Bone Turnover Flashcards
Inflammatory mediators
Cytokines
Cytokines
A group of proteins and peptides that are used to allow one cell to communicate with anither
Redundancy of cytokines system
Most functions of cytokines can be performed by many different cytokines
Pleiotropism of cytokine system
A single cytokine has many different functional effects on many different cell types or even on the same cell
Hormone mediators of osteoclast differentiation and activity
1,25 dihydroxyvitamin D
Parathyroid hormone
Oestrogen
Leptin
Paracrine/autocrine mediators of osteoclast differentiation and activity
Prostaglandins
Interleukin-1
Interleukin-6
Tumour necrosis factor TNF
Osteoprotegerin OPG (or osteoclastogenesis inhibitory factor OCIF)
Member of the tumour necrosis factor receptor superfamily
Inhibits the differentiation of myeloid precursors into osteoclasts
Decreases resorption by osteoclasts in vitro and in vivo
Derivation of osteoblasts
Mesenchymal stem cells
Effect of OPG
Inhibits osteoclast formation, function and syrvival
RANK ligand
Stimulates osteoclast formation, function and survival
What does RANK stand for
Receptor activator of nuclear factor K
How does osteoprotegerin work
Binding to RANK-ligand, thus blocking the RANK-RANK ligand interaction between osteoblasts/stromal cells and osteoclast precursor
Coupling
Bone formation occurs at sites of previous bone resorption
Balance - bone remodelling
Amount of bone removed by osteoclasts should be replaced by osteoblastic activity
Derivation of osteoclasts
Haematopoietic stem cells
Bone resorption
Osteoclasts break down bone
Calcium is taken from bone and placed into bloodstream
Lysosomes assist the process
Calcium and phosphate are released
Bone modelling
Gross shape is altered, bone added or taken away
When does bone modelling occur
During growth
Sculpt adult shape
Bone remodelling
All of bone is altered, new bone replaces old bone
Function of bone remodelling
Remove and replace old bone
Mobilise minerals for homeostasis
When does bone remodelling occur
In adult
Bone remodelling process
Cells lining the bone surface are activated to form/recruit osteoclasts in response to injury
Osteoclasts attach to surface and projections increase surface area and secrete acid- dissolving the bone mineral to form resorption cavities (pits)
Osteoblasts are recruited to the resorbed bone and secrete osteoid matrix (mainly collagen)
Over time osteoid matrix becomes mineralised to form bone
Primary osteons
Fill in holes that are left during very rapid formation
Don’t cut through the lamellae
Secondary osteons
Cut through layers of lamellae and drive remodelling
What are osteoclasts driven by
RANK-ligand/OPG balance
What are osteoblasts driven by
Cytokines
Growth factors
Wnt pathway
Activation leads to a series of events
Number of genes play a role in regulating bone
Eg naked, dkk1, drosophila-frizzled hair, LRP5
LRP5 mutation
Stimulates osteoblasts to make more hine
Sclerostin
Secreted glycoprotein
Down regulates Wnt signalling
Wnt pathway function
Bone formation and decreased bone resorption
Function of RANK-ligand
Induces osteoclast activity
Stages of bone formation and remodelling
Activation
Resorption
Reversal
Formation
Quiescence
Activation
pre-osteoclasts are attracted to the bone remodelling sites, activated by RANK ligand produced by osteoblasts
• Pre-osteoclasts fuse to form multinucleated osteoclasts
Resorption
osteoclasts dig out a resorption pit in spongy bone or burrow a tunnel in compact bone by releasing acid and cathepsin K
• Osteoclasts disappear
Reversal
mesenchymal stem cells appear along the burrow or pit and proliferate and differentiate into pre-osteoclasts
Formation
they mature into osteoblasts at the surface of the burrow or pit and release osteoid at the site, forming a new soft non-mineralised matrix
• The new matrix is then mineralised with calcium and phosphate
Quiescence
the site, with resting lining cells, remains dormant until the next cycle
• Osteoprotegerin mops up any RANK ligaments to prevent unnecessary remodelling
