BONE MICRODAMAGE AND CELL APOPTOSIS

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BONE MICRODAMAGE AND CELL APOPTOSIS Brendon
Noble Musculo-Skeletal Research Unit, University
of Edinburgh Medical School, Edinburgh, U.K.

PRESENTED BY KIRANMAI BANDARU
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• Key terms -
• Bone has 2 layers -
• Outer Cortical bone Compact
• Inner trabecular bone Scaffolding
• Types of cells -
• Osteoclasts
• Osteoblasts
• Osteocytes

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• Osteoclasts
• Modified macrophages
• Derived from bone marrow from osteoclast
  progenitor cells.
• Dissolve the bone
• Osteoblasts
• Originate from bone marrow
• Found on the surface of new bone
• Form new bone Osteoid
• Regulate Ca2 and mineral deposition in Osteoid.
• Osteocytes
• Derived from Osteoblasts
• Embedded in the bone matrix

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• Bone remodelling or Bone turnover -
• Living bone is continuously repairing itself.
• Through 2 types of cells
• Osteoclasts - bone resorption or removal
• Osteoblasts - bone formation

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• Introduction -
• Microdamage accumulates due to
• increased mechanical load
• heavy exercise
• repetitive stress
• Removed by osteoclasts and osteoblasts
• The protective mechanism is impaired with aging
• Osteocyte plays a role in the targeted destruction

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• Apoptosis
• Energy dependent, non immunogenic and potentially
  controllable process
• Normal response of a healthy cell to a damaging
  stimulus
• Characterized by
• Cell shrinkage,
• Chromatin condensation,
• Membrane blebs,
• Disintegration of nucleus.

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• Cellular contents packed into vesicles
  ( Apoptotic bodies) removed by macrophages.
• Caspases play an important role.
• Activated by external signals - Fas Ligand
• Internal signals -
  Cytochrome C
• Morphological changes - best evidence of
  Apoptotic cell death.
• Biochemical and Molecular changes also seen in
  Necrosis.

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• Necrosis -
• Characterized by
• Cell swelling and bursting
  spillage of
• cell contents.
• Non energy dependent process,
• immunogenic and
• not controllable.
• Necrotic cell debris - production of
• pro- inflammatory cytokines TNF-a
• Apoptotic bodies - production of
  
• anti inflammatory molecules ( TGF ß,
  PGE2,
• IL-10)

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• What triggers apoptosis ?
• Physical injury or infection
• Oncogenic transformation
• Radiation induced damage
• Lack of growth factors or nutrients
• Expression of specific molecules
• Cell membrane of apoptotic cell - ICAM3
• Loss of phospholipid
  symmetry
• Oxidized phospholipid surface molecules.

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• Phagocytes - Lectins
• - Scavenger receptors
• - Integrins
• - Complement receptors
• Disruption of Apoptosis
• Autoimmune diseases
• Initiation of oncogenesis
• Apoptosis - important response in health
• enhanced during disease

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• Bone and Apoptosis
• Unique property - No immediate impact of loss
  of cells on size and function of tissue.
• Microdamage decreases the strength of bones,
  increases the risk for fractures.
• Presence of a protective mechanism that removes
  micro damage important for bone integrity.
• Removal of micro damage not through random
  remodelling but through active destruction by
  osteoclasts.

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• How does this targeting system work ?
• No knowledge about
• The mechanisms
• Why targeting system decreases with age.
• Studies were done on the behavior of bone cells
  in conditions where targeted system is
  inefficient.

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• Microdamage is higher in females after 40 yrs.
• Post menopausal reduction in estrogen levels
  causes increased bone turnover and increased
  osteoclastic activity. This coincides with
  increased micro damage.
• High doses of bisphosphonates
• - reduce targeted removal
• - inhibit osteoclasts
• Accumulation of micro damage in these conditions
  - 2 reasons
• - Change in material properties of
  bone
• - Problem with cells involved in
  sensing,
• signaling and repair of the bone.

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• Increased osteoclast function associated with
  increased cracks supports the importance of
  targeted osteoclast activity in removal of
  Microdamage.
• Damage sensing cells are osteocytes - only
  cells found in close association with damage.
• Osteocytes decrease with age - associated with
  an impairment of targeted removal in old age.
• Lack of osteocytes lack of remodelling activity

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• Nature of signal
• Proresorptive signal or loss of inhibition of
  osteoclast
• Proresorptive signal favoured
• - ? accumulation of micro damage in
• sites with low Osteocyte number.
• - ? remodelling in the absence of
• Osteocytes.
• - Production of pro- osteoclastic signal

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• Osteocyte Apoptosis -
• Micro damage associated with increased osteocyte
  apoptosis
• Experiment in rat - induction of micro damage
• - Transient burst of Osteocyte
  apoptosis
• after 7 days in the region of damage.
• - Osteoclastic invasion several days
  later
• Osteocyte apoptosis represents source of signal
  that recruits osteoclasts

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• Discussion
• Apoptotic osteocytes more in growing bone with
  high degree of remodelling
• ? bone turnover seen with induction of medical
  menopause is associated with ? osteocyte
  apoptosis.
• Glucocorticoid induced bone loss in mouse and
  human is associated with ? Osteocyte apoptosis.
• All these situations of high apoptosis high
  remodelling
• Osteocyte apoptosis plays a role in normal bone
  turn over.
• Estrogen important for viability of osteocytes

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• How is apoptosis initiated ?
• Mechanically sensitive signaling pathways
• Direct damage to cells or canalicular system that
  supplies nutrients.
• Further studies
• Mechanisms of initiation of apoptosis by micro
  damage
• Molecular links between osteocyte apoptosis and
  osteoclast activation

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• Clinical relevance
• Identification of nature of signal - helps to
  design methods to control these signals
• May be important to prevent loss of bone
  integrity in some pathological diseases (
  Pagets disease, Osteoporosis, Bone tumors)

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