LUMBAR INTERVERTEBRAL DISC (IVD).

Nutrition of an inhospitable environment!

International Publicized Data

GMCD Instructional  Course Lectures

Author :  

Dr. med. Guy M.C. Declerck MD (GMCD)

Medical FRCS-, FRCS Ed Orth-, M Ch Orth-, PhD-studies

Spinal Surgical and Research Fellow, Perth, Western Australia

Spinal Orthopaedic Surgeon and Surgical Instructor

Consultant R&D Innovative & Restorative Spinal Technologies

President International Association of Andullation Technology (IAAT)

Copywriter / Translator:   Filip Vanhaecke PhD

Illustrative expertise:   Lennart Benoot, Mincko, Halle, Flanders, Belgium

Artistic illustrations:   Alonso Ríos Vanegas, sculptor and writer, Medellín, Colombia

Page layout:   Lennart Benoot, Mincko, Halle, Flanders, Belgium

Review scientific literature:   Medical Consulting Advice, Ostend, Flanders, Belgium

Support:   International Association of Andullation Therapy (IAAT)

Legal advice:   Anthony De Zutter, kornukopia.be

Dedication to my mysterious girlfriends. September 2014.

Relationships must be rich and rewarding and provide an environment in which everybody can grow and learn. I can’t imagine stepping in a relationship that didn’t have these qualities. These relationships die of blindness. Consequently, friendship becomes impossible because knowledge to replenish its source remains absent. Their omnipresent, marvelous and sweet smiles always were hiding mysteries and secrets. But in the practice of reading there is something that forces one to listen to people with a greater ability to embrace ambiguity and uncertainty. As Boz writes of Mr Pickwick: ‘the peculiarities and oddities of a man or woman … generally impress us first, and … it is not until we are better acquainted with him or her that we … begin to look below these superficial traits, and to know the better part of him or her’. A cognitive mismatch from a known category elicits both dread and fascination (Michael Shermer).

They all are gone now, slipped away quietly without fuss much as they’d lived. They seemed nice. Not the killing types, I think. Insults had never been their strong point. But their words always rattled like marbles in my skull. I could weight their fate again and again. It could go on like this until I would accept the futility of it. Indeed, they only had to suppress their past if they had to flourish again. They couldn’t! I’ve turned away, carried out my tasks, and made my reports – leaving them. That day, an involuntary tear traced its way down the contours of my face. It was the pinhole in the dam (Divya). My psychological GPS was busted. But I’ve escaped. Already, time has erased my most recent memories. I restart thinking for myself.  ‘Non, je ne regrette rien!’

Acknowledgements

Relying on the work of giants is the lifeblood of scientific research. Indeed, if I have seen further, it is by standing on the shoulders of giants. One might even say that I have always depended on the kindness of strangers in this regard (*).

The continuous support by professor BA Kakulas (Neuropathology), professor JR Taylor (Spinal Anatomy and Human Biology), and Sir George M Bedbrook (Spinal Orthopaedic and Rehabilitation Surgeon) made it possible to analyse 23539 post-mortem human spines, normal and pathological, in the Department of Neuropathology, Royal Perth Hospital/University Western Australia, Perth.

Note: in order not to disturb easy reading of the underneath scientifically based chapters, only a few authors are mentioned in the text where dr. Guy considered it essential. Their names are placed between brackets. Further information on their individual research can be read in the last chapter ‘Literature Encyclopedia’.

         (*) Mirsky Steve. Technology is making it harder for word thieves to earn outrageous fortunes. Scientific American, February 2014, p. 64

Contents

1. Introduction

2. All human cells need nutrient

3. Nutrient supplies to the IVD cells

4. Embryologic origin of blood supply to the IVD

5. Notochordal cells inhibit ingrowth of blood vessels in the nucleus pulposus

6. Mystery how a few cells can survive in a non-vascular intervertebral disc

7. Blood and nutrient supply to the IVD through the annulus fibrosus

8. Blood and nutrient supply to the IVD through the endplates

9. Aging processes occlude the capillary networks in the endplates

10. Metabolite transport depends on endplate changes

11. Avascularity is accompanied by lower levels of oxygen

12. How do the IV disc cells manage to perform their metabolic requirements?

13. An acid environment (low pH) in the center of the IVD

14. Nutrition and survival of nucleus pulposus cells rely on diffusion and fluid flow

15. Diffusion and fluid flow always remain dependent on endplate permeability

16. Nutrition and survival of annulus fibrosus cells rely on diffusion and fluid flow … but

17. Responsible factors for the degree of diffusion

18. Consequences of progressing mineralizing endplate processes

19. Is the nucleus pulposus immune-privileged due to its non vascular nature?

20. The author’s conclusion: the potential for regeneration of a degenerating IVD?

21. Literature Encyclopaedia

1. Introduction

In the healthy but in the aging and degenerating intervertebral discs (IVDs) as well, the few cells (1 % of the IVD mass) synthesize and maintain their surrounding extracellular matrix (ECM). Each of these cells contributes to the health of a normal IVD by producing the proteoglycans, collagen fibrils, and other molecules. The regulation of the balance between anabolic and catabolic ECM metabolism of the IVDs cells is modulated by a variety of their secreted substances. The anabolic regulators include growth factors (IGF,  TGF-β, BMPs) and TIMPs. The catabolic process are mediated by the MMPs, aggrecanases, and cytokines.

