want to treat osteoporosis you might want to prevent bone reabsorption, but it is not a good idea, as bone remodelling is supposed to occur. In other words, you are supposed to reabsorb old bone and form new bone. If you stop that process, your bone won’t be remodelled and so it will become more brittle.

Question 22

What happens during osteoporosis?

Answer 22

• Loss of bone density
• Increased fracture risk
• Increase in bone resorption over formation

Can be influenced by both modifiable and non modifiable factors