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Basic Disc Anatomy:
The intervertebral discs may be thought of as soft tough pads that separate the bones (vertebrae) of the spine from one another. Their basis function is three-fold: 1) they act as a ligament by holding the vertebrae of the spine together, 2) they act as a shock absorber which carries the downward weight of the body (axial load) while in an up right position, and 3) they act as pivot point, which allows the spine to bend and twist.
There are 23 discs in the human spine: 6 in the neck (cervical region), 12 in the middle back (thoracic region), and 5 in the lower back (lumbar region). We shall focus on the lumbar discs on this page.
The disc is made up of three basic structures: the nucleus pulposus, the anulus fibrosus, and the vertebral end-plates. Although their composition percentage differs, the latter three structures are made of three basic components: proteoglycan (protein), collagen (cartilage), and water. We will learn all about these structures below.
Figure #1 depicts a Front view (AP) of the lumbar spine. Here we can see how the discs (blue) lie in between every vertebrae. Spinal nerves (yellow) have emerged from between every two vertebrae and travel down the lower limbs to innervate (give life to) the skin and muscle. Note how the sciatica nerve is formed within the pelvis by branches from the last three lumbar spinal nerves. It is this giant nerve that causes so much trouble in many of us chronic pain sufferers.
Figure #2 Shows a cut-away posterior view of the lumbar spine. Now we can better visualize how the sciatic nerve is formed and see just how close the spinal nerve roots come to the intervertebral disc. Any herniation of the posterior disc may compress the spinal nerve root and result in severe lower back pain and lower limb pain (sciatica). For more information on sciatica please visit my 'Sciatica Page'.
Axial Disc Anatomy and Neurology:
The Nucleus Pulposus (#1) is the water rich gelatinous center of the disc which is under very high pressure when the human is up-right. It has two main functions, to bear or carry the downward weight (aka: axial load) of the body, and to act as a 'pivot point' from which all movement of the lower trunk occurs. It's third function is to act as a ligament and bind the vertebrae together. The Anulus Fibrosus (#2) is a much more fibrous structure that the nucleus pulposus. It has a higher collagen content and lower water content. Its job is to 'corral' the pressurized nucleus and keep that it from exploding outward. It is made of 15 to 25 concentric sheets of collagen, (a cartilage like substance) called the Lamellae (#9) . The lamellae are arranged in a special configuration which makes them extremely strong and easily able to contain that pressurized nucleus pulposus. The Spinal Nerves Roots (aka: Nerve Roots) (yellow and labeled L5, S1, S2, S3, and S4) and Spinal Nerves (L4 yellow) are extensions of the brain and spinal cord. Like super highways the spinal nerves and nerve roots are constantly carrying electric messages to and from the brain. The nerve roots exit the spine through bony holes called the Intervertebral Foramen (aka: IVF) (Red Zone) . As the nerve roots 'peal-off' from the cauda equina, one sensory nerve root and one motor nerve root, and head for their respective IVF. Note worthy is the fact that our two nerve root pass very close to the back of the disc. Once within the IVF the two nerve roots merge into one Spinal Nerve. The Spinal nerves are called 'mixed nerves' for they contains both sensory nerve fiber (aka: afferent) and motor nerve fiber (aka: efferent). After leaving the spine through the IVF, the nerve split into a posterior division (Dorsal Ramus) and an anterior division (Ventral Ramus). The Dorsal Ramus connect to the muscle and skin over the lower back and butt and the Facet Joint (#5). The Ventral Ramus combine in the pelvis and form the giant Sciatic Nerve and Lateral Femoral Cutaneous Nerve which connect to all the skin and muscle of the lower limbs. (See my 'Sciatica Page' for more information) As we will learn farther below, the ventral ramus has a 'recurrent branch' that connects to the back of the disc, as well as the sympathetic nervous system (Grey Ramus Communicans); this special nerve is called the Sinuvertebral nerve (SN) (see below). In the lumbar spine (below the L1 disc level) there is no spinal cord. Instead the nerve roots hang in an enclosed sac which is called the Thecal Sac (red stars). The thecal sac, which protects the dangling nerve roots, is made up of two distinct but tightly bound layers called the dura mater and arachnoid mater. A clear fluid called Cerebral Spinal Fluid is also found within the thecal sac. This fluid protects the nerve roots and also supplies nutrients. Note how the nerve roots (yellow - S1 - S5), that collectively are called the Cauda Equina (#4), are highly organized within the thecal sac. Because of this arrangement, which always puts the lower