Nutrition of the intervertebral disc

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Nutrition of the intervertebral disc

• A cause of disc degeneration?

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GLUCOSE
OXYGEN
LACTATE
H
H
LACTIC ACID IS THE MAJOR METABOLITE PRODUCED BY
DISC CELLS
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Disc cells require glucose and oxygen to maintain
viability and activity They produce lactic acid
as a metabolic product. Accumulation of lactic
acid is detrimental and can adversely affect
viability and activity
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Sections through human lumbar discs
Sagittal section
Cross section
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Blood supply to the avascular intervertebral
disc adapted from HV Crock and H Yoshizawa
Blood supply of the Vertebral column
Thin midsagittal section cut from adjacent upper
lumbar vertebral bodies from a young adult filled
by arterial injection
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Schematic view of nutritional routes into the
intervertebral disc
From Holm et al, 1981
Vertebral body
endplate
endplate
nucleus
Holm et al, 1981
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Details of blood vessels at disc-endplate
junction and of cartilaginous endplate
From Crock, Goldwasser, Yoshizawa, 1991 Roberts
et al, 1989
bone
disc
blood vessels
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Solute transport in the disc nucleus
capillaries
endplate
growth factors
Degraded matrix components
lactate
glucose oxygen
Matrix macromolecules
cell
Proteases and inhibitors
disc matrix
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• Transport of small solutes into the disc is by
  diffusion.
• Load induced pumping of fluid does not affect
  transport of glucose, oxygen or lactic acid
• (i) shown experimentally (Urban et al, 1982
  Katz et al, 1986 OHara et al, Garcia et al for
  cartilage)
• (ii) shown by modelling studies (Ferguson et al,
  2003 Mauck et al for cartilage)
• Hence transport profiles can be calculated by
  diffusion theory (Holm et al, 1981 Stairmand et
  al, 1991 Selard et al,2003)
• Calculated profiles appear to fit experimentally
  measured profiles

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Nutrient gradients develop as the result of the
balance between cellular activity and transport
to the cells
endplate
endplate
endplate
low O2 low glucose low pH
disc centre
endplate
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Diffusion model

• Concentrations of nutrients and metabolites in
  the centre of the disc are very sensitive to
• Disc thickness
• Rates of oxygen and glucose consumption
• Rates of lactic acid production
• transport through the endplate

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Gradients through the disc depend on conditions
at the disc boundary (Selard et al, 2003)
Oxygen concentration
Glucose concentration
Consumption rate
Exchange area
bone
disc centre
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Lactate concentration along axis for different
production rates P (E-6 mol/mm3-hr)
Normalised distance edge to center
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Adverse nutritional conditions

• Acidic pH in the disc centre
• Low oxygen and low glucose in the disc centre
• These conditions affect cellular metabolism
  adversely
• Under extreme conditions cells may die.

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• Disc tissue removed during routine surgery

Acid pH
Measure effect of pH on matrix turnover
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Effect of adverse nutritional environment on disc
cell viability 24 hours incubation
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Matrix synthesis falls with fall in pH
Protease activity remains high at acid pH
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Nutrient levels must be maintained above
critical values (estimated as 0.5mM
glucose pH6.7 2 oxygen) for adequate disc cell
activity and viability
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• Can the nutrient supply fail in vivo and lead to
  a drop in nutrient concentrations to sub-critical
  levels
• Is this a pathway to disc degeneration?

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Epidemiological Evidence relating nutrient
failure to disc degeneration

• Changes in blood supply
• Atherosclerosis (eg Kaupilla et al, 1997)
• Gauchers, sickle cell, Caissons
  disease.(Jones1997)
• Smokers, exposure to vibration (Lindal,1996)
• Changes in endplate permeability
• calcificiation increases with age, degeneration,
  scoliosis (Nachemson1970 Roberts, 1996)
• Changes in disc matrix
• Markers of oxidative stress (Nerlich, Boos et
  al,1997)

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Blood supply

• Blood supply is regulated and environmental
  factors can lead to acute loss of nutrient
  supply

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Effects of cigarette smoke components on blood
supply to disc (Holm and Nachemson, 1988)
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Details of blood vessels at disc-endplate
junction and of cartilaginous endplate
From Crock, Goldwasser, Yoshizawa, 1991 Roberts
et al, 1989
bone
disc
Severe calcification in scoliosis (Roberts et
al, 1993)
disc
blood vessels
bone
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Discs studied
Patients 10 normal controls 43 back pain
patients 150 discs
(Rajasekharan et al, (2004) Spine (in press)
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Serial T1 weighted images of a lumbar disc after
IV gadodiamide injection (Rajasekharan et al,
(2004) Spine (in press)
T1weighted images were obtained using a 0.5
Tesla MR Imager (SIGNA,General Electric,
Milwaukee, WI) precontrast and postcontrast
(after IV injection of Gadodiamide in a single
dose of 0.3mmol per/kg) at five minutes, ten
minutes, two, four, six, twelve and twenty-four
hours.
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Diffusion into discs in relation to degree of
degeneration
(Rajasekharan et al, (2004) Spine (in press)
Average enhancement percentage was lower in discs
of moderate degeneration grade and enhancement
was delayed to 12 hrs. Enhancement in severe
degeneration was normal or higher with a pattern
suggestion endplate damage and vascular invasion
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Disc Degeneration and Nutrition

• There now seems firm evidence that the nutrient
  supply to the cells of the disc, particularly in
  the centre, is inadequate in many degenerate
  discs
• Whether this loss of nutrient supply is causal is
  not yet known, but it must be a contributory
  factor to the degenerative cycle

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New biological treatments for disc degeneration

• Injection of growth factors to stimulate resident
  cells
• gene therapy
• tissue engineering or cell implantation

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Biological repair of the disc
Disc
Insert disc or disc section into defect
(a) reinsert cells into disc defect or
Grow up cells from disc fragments or ?
(b) insert cells into scaffold
Tissue engineer disc
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Can we stimulate resident cells to repair the
disc if many are dead or struggling to
survive? Can we keep the implanted cells or
tissue-engineered disc alive and functional in
situ in a disc which is nutritionally
compromised?
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Acknowledgements

• Jeremy Fairbank
• Sue Bibby
• Saj Razaq
• Eric Selard
• EU project EURODISC and the ARC and EPSRC for
  support