2. All human cells need nutrients

In order to survive, all cells in the human body require supply of nutrients (oxygen, glucose and amino acids) for their metabolic functions and the synthesis of their ECM. At the same time they need to remove their metabolic waste products (CO2, lactic acid, urea). Otherwise, they become afunctional and die.

3. Nutrient supplies to the IVD cells

At all times the metabolic activities of the nuclear chondrocytic-like cells in the mature IVD are influenced by nutrient supplies and by the varying daily mechanical loading patterns (changing in loading and mechanical stresses, hydrostatic pressure, static compression).

Repeated mechanical loading and declining nutrition have been implicated as the two most critical factors in the origin and further development of the degenerative processes.

For the IVDs to receive their nutrition, the disc cells like any other cell in the human body, depend on the presence of blood vessels which are located in the vertebral endplate and in the annulus.

4. Embryologic origin of blood supply to the IVD

During the embryologic development of the spine, the peripheries of the IVDs are well suppliedwith blood. Numerous vascular channels from the capillary networks of the vertebrae perforate the osseous and cartilaginous endplates till the margin with the nucleus pulposus. Capillaries, originating from the vessels at the periphery of the annulus, extend into the outer and inner annulus again till the nuclear limits.

But compared to all other organs in the human body, blood vessels never will extend into the central part of the IVD. Simply stated, a direct vasculature and direct nutrient supply to the central nucleus pulposus is nonexistent. Strangely enough, the few central cells are able to survive a while in such conditions.

5. Notochordal cells inhibit ingrowth of blood vessels in the nucleus pulposus

During the embryonic stages, the notochordal cells in the central nucleus pulposus synthesize high concentrations of proteoglycans. These high concentrations of aggrecans inhibit the ingrowth of blood vessels from the peripheral IVD structures (endplates and annulus) in the direction of the central nucleus pulposus (Fig. 5). This leaves the central portion of the mature nucleus pulposus without direct blood and nutrient supply.

During the growth of the IVD, the nonvascularity of the nucleus gives rise to harsh physiological conditions and decreased nutrition of the notochordal cells causing their early disappearance (*, **).

Fig. 5. The endplates (EP) and the outer annulus fibrosus (AF) in the healthy and young IVDs are vascularized. The NP always remains without blood supply. The young NP contains a high concentration of proteoglycans and water (80 %).

* The other factor in the disappearance is the start of the weight-bearing activities.

** Notochordal cells (with their intensive PG production) are important in delaying degenerative processes in the IVD.

6. Mystery how a few cells can survive in a non-vascular intervertebral disc

The mature nucleus pulposus (NP) only contains sparse chondrocytic-like cells. It remains a mystery how these few ‘nucleocytes’ are able to adapt, cope, and function in the extracellular matrix (ECM) of a large structure like the IVD which (1) is the largest non-vascular tissue in the human body, (2) harbours the most harsh physiological conditions, and (3) is continuously biomechanically stressed in the upright-walking individual.

The avascular nature, the acid and low oxygen conditions, and the biomechanical stresses account for a faster decrease in the already small amount of functionally active chondrocytes: cell divisions become limited, apoptosis (kind of self-elimination) appears earlier, and cell senescence and cell necrosis eventually result.

Then, how is it possible that a few cells in the mature NP can survive a long time when blood supply is not available, when oxygen is extremely low, when nutrients cannot be delivered directly, and when metabolic waste products (e.g. lactic acid) cannot be removed immediately?

Unfortunately, the aging processes in the IVD have a greater impact on the IVD than on the rest of the body.

7. Blood and nutrient supply to the IVD through the annulus

The cells in the peripheral outer third of the annulus fibrosus receive their supply of nutrients from a few penetrating capillaries which originate in the vascularized tissues and zones surrounding the IVD.

Although this sparse capillary penetration in the outer regions of the mature annulus is totally insufficient for the nutrient supply of the NP, in the older aging IVD (+/- 40 years) a high degree of vascularisation appears in the annulus. However, this vascular appearance which increases with age is not at all an indication of the cells in the center of the IVD seeking for nutrients. Vascular bundles grow into the granulation tissue during the repair processes of the out-to-in fissures.