level nerve root in front, it is possible for a large compressive L4 disc herniation to irritate the S1 and/or L5 roots. This may explain why disc herniations do NOT always match their dermatomal distribution - i.e., a disc herniation at L4 may clinically present as nerve root pain (aka: radicular pain, sciatica) and dysfunction in the S1 and/or L5 distributions! The Epidural Space (#8) is the space between the bony neural canal and the thecal sac, or the space 'outside' of the thecal sac. Unlike my drawing (Figure #9) this space is filled with blood vessels and fat. Note worthy is the fact that this is the region where 'epidural steroid injections' are placed. The Facet Joints (#5) (aka: zygapophyseal joints) of the spine are where the vertebrae articulate (join) with each other. Actually, the gap between the inferior and superior articular processes is the true facet joint (white region). Collectively the inferior and superior articular processes and the facet joint are called the Zygapophyseal Joints or articular pillars. These joints help carry the axial load of the body and limit the range of motion of the spine. They also make up the back of the intervertebral foramen and may cause stenosis if they hypertrophy in later life (lateral stenosis). The Ring Apophysis (#6) is the 'naked bone' of the outer periphery of the vertebral bodies. The very outer fibers of the disc (Sharpey's Fibers) anchor themselves into this region. Bone spurs (aka: Osteophytes) may arise from the ring apophysis as the result of the later stages of Degenerative Disc Disease (DDD) and/or Osteoarthritis (Spondylosis). Specifically, osteophytes arise from the prolonged 'pulling and tugging' of 'Sharpey's Fibers' at their anchor points. The Posterior Longitudinal Ligament (PLL) (#7) is a strong ligamentous tissue which courses down the anterior aspect of the vertebral canal and is attached to the outer fibers of the anulus fibrosus. This highly innervated (supplied with pain carrying nerve fiber) tissue is the last line-of-defense the posterior neural tissue has against the irritating and inflammatory effects of nucleus pulposus.
The Sinuvertebral Nerve: A nerve of mystery
The Sinuvertebral Nerves (SN), is a mixed nerve as well. It carries both autonomic fiber (sympathetic) and sensory (afferent) fiber. The sensory portion, which has the capability to carry the feeling of PAIN, arises from the outer 1/3 of the posterior anulus fibrosus (yellow balls) and PLL (#7). It then spilts and attaches to both the dorsal ramus and the grey ramus communicans, although this nerves anatomy and course seems to be quite anomalous. Of importance is the fact that if irritated, the nerve ending within the disc have the potential to generate both back pain and/or lower limb pain (Discogenic Pain). This lower limb pain-referral has been greatly studied by Ohnmeiss et al. and is quite an interesting phenomenon. Discogenic Sciatica is the term I have given this referred discogenic pain. It is believed that the sinuvertebral nerve-endings are 'sensitive' to the irritating effects of degenerated nucleus pulposus, that may be introduced into the outer region of the anulus from a grade three anular tear. (see may pages on Anular Tears for more information.) Amazingly, the sinuvertebral nerve also innervates (connects to) the disc above and below! So, the sinuvertebral nerve of the L4 disc also innervates the L5 and L3 disc. This may help explain why a L4 disc herniation/anular tear may clinically present with some signs of L5 and/or L3 involvement as well. It also carries autonomic nerve fiber to the blood vessels (not shown) of the epidural space. Sympathetic nerves control how the blood vessels function (vasomotor & vasosensory). Although rare, injury to these sympathetic nerves may cause RSD symptoms in the patients lower limbs; this usually would occur following surgery. (This may explain why I have a very slight case of RSD in my left foot following surgery - since my doc spent an hour cutting his way through a 'nest' of epidural vessels during my micro-discectomy)
The exact pain-pathway (how pain travels from the disc to the spinal cord) of discogenic pain is another fascinating and controversial subject. It seems that the sensory pathway from the sinuvertebral nerves into the spinal cord, does NOT take the 'expected' route in every patient. Some research (101) has demonstrated that pain-signals travel from the disc, re-enter the IVF (via sinuvertebral nerve) and DRG at the SAME level. Other, more recent research has indicated that pain-signals travel from the disc, through the sinuvertebral nerve, through the Gray Rami Communicans, into the Sympathetic Trunk (ST), up the sympathetic chain to the L2 vertebral level (yes I said L2), through the gray rami communicans, into the L2 dorsal rami, into the L2 IVF, and into the L2 DRG (80, 81). The latter pain pathway is why some investigators believe that lower level disc herniations may present as L2 dermatomal pain (groin region) in some patients!
