Cellular structure of bone

Question 1

What are the functions of the bone?

Answer 1

• Support and Movement: attachment site for muscles
• Protection for internal organs
• Provides home for bone marrow
• Mineral Reservoir (e.g. serum calcium)
• Endocrine Function: source of some ‘non-classical hormones’

Question 2

What are the types of bone structure?

Answer 2

Cortical (compact) bone

Trabecular (spongy, cancellous) bone

Question 3

What us the cortical bone?

Answer 3

• highly organised in repeating units called osteons, which are circular wrapped sheets of bone tissue (lamellae) organised around little central canals called Haversian canals (which contain blood vessels, nerves etc)
• forms outer surface of long and flat bones
• within the bone matrix (osteoid protein) there are cavities called lacunae where osteocytes reside, and are connected via minute canals called canaliculi

Question 4

What is the Trabecular Bone?

Answer 4

• consists of the same structure as cortical bone, but with less organisation
• meshwork of bone tissue with spaces in between
• forms inner surface of bone
• within the bone matrix (osteoid protein) there are cavities called lacunae where osteocytes reside, and are connected via minute canals called canaliculi

Question 5

What is the Composition of cortical and trabecular bone?

Answer 5

Same composition and cell types:

• protein: organic osteoid matrix (25%)
• mineral: 75% (hydroxyapatite- calcium and phosphate)
• cells

Question 6

What is the organic component of bone?

Answer 6

The osteoid matrix (mainly collagen)

Question 7

What gives bone its strength?

Answer 7

Organic osteoid matrix (mainly type 1 collagen) and mineral component (mainly calcium and phosphate) are mixed together to give bone its strength

Question 8

Type 1 Collagen in Organic Osteoid gives bone…

Answer 8

Flexibility and tensile strength

Question 9

Hydroxyapatite makes bone…

Answer 9

brittle and rigid, giving high compressive strength (strength longitudinally)

Question 10

What are the major classes of bone cells?

Answer 10

3 major classes:

• Osteoblasts
• Osteoclasts
• Osteocytes

Also, bone marrow cells:

• mesenchymal (stromal) stem cells
• haematopoietic stem cells

Question 11

What are the Bone forming cells?

Answer 11

Osteoblasts:
>forms organic osteoid matrix & promote its mineralisation

may terminally differentiate into osteocytes, found within the bone matrix (in lacunae)

may remain inert along the bone surface and become lining cells

Question 12

What are osteoblasts derived from?

Answer 12

Mesenchymal (stromal) stem cells

Question 13

What are the Bone reabsorbing cells?

Answer 13

Osteoclasts:
>large multinucleated cells which attach to bone surface and secrete:
-acid to dissolve bone mineral (releasing phosphate and calcium)
-enzymes (Cathepsin K- high affinity for type 1 collagen) to digest organic matrix

> life cycle controlled by apoptosis

Question 14

What are osteoclasts derived from?

Answer 14

Haematopoietic stem cells

Question 15

What are Osteocytes?

Answer 15

terminally differentiated osteoblasts encased in lacunae

extend multiple dendrites via minute canals in bone matrix (canaliculi) which connect lacunae to each other and to bone surface, where they will be in contact with blood vessels (lacunocanalicular system)

Question 16

What is the role of the Lacunocanalicular system in osteocytes?

Answer 16

maintains communication with bone surface and blood

Question 17

What is the Osteocyte activity?

Answer 17

thought to coordinate osteoblast and osteoclast activity to achieve a balance between bone formation and bone reabsorption (BONE REMODELLING)

Question 18

Describe Bone remodelling.

Answer 18

osteoclasts dissolve old bone and osteoblasts replace it with new bone in a continuous process of bone recycling

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

Question 19

What are the Stages of Bone Remodelling?

Answer 19

1) Activation
- stimulation of osteoclast differentiation
2) Reabsorption
- governed by the lifecycle of the osteoclast
3) Reversal
- signals to terminate osteoclast activity (osteoclast apoptosis) and promote further osteoblast differentiation
4) Formation
- osteoid mineralisation and new bone formation

Question 20

Describe how bone remodelling is controlled.

Answer 20

Load-Bearing Exercise
-leads to micro-stress fractures detected by osteocytes which then coordinate remodelling

Cytokines and other local signals

Endocrine Signals

• oestrogen inhibits osteocyte apoptosis and promotes osteoclast apoptosis, favouring bone formation over reabsorption
• androgens

Question 21

What induces osteoclast differentiation?

Answer 21

RANK (receptor activator of nuclear factors kappa-B) ligand binding to RANK receptor on pre-osteoclasts, activating a transcription factor promoting differentiation of pre-osteoclasts into osteoclasts’

Question 22

What is RANK ligand expressed by?

Answer 22

osteoclasts, osteoblasts and pre-osteoblasts

Question 23

What competes with the RANK receptor for the RANK ligand?

Answer 23

OPG (osteoprotogerin), a decoy receptor produced by osteocytes which prevents RANK-ligand from binding to RANK receptor, thus inhibiting osteoclast differentiation to prevent excessive bone reabsorption

Question 24

What is Denosumab (monoclonal antibody)?

Answer 24

RANK-ligand inhibitor, preventing RANK receptor activation and inhibiting osteoclast differentiation, thus inhibiting the reabsorption phase of the bone remodelling cycle

Question 25

What is denosumab used for?

Answer 25

osteoporosis (loss of bone density)

• inhibits osteoclast differentiation
• inhibits further bone reabsorption
• mimics osteoprotegerin (OPG)

Question 26

How are osteoblasts differentiated?

Answer 26

via the Wnt Signalling Pathway:

1) Wnt is a signalling protein molecule which will activate Wnt receptor (frizzled) in presence of co-factor LRP5
2) ß-catenin protein in the cytosol is released following Wnt binding and frizzled activation, allowing it to act as a transcription factor and promoting specific differentiation pathways (osteoblast differentiation)

Question 27

Describe the Negative Regulation of Wnt Signalling Pathway.

Answer 27

DKK (dickkopf) and sclerostin (SOST) proteins bind LRP5 co-receptor and prevent full activation of Wnt signalling pathway, preventing osteoblast differentiation

Question 28

What is Osteoporosis (common bone disease)?

Answer 28

loss of organic bone mineral density (normal part of ageing), resulting in brittle bones making you more prone to fractures

Question 29

What is Osteomalacia (less rare)?

Answer 29

loss of the bone mineral component/failure of mineralisation of the osteoid, resulting in the softening of the bones

Question 30

What is Osteoporosis Pseudoglioma?

Answer 30

Co-receptor LRP5 gene mutation in the Wnt signalling pathway, affecting key signals:

• no osteoblast differentiation
• very poor bone development
• very fracture prone
• early blindness due to failure and abnormalities of retinal development

Question 31

What is Sclerosteosis and Van Buchem Disease?

Answer 31

SOST gene mutation:

• inactivated sclerostin protein of the Wnt signalling pathway
• overaction of Wnt signalling pathway
• increased osteoblast differentiation causing excess bone formation
• high bone mineral density above average

Question 32

What is Osteopetrosis?

Answer 32

Mutation inactivates RANK-ligand protein:

• prevents osteoclast differentiation
• preventing bone reabsorption
• bone more rigid and brittle

Question 33

Describe Bone density loss with age.

Answer 33

peak bone density achieved at 25-30, and thereafter it is a slow downhill process, somewhat accelerated in women due to the fall in oestrogen levels post-menopause