8. Blood and nutrient supply to the IVD through the endplates

The major source of nutrition to the cells in the NP nearly entirely depends on the blood vessels within the bone marrow of the vertebral bodies. Although their capillaries do not enter the nucleus pulposus, the centrally localized vascular channels in the endplates always remain particularly vital for maintaining the nutrition of the avascular NP. However, nutrients from the capillaries in the vertebral bodies only can be transported directly through the endplates during the first decade of life.

During further growth of the IVD (and disappearance of the notochordal cells), vascular channels at the endplate proliferate to maintain adequate nutrition of the disc. It has been claimed that the induction of new blood vessels in the endplate is facilitated by activation of enzymes such as matrix metalloproteinases (Crean). However and finally, the channels in the endplates become occluded through calcification and ossification (see topic: IVD, Lumbar Disc Structure).

9. Aging processes occlude the capillary networks in the endplates

The blood vessels in the endplates already decrease early during infancy (before the age of 5 years).

By the start of weight-bearing activities, the structure of the endplates begins to disorganize allowing less permeability.

Further aging processes during the following ten years progressively calcify and ossify the cartilaginous endplates till the sclerotic phase is achieved. By then, the vascular channels in the endplates have disappeared. By the age of 20, the IVD is sealed-off from the capillary networks in the vertebral bone. The adolescent and adult IVDs become more and more avascular except for a few capillaries penetrating the outer annulus.

Hence, the cells of the NP always have been left without direct vascular and nutritional supply.

10. Metabolite transport depends on endplate changes

The closure of the blood channels at the bone-cartilage junction of the IVD results in a decreased permeability and a barrier to nutrient transport from the vertebral bone into the IVD tissues and vice versa.

Due to these increasing difficulties in metabolite nutrient transport within the large avascular disc, the cells in the nucleus pulposus further limit their anabolic proteoglycan synthesis. Further aging of the IVD leads to an increase in ECM breakdown as well.

Indeed, as the permeability declines after the first decade of life, the first signs of aging may become evident at very young age. Degeneration may start in youngsters!

11. Avascularity is accompanied by lower levels of oxygen

Low vascularity and the lack of vasculature is accompanied by lower levels of oxygen concentrations.

Being virtually avascular, the mature IVDs have a lower oxygen content (2-8 mm Hg)than any other structure/organ elsewhere in the body.

On the other hand and contrary to most mammalian cells, it is well known that the cells of the human nucleus pulposus use very little oxygen. They can survive many days in 0 % oxygen conditions. Then, oxygen does not seem to be required for maintaining the disc cells alive. But all cells require oxygen for their (biochemical) metabolic requirements.

Although not fully proven by scientific certainty, it then seems logical that hypoxia 

(1) causes the cells to decreased proteoglycan production and increased lactate production, and

(2) accelerates aging and degeneration by causing cellular apoptosis and ECM damage.

12. How do the IV disc cells manage to perform their metabolic requirements?

As there is nearly no oxygen, the nucleus pulposus cells have no choice but to produce energy through an anaerobic metabolism. Anaerobic glycolysis utilizes glucose and generates lactic acid as end product.

As mentioned above, the cells have to work in an extremely inhospitable environment. Residing in the center of the disc at a long distance (8 to 10 mm) from the nearest blood supply along the vertebral endplates, removal of waste products from the large avascular mature IVD is difficult. Lactic acid accumulates and high concentrations of lactic acid create an acidic pH (to near pH 6.3).

13. Acid environment (low pH) in the center of IVD

A low pH reduces the rate of oxygen uptake, hence reduces the production of ATP energy (adenosine triphosphate).

A low pH is detrimental to the extracellular matrix components as it decreases the production of glycosaminoglycans (chondroitin and keratan sulfate chains), activates the proteolytic functions of the ECM metalloproteinases, decreases the production of TIMP (the tissue inhibitors of metalloproteinase which counteract the degradative function of MMPs and ADAMS), decreases cell proliferation, accelerates cellular apoptosis, increases cell senescence and the rate of cell death. In this inhospitable acid environment without blood vessels, the few IVD cells in the nucleus pulposus need to compete for nutrition and survival, which make it impossible to sustain high cell densities in the center of an adult lumbar IVD.

All these unfavourable factors make the potential for spontaneous healing or even for regeneration (in the future?) by the NP impossible.

14. Nutrition and survival of nucleus pulposus cells rely on diffusion and fluid flow

Biologically, the nucleus pulposus functions as a fluid pump to facilitate body fluid diffusion resulting in carrying the nutrients and removing the metabolites from the avascular mature IVD.

Indeed, nutrition and survival of nucleus pulposus cells rely on diffusion and fluid flow which occur across the endplates. The capillary blood bed terminates within the vertebral bodies just above the osseous endplate. Nutrients and oxygen then move passively along concentration gradients down across the endplate and through the extracellular matrix (ECM) to reach the embedded cells in the center of the IVD.