To drive-home my point that the pain path from the disc does NOT always re-enter at the same vertebral level, I present the 2004 randomized controlled investigation by Oh and shim (26). In an incredibly well designed outcome study, the latter investigators demonstrated that by 'cutting' (RF neurotomy) the Gray Ramus Communicans, the majority of chronic discogenic pain sufferers achieved substantial relief of their pain and avoid fusion surgery. (26) This proves that at least some of the incoming pain signals were traveling toward the sympathetic trunk (which is on the anterior side of the vertebra) and NOT re-entering the spinal nerves at the same level.
A Committee Error?
Another interesting oddity about the design of the nervous system is the fact that 'the committee' decided to put the delicate sensory nerve cell bodies within the IVF and NOT the within spinal cord, which is where the motor nerve cell bodies are located. The Dorsal Root Ganglion (DRG), which houses these sensory nerve cell bodies, is seen as a tiny bulging structure within the IVF. This structure is 'super-sensitive' to compression (because it houses all these sensory nerve cell bodies) and can cause extreme back and leg pain if compressed and irritated by discal material and/or bony outgrowth (stenosis). The placing of these sensory nerve cell bodies in such close proximity to the disc and within such a narrow bony tunnel (the IVF) was not 'the committees brightest idea! You see if you damage the axon (nerve fiber) of a nerve, the chances are quite good for recovery, but if you damage the 'brain of the nerve fiber' (nerve cell body) the nerve's chances of recovery are much less. This explains why patients often never recover completely from that tingling burning, and numbness following a major attack of sciatica (disc herniation-induced radicular pain and dysfunction).
The View from the Side: (the Sagittal view)
Fig. #2 Is a sagittal view (aka: lateral view) of the 'motion segment'; Two vertebrae which are 'sandwiching' the intervertebral disc.
The disc [which is made of a anulus fibrosis (blue) and the nucleus pulposus (green)] is made up of three distinct areas: 1) The nucleus pulposus (green), which is a water rich (due to proteoglycan aggrecan & aggrecate molecules which trap and hold water within the disc) gel in the center of the disc; 2) The anulus fibrosis (blue), which is the fibrous outer portions of the disc that is made up of type I collagen; and 3) The vertebral end-plates (yellow), which are cartilaginous plates that attach the discs to the vertebrae and supply food (nutrients) to the inner 2/3 of the anulus and entire nucleus pulposus.
To further increase the strength of the anulus fibrosus, individual sheets of collagen are layered throughout the anulus. There sheets of collagen are called lamellae (black curved lines within blue). The very outer lamellae (Sharpey's fibers), unlike the inner lamellae, are anchored into the solid bony periphery (Ring Apophysis) of each vertebral body. This is the region that 'osteophytes' or bone spurs typically like to form. (Click here to see a real axial view of a 'motion segment'.)
Disc Physiology 101:
The normal human intervertebral disc, which is considered the largest avascular structure in the human body, is made up of two main components, proteoglycan and collagen (type I and type II). The anulus is mostly made of collagen, which is a tough fibrous tissue similar to the cartilage that is found in the knee, and the nucleus is made mostly of proteoglycan. Proteoglycans, which are produced by disc cells that resemble chondrocytes, are extremely important for disc function (see next paragraph) and are what 'trap' and hold water molecules (H20) within the tissue of the disc. In fact both the disc and anulus are comprised mainly of water, i.e., the nucleus is 80% water, and the anulus is 65% water. Proteoglycans are the building blocks of the aggrecan molecule which is the true 'water trap' of the disc. Aggrecans combine within the disc on strands of hyaluronan acid to form huge structures called 'Aggregates'. These super water-filled proteoglycan aggregates are what give the healthy young disc its amazing strengths and pliability, in fact a well hydrated disc is often even stronger than the bony vertebral body. Fig. #3: Here we have the healthy disc of a teenager (cadaver). The water content is extremely high as you can even see by the 'glistening' appearance of the nucleus (which is the gray center of the white disc).
