The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 88, Issue suppl 2

Workshop Articles | April 01, 2006

Nutrient Supply and Intervertebral Disc Metabolism

Thijs Grunhagen, MSc; Geoffrey Wilde, BSc; Dahbia Mokhbi Soukane, BSc; Saeed A. Shirazi-Adl, PhD; Jill P.G. Urban, PhD

In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from the Arthritis Research Campaign and the European Union (EU consortium, Eurodisc QLK6-CT-2002-02582). None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

The Journal of Bone and Joint Surgery, Incorporated

J Bone Joint Surg Am, 2006 Apr 01;88(suppl 2):30-35. doi: 10.2106/JBJS.E.01290

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Abstract

The metabolic environment of disc cells is governed by the avascular nature of the tissue. Because cellular energy metabolism occurs mainly through glycolysis, the disc cells require glucose for survival and produce lactic acid at high rates. Oxygen is also necessary for cellular activity, although not for survival; its pathway of utilization is unclear. Because the tissues are avascular, disc cells depend on the blood supply at the margins of the discs for their nutrients. The nucleus and inner anulus of the disc are supplied by capillaries that arise in the vertebral bodies, penetrate the subchondral bone, and terminate at the bone-disc junction. Small molecules such as glucose and oxygen then reach the cells by diffusion under gradients established by the balance between the rate of transport through the tissue to the cells and the rate of cellular demand. Metabolites such as lactic acid are removed by the reverse pathway. The concentrations of nutrients farthest from the source of supply can thus be low; oxygen concentrations as low as 1% have been measured in the discs of healthy animals. Although gradients cannot be measured easily in humans, they can be calculated. Measured concentrations in surgical patients are in agreement with calculated values.

Figures in this Article

Factors that reduce the blood supply to the disc (e.g., sickle cell anemia or other disorders that affect the blood supply or cause calcification of the cartilaginous end plate, limiting its permeability) can cause nutrients to fall to levels that can no longer support cell activity or viability. Increases in cellular demand, which can be caused by the presence of cytokines or growth factors or a sustained rise in osmolarity, can similarly lead to an inappropriate fall in nutrient levels away from the nutrient source. The balance between cellular demand and transport limits the number of cells that can be supported in any tissue and governs the inverse relationship between tissue thickness and cell density. Such limitations apply to all avascular tissues, including tissue-engineered constructs.

Background

The cells of the intervertebral disc are its architects, builders, and maintenance staff. Without their continuous activity, the fabric of the disc would fall into disrepair, and degeneration, with all its unfortunate consequences, would eventually occur. Like all cells, those of the disc require nutrients to sustain themselves and fulfill their functions, while their metabolic wastes must be removed before they accumulate to dangerous levels. Nutrient transport to the disc cells is precarious because of the avascular nature of the tissue. Interruptions in the supply of nutrients are strongly linked to the development of disc degeneration. This article will briefly review nutrient supply in normal and pathologic discs and discuss its role in the development of cell-based repair therapies.

What Nutrients Do Disc Cells Need?

Although only a few studies on disc cell metabolism have appeared in the literature, the cells of the disc evidently obtain their energy primarily through glycolysis, even in the presence of air¹. The cells of the nucleus, at least, thus use very little oxygen compared with most mammalian cells² and produce little CO₂; most of their energy in the form of adenosine triphosphate (ATP) is formed by near quantitative conversion of glucose to lactic acid. Nevertheless, disc cells, such as those of articular cartilage³, require oxygen to function; at low oxygen tensions, rates of production of macromolecules, such as sulfated glycosaminoglycans or proteins, are severely inhibited⁴. The pathways of oxygen utilization by disc cells, however, remain obscure.

Very little is known about other cellular requirements. Radiolabeling studies demonstrate that amino acids and sulfate, necessary for production of proteins and other macromolecules, are supplied extracellularly⁴ and are taken up by disc cells, but at rates lower than those seen with glucose and oxygen. Disc cells also respond to growth factors in the extracellular fluid^5-8; whether these growth factors reach disc cells from the blood supply in vivo is unknown.

