Bone in Health and in Rheumatoid Arthritis Flashcards
Recall the structure of bone.
The space within the bone is filled with bone marrow cells, adipocytes, and blood vessels. The outer surface of bone will be adjacent to tissues such as ligament, synovium, and muscle
Recall the composition of bone tissue.
- Organic matrix
- Collagen: 90% of matrix (10% of adult bone mass)
- Other proteins to help bind mineral (also GF and chemotactic proteins)
- Mineral
- Hydroxyapatite: an insoluble salt of calcium and phosphorous: 60-70% of adult bone mass
- small amounts of Mg, Na, and bicarbonate
- Water: 10-20% of adult boen mass
Mention some of the functions of bone.
Recall the “Basic Multicellular Unit”.
BMU refers to the cellular makeup of the site of bone remodelling.
- Red bone marrow:
- Red and white blood cells, platelets
- Yellow bone marrow:
- Some white blood cells, adipocytes (fat cells)
- Haematopoetic cells
- blood cell precursors
- Stromal cells
- other supporting cells, including adipocytes, chondrocytes, mesenchymal stem cells
Bone remodelling is a balance in _______________ and _______________.
Bone resorption and bone formation
What are osteoclasts?
Osteoclasts are large, multinucleated cells (4-20 nuclei/cell), enriched with mitochondria. It is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodelling of bones of the vertebral skeleton.
Recall the mechanism of bone resorption.
Osteoclasts resorb bone by:
- forming a “sealing zone” by integrin-mediated attachment to the bone
- acidification of resorptive lacunae to dissolve mineral component
- release of collagenases and other enzymes to degrade the organic component
- bone degradation products are taken up by the osteoclast and released
________________ and ________________ regulate osteoclast differentiation.
Receptor Activator of NF-kB Ligans (RANKL)
Osteoprotegerin (OPG)
What is RANKL?
- Member of the TNF family of ligands
- Mostly membrane-bound but can be cleaved to a soluble form
- Induces osteoclast differentiation and activation
- Necessary and sufficient for osteoclast generation
- In normal physiologic (healthy) conditions, it is provided by osteoblasts and osteocytes
What is RANK?
What is OPG?
Osteoprotegerin (also known as osteoclast inhibitory factor - OCIF)
- member TNF-receptor family
- soluble receptor
- structurally distinct from RANK but binds RANKL (decoy receptor)
- Blocks RANKL-induced osteoclast differentiation and activation
- In normal physiological condition, it is provided by osteoblasts
OPG-/- mice would develop __________________. RANK-/- would develop _________________. RANKL -/- would develop __________________.
osteoporosis
osteopetrosis
osteopetrosis
M-CSF is required for ____________________ and ______________________. It is released by _____________.
proliferation of myeloid precursors and survival of osteoclast progenitors and mature osteoclasts.
osteoblasts
Recall the patterns of bone loss in RA.
Recall the multiple cellular sources of RANKL in RA synovium.
RANKL expression “outweighs” OPG expression at the _____________ in RA.
pannus-bone interface
Cytokines and factors produced by cells within the ______________ in RA augment osteoclastogenesis indirectly.
inflammatory infiltrate
Note: they indirectly promote osteoclast differentiation by inducing RANKL expression in T cells, synovial fibroblasts, and osteoclast-lineage cells
________ and ________ directly promotes osteoclast differentiation.
TNF acts directly on osteoclasts by increasing the number of osteoclast precursors and Increases their expression of RANK.
IL-1 acts directly on osteoclasts to promote fusion of the mononuclear precursor cells and supports the survival of the mature cells.
Recall the summary of the regulation of osteoclast differentiation in healthy bone.
Recall the summary regarding osteoclast differentiation and function in RA.
Recall the process of bone formation.
Following the cessation of osteoprogenitor proliferation:
- secretion of extracellular matrix proteins (osteoid) including collagen, bone sialoprotein, osteocalcin
- expression of alkaline phosphatase
- renders the osteoid (non-mineralised matrix) complement for mineral deposition
- some osteoblasts become embedded in bone => osteocytes
Recall the process of osteoblast differentiation.
Osteoblast differentiation depends on the expression of two key transcription factors, Runx2 and its target Osterix 1, which confer the differentiation of these cells into osteoblasts in response to external stimuli.
Wnt proteins are potent stimulators of osteoblast
differentiation.
In RA, at the interface of synovial inflammation and bone, osteoblasts are _______________ and _____________.
immature and do not form bone properly
Note: osteoblasts differentiation and bone function are impaired
Recall the role of the Wnt signalling pathway in RA.
Expression of Wnt signalling antagonists (including DKK proteins and sFRP proteins) is increased in inflamed synovial tissue. This leads to:
- inhibition of Wnt signalling at these sites
- inhibition of osteoblast maturation and bone formation at these sites
DKK-1 expression is increased by ________ in synovial fibroblasts.
TNF
TNF acts on osteoblasts directly to impair their ______________ and _________________.
differentiation and function
increase their expression of RANKL
Recall the effects of TNF on osteoblasts in vitro.
Recall the dysregulation of bone remodelling in RA.
