Lecture 26 - Healthy Bone Flashcards by Jack Cuthbertson

Composition of healthy bone
1)
2)
3)

1) Organic matrix
2) Mineral
3) Water

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Organic matrix of healthy bone composition
1)
2)

1) 90% collagen (collagen makes up ~10% healthy bone mass)

2) Other proteins that help bind mineral

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Mineral composition of healthy bone
1)
2)

1) 65% adult bone mass is hypoxyapatite

2) Smal amounts of calcium, magnesium, bicarbonate

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How much of adult bone mass is water?

25%

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Hypoxyapatite

Insoluble salt of calcium and phosphorus

~65% healthy adult bone mass

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How much adult bone is replaced each year?

5-10%

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Number of microscopic bone remodelling foci

1-2 million

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How is bone remodelling carried out?

Asynchronously.

At sites that are geographically and temporally separate

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Reasons for bone remodelling
1)
2)
3)

1) Maintain ion concentration in the body (EG: Ca2+)
2) Adapt shape and structural organisation to alterations in biomechanical forces (mechanostat)
3) Maintain structural integrity, repair microdamage

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Proportion of body’s calcium in bone

99%

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Proportion of body’s phosphorus in bone

85%

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Basic multicellular unit of bone
1)
2)
3)

1) Osteocytes
2) Osteoblasts
3) Osteoclasts

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Name of cavity formed by osteoclast

Resorption cavity

Lacuna

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Time taken for bone resorption

3 weeks

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Time taken for bone formation

3-4 months

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Disease where bone density is too low

Osteoporosis

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Disease of net bone gain
1)
2)

Osteopetrosis

Osteosclerosis

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Osteoclast phenotype
1)
2)

1) Large, multinucleated cells (4-20 nuclei)

2) Rich in mitochondria

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Process by which osteoclasts resorb bone
1)
2)
3)
4)

1) Form a sealing zone (integrin-mediated)
2) Release H+, acidify lacuna, degrade mineral component
3) Release of collagenases, other enzymes to degrade organic component
4) Bone degradation products are taken up by osteoclast, released

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What do osteoblasts differentiate from?

Mesenchymal stem cells

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Other cells which differentiate from mesemchymal stem cells
1)
2)
3)

1) Muscle
2) Chondrocytes
3) Adipocytes

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Three fates of osteoblasts
1)
2)
3)

1) Osteocyte (encased in bone)
2) Lining cell (sits on surface of bone)
3) Apoptosis

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Bone formation of osteoblasts
1)
2)
3)

1) Secretion of ECM proteins (osteoid) including collagen, bone sialoprotein, osteocalcin
2) Expression of alkaline phosphatase
3) Mineral deposition

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ECM proteins secreted by osteoblast during bone formation
1)
2)
3)

Study These Flashcards

1) Collagen
2) Bone sialoprotein
3) Osteocalcin

Function of alkaline phosphatase

Renders the osteoid competent for mineral deposition

Osteoid

Unmineralised bone

What is unmineralised bone called?

Osteoid

``` RANKL 1) 2) 3) 4) 5) ```

1) Receptor activator of NF-kB ligand 2) Key differentiation factor in osteoclast development 3) Binds to osteoclast precursor 4) Member of TNF superfamily 5) Mostly membrane-bound, but can be cleaved to soluble form

``` Osteoclast differentiation 1) 2) 3) 4) ```

1) Haematopoietic stem cell 2) Myeloid progenitor develops into osteoclast progenitor by binding M-CSF released by osteoblast-lineage cells 3) Osteoclast progenitor expresses RANKL receptor, RANK-L receptor binds RANKL released by osteoblast lineage cells 4) Cell binds to bone, becomes osteoclast

Factor released by osteoblast-lineage cells that causes myeloid progenitor to differentiate into osteoclast progenitor

M-CSF (macrophage colony stimulating factor)

Effect of absent RANKL/RANK

RANKL-/- mice develop severe osteopetrosis

RANK 1) 2) 3)