Influence of Metabolite Concentrations on Disc Cell Activity

Disc cell activity is regulated by extracellular oxygen concentrations and extracellular pH. The rates at which disc cells metabolize glucose and consume oxygen and hence produce ATP depend on the local acidity and concentration of nutrients^1,2. However, the effect of oxygen concentration on rates is still unclear. Low oxygen has been observed to diminish the rate of glycolysis in some studies², i.e., a negative Pasteur effect. Other studies have demonstrated the opposite; under low oxygen, glycolysis rates (and hence production rates of lactic acid) rise—a positive Pasteur effect^1,4. The reasons for these differences in response are unclear. All studies, however, have found that an acidic pH level markedly reduces the rates of glycolysis and the rate of oxygen uptake, and hence the production of adenosine triphosphate^2,9. In addition to the availability and concentrations of substrates, other factors influence the rates at which the cells generate energy. The presence of growth factors, changes in the stresses in the surrounding matrix, and the osmotic environment have each been observed to modify the rates of energy metabolism¹⁰.

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Fig. 1: Graphs showing the effect of nutrient-metabolite concentrations on survival of disc cells. Nucleus cells were cultured at low cell density to maintain nutrient concentrations under the conditions shown. (a): Cells were cultured at 0% oxygen under stated conditions; after 24 hours of incubation, cells cultured at low glucose showed loss of viability, particularly under acid pH. (b): Cells were cultured at 0% oxygen. Cells at pH 7.4 and with adequate glucose showed no loss of viability after six days in culture; at low glucose or low pH, few cells were still alive at this point. (Adapted, with permission, from Bibby SRS, Urban JPG. Effect of nutrient deprivation on the viability of intervertebral disc cells. Eur Spine J. 2004;13:695-701.)

The rates of matrix synthesis and degradation are also influenced by local extracellular oxygen and pH levels. Synthesis rates appear to be highest at around 5% oxygen, where they are greater than the rates found in air⁴. However, once oxygen tension falls below 5%, synthesis is inhibited appreciably in an oxygen-tension-dependent manner; at 1% oxygen, rates of sulfate incorporation are only one-fifth of the rates seen at 5% oxygen. Low oxygen switches gene expression in other cell types¹¹, but there is little information on this subject with regard to native disc cells. Extracellular pH also has a marked effect on the synthesis rates of matrix components; rates are 40% higher at pH 7.0 than at pH 7.4 but fall steeply once the environment becomes acidic⁹. Extracellular matrix degradation, however, appears less sensitive to pH; production of active matrix metalloproteinases is similar at pH 7.0 and pH 6.4¹². Thus, acidic pH levels, by inhibiting synthesis but not degradation, may increase the rate of matrix breakdown.

For the disc cells to remain viable, the levels of extracellular nutrients and pH must remain above critical values. Because disc cells obtain ATP primarily by glycolysis, glucose is a critical nutrient; cells start to die within twenty-four hours if glucose concentration falls below 0.2 mM; at this glucose concentration, the efficiency of glucose transport into the cell is likely reduced¹³. The rate of cell death increases when pH levels are acidic; cell viability is reduced even with adequate glucose at pH 6.0¹⁴. Although necessary for maintaining matrix synthesis, oxygen is not required for maintaining disc cell viability; disc cells can remain viable for many days with no oxygen present^14,15, thereby supporting the findings that these cells produce ATP primarily through glycolysis (Fig. 1).

Thus, it appears that local nutrient and pH levels must be maintained within certain limits, which are currently not well defined, to allow optimal cell activity. Moreover, if these nutrient levels fall below some critical value, disc cells will die—but whether death occurs by apoptosis or necrosis is unknown.

Supply of Nutrients to the Disc Cells

The disc of an adult human is virtually avascular, apart from a sparse penetration of capillaries and nerves into the outermost regions of the anulus¹⁶. Thus, blood vessels at the margin of the disc are responsible for the supply of nutrients and the removal of wastes. The outermost regions of the disc are supplied by capillaries in the adjacent soft tissues. The nucleus, inner anulus, and part of the outer anulus^1,17 are supplied by a capillary network that arises from the vertebral arteries and penetrates the subchondral plate to terminate in loops at the bone-cartilage end-plate junction^18,19.