Disc Function:
In order for a disc to function properly, it MUST have high water content; this is especially true of the nucleus. A well hydrated (with water) disc is both strong and pliable. The nucleus pulposus needs to be strong and well hydrated to do its job (axial load), for it is this structure that supports or carries the lion's share of the axial load (downward weight of body) of the body. With an undamaged anulus, strongly corralling a fully hydrated nucleus, the disc can easily support even the heaviest of bodies! As the disc dehydrates (loses water) the disc loose ability to support the axial load of the body (loses hydrostatic pressure); this causes a 'weight bearing shift' from the nucleus, outward, onto the anulus, outer vertebral body, and zygapophyseal joints (facets). Now, we have an 'over-load' on the anulus (which may trigger other destructive biochemical reactions) which, if severe and/or is imposed upon a genetically inferior anulus, will result in pathological DDD. ( see below)
Hydration also is important with respect to disc nutrition. As we have already mentioned, nutrients (which all living tissue needs in order to survive) must diffuse (soak) through the discal tissue in order to reach the hungry disc cells. This diffusion process is much faster and easier IF the diffusing tissue has a high water content. We may use 'swimming' as an analogy: It's easier to swim through the water, than through the sands of a desert. The sands of the desert would be a dehydrated disc, and the water would be a hydrated disc. So, water and disc hydration are one of the key factors for a normally functioning spine and well feed disc.
So, we've learned WHY disc hydration is so important. Now it time to learn HOW this disc hydration is accomplished:
Water is held within the disc by tiny sponge-like molecules called proteoglycan aggrecans. These 'super sponges' have an amazing ability to attract and hold water molecules (324), and can in fact hold over 500 times their own weight in water; this gives the non-dehydrated disc the tremendous 'hydrostatic pressure' which is needed to bear the axial load of the body. Amazingly, the aggrecans water absorption is so powerful that over night (non-axial loading) the height of the disc and the body will actually measurably increase due to the discs engorgement with water. This phenomenon is called 'Diurnal Change' and is only present in non-degenerated discs.
Disc cells, particularly the chondrocyte-like cells of the nucleus and inner anulus, manufacture proteoglycan aggrecan molecules. Like little factories, they create, replace and rebuild aggrecan molecules. As long as the disc cells have food (glucose), building material (amino acids) and oxygen all is well in disc-land. It is also important for them of have a non-acidic working environment, which is taken care of, since wastes are diffused out of the disc the same way nutrients diffuse in. In the living disc up to 100 aggrecans combine on a long piece of 'hyaluronan acid' to form giant proteoglycan aggregate molecules. It's these aggregates that are found within the disc in the real world.
Disc Nutrition:
The intervertebral disc is the largest avascular structure in the human body. The reason for this is because it has no direct blood supply like most other body tissue. Nutrients (food) for the disc are found within tiny capillary beds (black arrows) that are in the subchondral bone, just above the vertebral end-plates . This subchondral vascular network 'feeds' the disc cells of the all important nucleus and inner anulus through the diffusion process. The Figure on the left shows the 'disc feeding setup' for disc. Note that the outer anulus has its oven blood supply that is embedded within the very outer anulus. This is a much more efficient system and nutrients don't have to diffuse very far to find their hungry disc cells. The 'more direct' blood supply of the outer anulus is why tears of the outer 1/3 of the anulus will heal/scar shut with the passage of time, which unfortunately is not true of the rest of the disc. Research has indicated that disc tears will not heal in the inner zones of the disc - probably because of the avascular nature of the inner two thirds of the disc. Note the nutrients (pink balls) diffuse directly into the tissue of the outer anulus, where as the nucleus and inner anulus has a much longer diffusion route that is block by the vertebral end-plates. Note how the nutrients (pink balls) are released from the blood vessels (red) in the subchondral bone just under the vertebral end-plates. These nutrients must 'diffuse' or soak their way through the vertebral end-plates and into the disc. This 'diffusion method' is how the cells of the disc get the nutrients oxygen, glucose, and amino acids which are required for normal disc function and repair. This poor blood/nutrient supply to the disc is one of the main reasons that the disc ages and degenerates so early in life. (Read my Disc Degeneration page for more information.)
