BIOM30002 Lecture Notes - Lecture 10: Rankl, Myelocyte, Osteoclast
12 Jun 2018
School
Department
Course
Professor
L10 Bone in Health and Disease
Summary
Part 1 – Regulation of osteoclast differentiation in healthy bone
- Osteoclasts are derived from the myeloid cell lineage of haematopoietic stem cells
- M-CSF is required for proliferation of myeloid precursors and survival of osteoclast
progenitors and mature osteoclasts
- RANKL is the essential cytokine required for osteoclast differentiation, survival and function
In healthy bone it is produced predominantly by early-mid stage osteoblasts;
osteocytes may also produce RANKL
- RANKL binds RANK and induces osteoclast differentiation
- OPG is an endogenous decoy receptor for RANKL which prevents it from interacting with
RANK, blocking osteoclast differentiation
In healthy bone mid-stage-mature osteoblast produce OPG
- Disruption of RANKL or RANK osteopetrosis due to absence of osteoclasts
- Disruption of OPG osteoporosis due to proliferation of osteoclasts
Part 2 – Osteoclast differentiation & function in RA
- Osteoclasts are the only cell responsible for bone erosion in RA
- At pannus-bone interface there is increased expression of RANKL relative to OPG, promoting
osteoclast differentiation and function at this site
- In RA, synovial fibroblasts and T cells as well as osteoblast-lineage cells are additional source
of RANKL
- Inhibition of TANKL (either by gene deletion, or blockade with OPF.Fc) protects against focal
bone erosion in mouse arthritis models BUT has no effect on synovial inflammation
- Cytokines including TNF, IL-1 and IL-6 act indirectly to promote osteoclast differentiation by
inducing RANKL expression in T cells, synovial fibroblasts and osteoblast-linage cells
- TNF acts directly on osteoclasts by increasing the number of osteoclast precursors and
increase their expression of RANK
- IL-1 acts directly on osteoclasts to promote fusion of the mononuclear precursor cells and
supports survival of the mature cells
Part 3 – osteoblast differentiation & function in RA
- Bone formation is impaired at bone surfaces adjacent inflammation (pannus) in RA
- Osteoblasts fail to mature properly leading to impaired capacity to form proper mineralised
bone
- Expression of Wnt signalling antagonists (including DKK proteins and sFRP proteins) is
increased in inflamed synovial tissue
1. Inhibition of Wnt signalling at these sites
2. Inhibition of osteoblast maturation and bond formation at these sites
- DKK-1 expression is increased by TNF in synovial fibroblasts
- TNF acts on osteoblasts directly to impair their differentiation and function, and increase
their expression of RANKL
Document Summary
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