Supply Route from the Vertebral Body

Nutrient supply to the disc is affected by the architecture of the capillary bed and the porosity of the subchondral plate. The capillary network supplying the disc arises from the arterial supply to the vertebral bodies¹⁸ and can be adversely affected by atherosclerosis of these arteries²⁰. The architecture of the capillaries is regulated by external signals²¹, possibly explaining loss of nutrient transport in response to smoking²² and vibration²³. The density of the capillary network feeding the disc diminishes with age^5,9 and varies across the end plate. The density is greatest above the nucleus, lessening toward the outer anulus^18,24,25. In animal models, remodeling of this capillary bed in the long term has been demonstrated in response to nicotine^26,27 and calcium agonists²⁷. The density of the subchondral plate through which the capillaries pass has also been shown to vary across the disc, and the apparent permeability of this plate decreases with age as the end plate becomes more sclerotic^28,29.

The capillaries are protected by a dense hyaline cartilage end plate that is lower in hydration than that of articular cartilage^30,31; it limits transport of large molecules into and out of the disc³². In aging, degeneration, or disorders such as scoliosis, this end plate tends to calcify by unknown mechanisms; severe calcification acts as a barrier to nutrient transport and is thought to be a major factor in the development of disc degeneration³³. In scoliotic discs at least, cell death correlates with loss of nutrient supply and end-plate calcification^34,35.

Solute Transport and Nutrient Gradients

Nutrients move from the capillaries that supply the disc, through the cartilage end plates and the dense matrix of the disc, to the cells. For small solutes such as glucose, lactic acid, and oxygen, both experimental and modeling studies have shown that solute transport is accomplished mainly by diffusion^36-38; hence, the movement of fluid in and out of the disc as a result of the diurnal loading pattern has little direct influence on transport. Gradients in the concentration thus arise depending on the balance between the rate of supply of glucose or oxygen from the blood supply to the cells and the rate of cellular consumption^1,39,40. For solutes such as glucose and oxygen, which are used at high rates, the gradients are steep. Calculations show that concentrations of oxygen, glucose, and pH levels in the center of the disc fall with decreased end-plate permeability or solute diffusivity and with increased disc height^39,41 (Figs. 2-A, 2-B, and 2-C). Cellular parameters are also very important in regulating nutrient levels, with levels of oxygen or pH falling with increases in rates of cell metabolism or in cell density^39,41.

Although fluid convection induced by diurnal loading may not contribute directly to nutrient transport, loss and regain of fluid itself affects nutrient diffusive gradients. Mechanical loading of the disc appears to have opposing effects on disc nutrition; on the one hand, it decreases disc height, which facilitates the transport of nutrients from the end plates to the disc center, while, on the other hand, it decreases the fluid content in the tissue, which reduces solute diffusivities and possibly affects metabolic rates^40,42. The relationship between loading conditions and nutrient gradients is at present undefined.

The varying gradients that arise from the diffusive transport in the disc cause the cells at various locations to operate at different metabolic rates. The center of the disc will have the lowest concentrations of the nutrients glucose and oxygen, and the highest concentration of the metabolite lactic acid, producing a low pH¹. Under conditions in which supply becomes limited, such as calcification of the end plates or atherosclerosis of the vertebral arteries, nutrient supply may fall to a level in which cell viability can no longer be sustained and the cells in the center of the disc may be the first to die; thus, it is noteworthy that the first signs of disc degeneration are seen in the disc center¹⁶.

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Figs. 2-A, 2-B, and 2-C: Schematic showing the concentrations of oxygen, glucose, and pH levels across the disc from end plate to end plate. Graph showing the effect of loss of end-plate permeability on glucose concentrations across the disc from the end plate to the nucleus center. (Adapted, with permission, from Sélard E, Shirazi-Adl A, Urban JPG. Finite element study of nutrient diffusion in the human intervertebral disc. Spine. 2003;28:1948.) Graph showing the effect of exchange area (end-plate permeability) on concentration of nutrients/metabolites in the disc center, showing that concentrations change dramatically once permeability drops below approximately 20%. (Reprinted, with permission, from Mokhbi Soukane D, Shirazi-Adl A, Urban JPG. Nonlinear coupled diffusion of glucose, oxygen and lactic acid in the intervertebral disc. Presented as a poster exhibit at the Annual Meeting of the Orthopaedic Research Society; 2006 Mar 19-22; Chicago, IL.)

