Lecture 14 - Tissue remodelling (part 2) Flashcards
What are the stages of osteoblasts formation?
Mesenchymal stem cell -> osteogenesis progenitor cell -> transitory osteoblast -> mature osteoblast (then a bone osteocyte would form, that’s it’s terminal differentiation)
What 2 types of components make up bone, and what are they exactly?
Mineral - calcium hydroxide
Organic - type 1 collagen, osteopontin, osteocalcin, osteonectin
What are the primary functions of osteoblasts?
To line the bone surface and synthesise type 1 collagens and other bone matrix proteins
Initiate mineralisation
What percentage of osteoblasts will become embedded osteocytes?
15%
How are osteoblasts regulated (what type of signalling do they respond to)?
Regulated in an autocrine and paracrine manner by a range of growth factors (IGF, bFGF, TGFbeta, wnt, Bone Morphagenic Proteins <- bumps actually regulated themselves at local level).
Also respond to endocrine signals including:
Parathyroid hormone, vitamin d3, growth hormone, progesterone, oestrogen
How are osteoblasts connected to one another?
Gap junctions
Integrins
Projections
How do osteoblasts initiate mineralisation
1stly they’ve deposited the non-mineralised matrix, mainly made of collagen 1.
They then deposit matrix vesicles, where hydroxyapatite (HA) formation initiates
HA crystals cluster and coalesce
How long is the delay from invitation to actual mineralisation?
What is new bone iniatlly formed as?
10 days
Un mineralised osteoid
What are the possible fates of osteoblasts?
Most undergo apoptosis
Remaining ones become quiescent lining cells <-ready to be activated and lay down bone when needed
OR osteoblasts can differentiate into embedded osteocytes
Describe the location and properties of the osteocyte habitat
Always remain enclosed in the lacuna, ie. they’re buried in the matrix forever
They reach out and connect to other osteocytes via extensions through the bone, but never actually see them
Remain viable for the life of the individual
What is the purpose of osteocytes
To detect damage and changes to the environment
And subsequently when needed secrete sclerostin, which is involved in the wnt signalling pathway and is not really secreted by anything else
What is the process of origin for an osteoclast
Haemapoetic stem cell -> CMP -> Oc- CFC (debatable) -> osteoclast
General properties of osteoclasts (cell structure)
Large and multinucleated
Have a ruffled border (to increase SA)
Contains actin rings (which help with adhesion)
What is the purpose of osteoclasts?
Overall: absorb and digest mineralised bone, have a clearance mechanism to absorb bone material and shunt it through apical membrane
How achieve this:
Secrete H+ and Cl- to form acidic environment
Also secrete enzymes (e.g. Tartare resistant acid phosphotases) to aid bone reabsoprtion
And secrete cathepisin k
And express calcitonin receptors
Why do we ultimately have osteoblasts, osteocytes and osteoclasts?
BONE REMODELLING
How often do you get a new skeleton?
Every 10 years
Define bone remodelling and what it does
=Highly coordinated turnover of bone tissue involving sequential activity if blasts then clasts
It: repairs micro damaged bone
renews old bone tissue
Maintains ca2+ homeostasis (99% calcium store in bone, is released as needed)
Has a functional adaptation too-as increased muscular load bones get bigger as they’re used more
What are the 2 types of bone remodelling
Cancellous and haversion
Describe cancellous remodelling
Surface remodelling
Clasts attack and move along bone to the ‘furrow’
Then blasts arrive and begin remaking the bone
Osteoid mineralised to form bone
Technical stages of the process: quiescence -> resorption -> reversal-> formation -> mineralisation -> quiescence (CYCLE)
Describe haver sham remodelling
Basically drilling through to the centre of the bone for repair there
Occurs in thickened bone
Head of the clasts tunnels through the bone (behind it is filled in)
-this gives rise to the concentric ring appearance
As the clasts tunnel down they are connected to other cells and blood vessels
-blood vessels provide nutrients and O2’ blasts are what lay down the new bone.
Through what receptor and ligand to blasts and clasts communicate?
RANK and RANK ligand
Describe the process of how new osteoclasts are signalled to form
Macrophage stimulating colonies released from blast
These attaché to mCSF receptors in monocytes
- this encourages the monocytes to become clast precursors (aka NFKB) (which have rank on the surface)
The blast has rank ligand in it’s surface, and this fuses with rank on clast precursors
-stimulates precursors to become proteoclasts, which then become quiescent osteoclasts then functional osteoclasts
Can quiescent osteoclasts be stimulated directly to form functional osteoclasts?
Yes. They have rank so rank ligand can attach and make them become functional
How is osteoclast formation regulated?
Indirectly. (Because blasts being signalled not clasts)
PTH and 1,25(OH)2D5 are signalling molecules, which are bone resorting agents
To increase clast formation:
They act directly on blasts and increase rank ligand expression
MCSF expression also increases so more monocytes are created
All together this stimulates osteoclasts genesis
Simulataneously (still for increasing clasts), calcitonin acts DIRECTLY in osteoclasts to inhibit resorption
What can cause bone loss, also give details of how much and when
Being in space-1%lost per month in 0 gravity cos just not needed
Aging-bone mass increases till you’re 30
Then falls: steadily for men, sharp drop at menopause for females because sudden loss of protective oestrogen
What is a dodgy consequence of bone loss
Elevated circulatory ca2+ levels
Is oestoporosis bad and big problem
Yes. There is no way we need to know the monetary statistics etc. just do that there’s no screening, it’s expensive, and deadly
What are the features of osteoporosis
There is less thickening and less connectivity in the bone
Osteoclasts act in ‘nibbled’ sites (how they appear to look at)
Clasts perforate the bone, resulting in more nibbling
BINER REABSORPTION IS GREATER THAN BONE FORMATION (called uncoupled modelling)
What are current osteoporosis treatments?
Calcium supplementation
Hormone replacement therapy
Biphosphonates - potent inhibitors of bone REABSORPTION it will now only write that in capitals
Calcetonin
Selective oestrogen receptor modulators
Raloxifone
Drugs to target wnt signalling
Does wnt signalling promote bone formation?
Yar
Describe the Process of wnt signalling
Wnt binds to frz and lrp5/6 (which come together to form it’s receptor)
This activates dishevelled
A signalling cascade occurs
This turns on TCF gene transcription
Describe how sclerostin acts on wnt
It’s a wnt INHIBITOR, it prevents it binding to it’s receptor so no signalling cascade and no ctf gene script ion
Remember sclerostin is released by osteocytes
What are the effects of having a mutation in LRP5/6?
If the mutation is activating: higher bone mass because more wnt signalling
Inactivating mutation: lower bone mass
Describe general high bone mass disorders and what they’re caused by
Bone thickening throughout skeleton, especially skul
Cranial nerves can be trapped causing deafness and facial palsy
Caused by: mutation in sost gene (encodes sclerostin)
What is the evidence that sclerostin regulates wnt signalling?
Mutation in sclerostin gene leads to unregulated bone formation therefore higher bone mass
Talk through the process of bone remodelling in the context if wnt and sclerostin
Normal bone-chutes secrete sclerostin, wnt signalling inhibited
Micro fracture-osteocyte apoptosis. Decrease in sclerostin so more wnt signalling. Osteoblast differentiation and rank ligand expression promoted (<-what wnt cascade actually leads to). Therefore more clasts now present at injury site because blast have differentiated. These resorb damaged bone.
Mature osteoblast replace damaged bone, including osteocytes and sclerostin levels return to normal
The end.