1) Receptor for RANKL/ODF 2) Member of TNF receptor family 3) Expressed on osteoclasts and osteoclast progenitors

``` OPG 1) 2) 3) 4) ```

1) Osteoprotegerin 2) Member of TNF receptor family 3) Binds RANKL as a decoy receptor 4) Blocks RANKL-induced osteoclast differentiation

Effect of absent osteoprotegerin

Osteoprotegerin-/- mice develop osteoporosis

Key regulator of osteoclast differentiation

Osteoprotegerin:RANKL ratio

M-CSF roles 1) 2)

1) Proliferation of myeloid precursors | 2) Survival of osteoclast progenitors and mature osteoclasts

Producers of RANKL 1) 2)

1) Primary producers are early-mid stage osteoblasts | 2) Can also be produced by osteocytes

Main producers of OPG

Mid- to late-stage osteoblasts

Promoters of osteoblast differentiation and function

Wnt ligands

Differentiation induced by wnt ligands

Osteoblastic progenitor to pre-osteoblast

Effect of wnt activation in osteoblasts 1) 2)

1) Promotes bone formation | 2) Inhibits bone resorption

How do wnt ligands promote bone formation? 1) 2) 3)

1) Wnt ligand binds coreceptors frizzled or LRP5/6 2) Beta-catenin in cytoplasm is stabilised 3) Beta-catenin translocated to nucleus, acts as a transcription factor, induces genes that induce osteoblast differentiation, increase OPG expression

Factors that inhibit wnt signalling in osteoblasts 1) 2) 3)

1) Sclerostin binds LRP5/6 2) Dikkopf (DKK) binds LRP5/6 3) Secreted frizzled-related protein 1 (sFRP1) binds wnt ligands

Effect of increased sclerostin/DKK/secreted frizzled-related protein 1

Increased bone resorption by reducing osteoblast differentiation, increases osteoclast differentiation (increases RANKL:OPG ratio)

Cell that produces endogenous wnt antagonists

Osteoblast

Osteocyte

Terminally-differentiated osteoblast, encased in bone matrix

``` Osteocyte features 1) 2) 3) 4) ```

1) Longest-lived cell in the body (20-25 years) 2) Sit within bone matrix in lacunae 3) Dendrite-like cell processes (canaliculi) that sense mechanical loading, communicate between other osteocytes, cells on bone surface 4) Regulate osteoblasts and osteoclasts

How do osteocytes regulate osteoblasts and osteoclasts?

1) Regulate levels of DKK and sclerostin | 2) Can release RANKL

What is sclerostosis?

Mutation in sclerostin, which inactivates it | Very thick bone, osteosclerotic condition

Effect of increased mechanical loading on osteocytes

Reduce expression of DKK, sclerostin | This increases bone formation, reduces resorption, because of activation of wnt signaling

Treatment strategies for osteoporosis 1) a,b 2) a

1) Target osteoclast a) Inhibit osteoclast b) Inhibit RANKL 2) Target osteoblast a) Target osteoblast progenitor differentiation

Bisphosphonates 1) 2) 3)

1) Inhibit osteoclasts, lead to apoptosis 2) Used to treat osteoporosis 3) EG: Zoledronate

Denosumab 1) 2)

1) Anti-RANKL, fully-humanised MAb | 2) Inhibits osteoclast differentiation and survival

Effect of bisphosphonates and anti-RANKL MAbs

1) Reduces number of fractures 2) Reduces bone loss 3) No increase in bone volume

Osteoporosis treatments that target osteoclasts 1) 2)

1) Bisphosphonates | 2) Anti-RANKL MAbs

Osteoporosis treatment that targets ostoblasts

Recombinant parathyroid hormone, amino acids 1-34 (rhPTH,1-34, teriparatide)

Recombinant parathyroid hormone, amino acids 1-34 1) 2) 3)

1) Only approved anabolic therapy for osteoporosis 2) Given as an intermittent injection. Constant exposure doesn't lead to increased bone density 3) Induces mesenchymal stem cell differentiation into osteoblasts

Emergin osteoporosis therapy that promotes bone formation

Anti-sclerostin MAb | AMG785 or Romosozumab

Lecture 26 - Healthy Bone Flashcards

(58 cards)