The 'diffusion feeding process' is enhanced somewhat by a phenomena called 'Diurnal Change'. Our discs have the ability to expand and compress over the course of a day. As we start the day our discs, like squeezing out a sponge, will compress and dehydrate because of the gravity and physical activity which place axial loads upon the discs. In fact a healthy disc will shrink down some 20% (104), which in turn decreases our height by 15 to 25mm (194,441,815). As we sleep and decompress our spines, our discs swell with water plus nutrients and expand back to their fully hydrated state. This tide-like movement of fluids in and out of the disc will help with the movement of nutrients into the avascular center of the disc. (Click here to learn more on Diurnal Change).
Super Advanced Anatomy & Physiology:
The Nucleus Pulposus:
The nucleus pulposus is a hydrated gelatinous structure located in the center of each intervertebral disc that has the consistency of toothpaste. Its main make-up is water (80%). Its solid/dry component make-up are proteoglycan (65%), type II collagen fiber (17%) and a small amount of elastin fibers . Collectively the proteoglycans and the collagen are called the 'nuclear matrix'. The cells of the disc, which produce the water holding proteoglycan molecules are very similar to chondrocytes seen in articular cartilage and are also held within the matrix.
Proteoglycans are found in several structural forms within the disc but the most important 'arrangement' is called a proteoglycan aggrecan. These aggrecans main function is to trap and hold water, which is what gives the nucleus its strength and resiliency. Like a 'super sponge', aggrecans can trap and hold over 500 times their weight in water!
The nucleus has two functions. The first is to bear most of the tremendous axial load coming from the weight of the body above and second to 'stand-up' the lamellae of the anulus - so that the anulus can reach its full weight baring potential. In order for proper weight bearing the nucleus and the anulus MUST work hand in hand.
The Anulus Fibrosis:
The anulus is the outer portion of the disc that surrounds the nucleus. It is made up of 15 to 25 collagen sheets which are called the 'lamellae'. The lamellae are 'glued' together with a proteoglycans. These sheets encircle the disc and, in concert with the nucleus, give the disc tremendous axial load strength.
The posterior portion of the anulus if further strengthened by the 'posterior longitudinal ligament'. This structure is the final barrier between the disc and the delicate spinal cord, and nerve roots.
The biochemical make up is similar to that of the disc only in different proportions. The anulus is 65% water, with the collagen, both type I and II making up 55% of the dry weight, and proteoglycans (mostly the larger aggregate type - 60%) making up 20% of the dry weight. 10% of the anulus also contain 'elastic fiber' that are seen near where the anulus attaches into the vertebral end-plate.
The lamellae are made up of both Type I (very strong type) and Type II collagen fiber. The very outer lamellae are almost all Type I. As we move inward toward the nucleus the more Type II is seen and less Type I. The very inner layers are very hard to distinguish from the nucleus. There is not a clear boundary between the nucleus and the anulus.
A simply amazing fact about the lamellae design is that the collagen fibers that make-up each lamellae all run parallel at a 65 degree angle to the sagittal plane. Even more amazing is the fact that the each lamellae are flipped so that the 65 degree angle alternates between every lamellae, one to the right then one to the left. This design greatly increases the shear strength of the anulus and makes it had for cracks to develop through the layers of the anulus. This is just amazing if you think about it!! Brilliant design!
The function of the anulus is to help the nucleus support the axial weight from the body. The anulus does need some help from the nucleus in order to achieve its strongest configuration. It relies on the nucleus to push it outward which keeps the lamellae from collapsing inward. The nucleus must keep a very high hydrostatic pressure to achieve this. We saw what happens when the nucleus losses hydrostatic pressure under the 'Disc Degeneration' page. Bogduk used the analogy of a rolled up telephone book standing on end, to describe how strong the anulus could be when the nucleus holds the inner lamellae or phonebook in a rolled up position. If you unroll the phone book our 'on end phone book' it would not longer be able to support much axial loading.