Cells need nutrients (glucose, oxygen and amino acids) for their cellular metabolism and synthesis of their ECM. But their metabolic waste products (lactic acid) need to be removed as well.

Concentration gradients guarantee the continuous voyage of molecules in and out the cells in their surrounding ECM.

15. Diffusion and fluid flow always remain dependent on endplate permeability

There is no doubt that the complex processes of diffusion and fluid flow always will depend on the remaining permeable vascular channels in the endplates.

Diffusion is only efficient for small solutes (e.g. glucose and oxygen). Fluid flow, in response to changing mechanical loading patterns (mechanical disc compression and recovery), is responsible for the transport of larger molecules (proteins).

Decreasing diffusion capacity creates a lower oxygen tension, decreased pH, and accumulation of catabolic by-products.

16. Nutrition and survival of annulus fibrosus cells rely on diffusion and fluid flow but …

Similarly, the nutritional supply of the cells in the annulus fibrosus depends on equal diffusion and fluid flow processes from the capillaries in the outer third of the annulus which originate from the vascularisation of the surrounding of the IVD.

The peripheral annulus maintains blood supply throughout life. With advancing degeneration, higher ingrowth of blood vessels may occur from the peripheral annulus. When complete degenerative (in-to-out) annular tears becomes evident, the annulus fibrosus has the potential to repair itself. Vascular invasion of the healing ingrowing granulating tissue gradually becomes more evident in the annulus.

By the age of 40 years, more blood vessels grow in the peripheral zones of the disc than are seen in the endplates.

17. Responsible factors for the degree of diffusion

The degree of diffusion to the IVD not only depends on the rate of nutrient consumption of the IVD itself and their adjacent vertebral blood supply, but to the diurnal loading patterns on the IVD as well.

The blood flow through vessels can be regulated and adapted by vasoactive agents (noradrenaline and acetylcholine) and by vibratory stimuli to assure the IVD nutrition under altered physiological conditions. The diurnal loading patterns arising from alternating periods of activity and rest may pump up to 20 % water and large molecules in and out of the IVD.

Smoking (nicotine) and atherosclerosis seem to adversely affect the arterial supply.

18. Consequences of progressing mineralizing endplate processes

The progressing mineralizing processes of the endplates gradually increase over time and disturb the physical permeability structure of these endplates which leads to an ever diminishing metabolic nutrient transport.

Because the center of the IVD has a very low chondrocytic-like cell content (1 %), the lowest concentrations of nutrients, the highest rates of metabolic waste, and the highest acidic pH, the cells cannot survive in this extremely inhospitable intradiscal environment.

Indeed, growth and aging of the IVD compromise the permeability of the endplates leading to the first signs of biochemical and morphologic deterioration to be seen in the nucleus pulposus of the IVD. During aging of the IVD, structural changes increase progressively through the more consolidating fibrous matrix and include fibrocartilage replacement of the nucleus, loss of NP/AF distinction, endplate subchondral bone sclerosis, and focal endplate cartilage disorganization.

19. Is the nucleus pulposus immune-privileged due to its nonvascular nature?

An autoimmunity hypothesis states that the nucleus pulposus is an immune-privileged site and can stimulate an autoimmune response.

Based on autopsy analysis of the discovertebral compartments of the lumbar spine by the author, it is evident that endplate fractures enhance decreased metabolism and rapidly increase the (already?) existing and developing degenerative changes in the nucleus, the annulus, and the endplates.

When the endplate is damaged, components from the nucleus may enter the blood vessels of the vertebral body and elicit an immune antigenic-antibody response in the vertebral body (~ Modic changes) and lead to an inflammatory reaction within the IVD. Indeed, inflammatory cells are regularly encountered in the IVD.

Weakening of the immune privilege of the IVD may lead to the infiltration of host immune cells (e.g. macrophages) resulting in the death of disc cells, the initiation or further advancement of the IVD degenerative processes, and final disc resorption of the IVD.

However, the autoimmunity hypothesis, has till now never been substantiated as an initiator of the degenerative processes in the intervertebral disc.

20. The author’s conclusion: The potential of regeneration of a degenerating IVD?

In such inadequate nutritional conditions the remaining nucleus pulposus cells are too small and have a limited ability to recover from any metabolic injury and effect repairs.

Actual research strategies involve stimulation of the resident cells (growth factors and gene therapy) or transplantation of cells to activate the production of new extracellular matrix.

However, every innovative strategy to repair or to replace degenerative IVD tissue in the hope to restore the function of the IVD will fail as long as the supply of nutrients (glucose, oxygen) and the elimination of waste (lactic acid) remains inadequate or impossible.

On the other hand, it remains a very interesting field of research, particularly as this is one area of research endeavour that might shed some light on the still elusive events that initiate degeneration.

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