Measurement of Nutrient Transport in Normal and Degenerative Discs

The transport of solutes into animal and human discs has been examined with magnetic resonance imaging and can be determined from the increase in tissue contrast after intravenous injection of paramagnetic contrast medium. The transport pathways in the disc can be studied by following the diffusion of the contrast medium into the disc, with the amount of enhancement related to the type and amount of contrast medium used (molecular size and charge) and the composition of the intervertebral disc^43-46. A solute that has a high molecular weight or that is negatively charged will diffuse into the disc more slowly than will a solute that has relatively low molecular weight and is neutral.

Transport of contrast medium has also been investigated in a number of human studies. In one recent study⁴⁷, the diffusion pattern over a period of twenty-four hours following injection of contrast medium was examined in a large number of normal and degenerative discs. Transport was measured at regions of interest in the vertebral body, the subchondral bone, and the end-plate zone as well as in the disc. Diffusion characteristics differed appreciably with age and degeneration, and the authors were able to differentiate between the two. Most importantly, the status of the end-plate zone was found to be the principal factor influencing diffusion to the center of the disc.

Whereas magnetic resonance imaging has been used to study the diffusion of solutes into the disc, electrodes can be used to monitor the transport of dissolved gases. Electrodes provide continuous measurement of the substrate of interest in real time with a high degree of accuracy, precision, and, in the case of microelectrodes, minimal tissue trauma. Oxygen electrodes have been utilized to monitor changes in oxygenation of dog discs following an increase in blood oxygen¹ and in human patients with scoliosis and back pain⁴⁸. Both of these studies confirmed that oxygen levels in the center of the disc are very low. More recently, electrode studies were conducted to monitor both oxygen and nitrous oxide. Nitrous oxide is administered as an anesthetic gas during surgery and can be used as a tracer for determining transport of dissolved gases. Its molecules are small, it is freely soluble, and—unlike magnetic resonance imaging contrast media—it is not excluded from any area of the disc. Because nitrous oxide is not metabolized, the measured concentration in the disc reflects transport characteristics only. A study of scoliotic discs demonstrated that transport is severely reduced, particularly in the curve apex, possibly because calcification of the end plate hindered nutrient transport into the disc³⁴.

These measurements provide important information on nutrient transport and support the hypothesis that loss of nutrient supply is strongly related to disc degeneration. However, more experimental studies and modeling need to be done to gain a better understanding of the mechanisms that regulate nutrient transport.

Nutrient Supply and Biologic Repair

Over the past few years, following the apparent success of autologous chondrocyte implantation, there has been increasing interest in devising ways to induce biologic repair of the intervertebral disc⁴⁹. Some solutions involve stimulating the resident cells of the disc with use of growth factors⁵⁰ or through a gene therapy approach⁵¹. Another approach is to insert tissue-engineered discs⁵² or, alternatively, living disc cells⁵³ into the disc, in the hope that the stimulated or newly inserted cells will restore disc function by producing new matrix to replace the degenerative disc tissue. The success of these approaches is contingent on the cells remaining viable and active, and hence requires that the amount of nutrients supplied to these cells is sufficient to maintain extracellular concentrations at optimum levels. The extent to which this will be possible in the treatment of degenerative discs is unknown. As shown by magnetic resonance imaging and electrode studies, the nutrient supply to many degenerative discs is poor^34,47,54. Many cells in degenerative discs are dead⁵⁵. Such discs may not be able to support the added nutrient demands arising from an increase in cellular activity or cell number; if this is the case, the treatments will fail. Accordingly, these treatments should be offered only to patients in whom the nutrient supply is shown to be adequate. Some method of selecting such patients must be urgently developed if these biologic treatments are to be successful. Adequate nutrition of the disc influences the outcome of such therapies and, hence, must be considered to be a crucial parameter. ?

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Topics

oxygen ; metabolism ; glucose ; intervertebral disc ; nutrients

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Thijs Grunhagen, Geoffrey Wilde, Dahbia Mokhbi Soukane, Saeed A. Shirazi-Adl, Jill P.G. Urban; Nutrient Supply and Intervertebral Disc Metabolism. The Journal of Bone & Joint Surgery. 2006 Apr;88(suppl_2):30-35.

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