The Vertebral End-Plates:
Both the top and the bottom of each vertebrae (spinal bones) are capped with a thin ¾ millimeter cartilaginous pad called the 'Vertebral End-Plate' (Figure #1). Despite their name, these end-plates are NOT attached to the subchondral bone of the vertebrae but are instead strongly interwoven into the anulus of the disc (156, 388). It is for this reason, as well as strong morphological similarities, that the vertebral end-plates are considered part of the disc and NOT part of the vertebral body.
The biochemical morphology of the end-plates is extremely similar to that of the disc: Water, proteoglycans, collagen and cartilage cells (chondrocytes). The concentration scheme of these components also mirrors that of the disc: The center of the end-plate is mostly water and proteoglycan. As we move outward toward the periphery, more and more collagen is seen with less and less proteoglycans. This similar biochemical makeup and distribution scheme helps the diffusion of nutrients between the subchondral bone of the vertebra and the depths of the disc.
The very outer rim of the vertebrae is NOT covered by the end-plate, which leaves a ring of exposed bone on the periphery of the top and bottom of each vertebra. This exposed peripheral area is called the 'Ring Apophysis' and is often a site for the development of spur formation associated with the degeneration process.
References:
12) Marchand F, et al. (1990) "Investigation of the laminate structure of lumbar disc anulus fibrosus." Spine - 1990; 15:402-410
80) Nakamura SI, Takahashi K, Takahashi Y, et al. "Origin of nerves supplying the posterior portion of lumbar Intervertebral discs in rats." Spine 1996; 21:917-924
81) Nakamura SI, Takahashi K, Takahashi Y, et al. "The afferent pathways of discogenic low-back pain. Evaluation of L2 spinal nerve infiltration." J Bone Jont Surg. 1996;78:606-612
101) Bogduk N, et al. "The nerve supply to the human lumbar intervertebral disc." J Anat 1981; 132:39-56
26) Oh WS, Shim JC. "A randomized controlled trial of radiofrequency denervation of the ramus communicans nerve for chronic discogenic low back pain." Clin J Pain 2004; 20(1):55-60
Degenerative Disc Disease
Unlike other tissues of the body, the intervertebral disc under goes an early and often severe form of aging and degeneration (6 ,8,14,151,152 ). In most humans, this aging/degeneration process is slow and steady, but in some the process rapidly accelerates and may lead to catastrophic failure of the disc; which in turn may lead to chronic pain and disability. This 'accelerated' form of aging/degeneration may be called Degenerative Disc Disease (DDD), although the term is commonly and erroneously used to describe any form of disc degeneration.
Research has strongly linked DDD to back pain, and sciatica (201,206,219,227), although not in every case, for it is well known that DDD, disc protrusion, and stenosis do occur in completely asymptomatic people (100-106), but for about 10% of the population, DDD will result in permanent chronic pain and disability (250-253). Technically it's not the actual process of DDD that results in pain; it's the evil 'end-phases' of the disease that have the potential to generate back pain. These end-phases include anular tears (aka: Internal Disc Disruption or IDD) (203,209,216,231); disc protrusions (227); nerve in-growth (900,904,905,906); and the ultimate end-phase, stenosis.
The diagnosis of DDD is best made on T2-weighted MRI imaging (27), although some of the late appearances of DDD (disc collapse, osteophytosis, and sclerosis) may also be seen on CT scan and X-ray. The MRI appearance of DDD is easy to spot, even for the layperson, and is characterized by a loss of 'signal intensity' (loss of whiteness) of discal tissue, which makes the disc appear black instead of bright white. Technically, this 'Blackening' of the disc occurs because the disc has greatly lost its water content and become dehydrated. This 'blackening' is called disc 'Desiccation'. Since the MRI signal intensity (whiteness) is directly related the disc's water content (215,226), any loss of discal water will proportionally decrease the 'whiteness' of that disc on T2-weighted MRI. So, in layman's terms, the dryer the disc, the blacker and more degenerated it will look on MRI.
Why some discs prematurely degenerate (DDD) and cause chronic pain and others don't is still somewhat controversial, however, it is becoming clearer that poor genetics (397-399,403,413a); a past history of moderate to severe spinal trauma; or have an occupation that is heavy, and labor-intensive are the main risk factors (201,16). These factors will be discussed in depth below.
Warning:
In order to really understand DDD and disc aging, you must understand a few basic principles of disc physiology. I'm going to assume that you understand normal disc physiology and anatomy. If you don't please go (here) and learn your basic structures, and more importantly, learn the basics physiology of the disc. You will need to know why water (hydrostatic pressure) is so very important for normal disc function (allows the nucleus to support the axial load of the body), and how the cells of the disc maintain discal water content (via proteoglycan aggrecan production)
In order to understand DDD, we must first understand the natural disc aging process, or the 'normal pathway' of degeneration, which occurs in all humans to varying degrees and does NOT lead to pain.
Natural Disc Aging: (NDA)
The most common and striking feature of disc aging and degeneration is the loss of the proteoglycan molecule from the nucleus of the disc (333, 26). Other findings of aging include a progressive dehydration (18), a progressive thickening (via cross-linking, glycation and CML formation), brown pigmentation formation (66) and increased 'brittleness' of the tissues of the disc (62).
There are two main factors that are involved in the aging process of the disc and both of these factors are amplified because of the already poor vascular supply of the disc:
1) Idiopathic blood vessel/nutrient loss and dehydration:
The short explanation: For unknown reasons the nucleus of the disc losses much of its vital blood supply during the first decade of life (6). Without sufficient nutrients (which are contained in the blood) the cells of the disc begin to die (500) and the disc (especially the nucleus) becomes depleted of water. The drop in water/proteoglycan content is one or the classic signs of disc aging (333). Because of this dehydration of the nucleus, there is ultimately a 'weight-bearing shift' that occurs from the nucleus onto the outer anulus, ring apophysis, and the zygapophyseal joints. This increase stress upon the preceding posterior structures may lead to further more severe forms of aging, i.e., DDD.
The long version: Under the physiology section we have learned how important disc nutrition is in maintaining a normally functioning disc. To recap; as long as the cells of the disc receive an adequate nutrient supply (which is obtain from the diffusion of oxygen, glucose, and amino acids from capillary beds just above the end-plates, into the disc), they will happily manufacture the proteoglycan molecule, which combines within the disc to form the larger aggrecan and aggregate molecules. It is these aggrecan molecules that trap and hold water within the disc. A fully hydrated disc will have a very high hydrostatic pressure (osmotic pressure) which makes the nucleus pulposus (which is 80% water in a normal disc) incredibly strong and able support the lion's share of the axial load from the body.
Without an adequate supply of nutrients, the cells of the disc will die. The preceding fact was substantiated by the 2001 Volvo Award winning study of Horner and Urban (500), who studied the viability of living human disc cells under different conditions. They concluded that if the cells of the disc failed to get proper nutrients - such as oxygen, or glucose - or if the pH level of the disc rose (because waste is not being diffused out of the disc), disc cells would die and stop producing the vital proteoglycan molecule; without proteoglycans, the disc losses its water content (dehydrates) and losses its hydrostatic pressure (osmotic pressure) (241). This lost proteoglycan content is the most striking feature of disc aging and degeneration (333). Other research has confirmed this cell death as well. In 1982, Trout and Buckwalter discovered that by adulthood over 50% of the cells of the disc were dead (321).
So what's killing the disc cells and resulting in this loss of proteoglycan content?
Starvation! It seems that the human disc becomes 'nutritionally compromised' from the moment we begin to stand and walk. In 2002, Boos et al. observed an idiopathic "obliteration" of portions of the nutrient-providing capillary beds, which lie just above the vertebral end-plates. (Remember that these capillary beds are the ONLY source of nutrients for the cells of the inner anulus and nucleus.) Amazingly, this 'auto-destruction' begins within the first two years of life, and worsens over the next 8 years. Specifically, they stated that between the ages of 3 and 10 there was "a dramatic decrease of physiologic vessels in the end-plate..and an abundance of areas with obliterated vessels. and a substantial increase in (disc) cell death." (6) THESE FINDINGS WERE THE 'SMOKING GUN' that scientists had been waiting for and suggested that the initial causation of disc aging and degeneration was 'nutritional compromise', secondary to an idiopathic loss of the discal blood supply above the vertebral end-plates. Needless to say, Boos and company won the '2002 Volvo Award in Basic Science' for this most shocking discovery.
Other factors affecting disc nutrition via diffusion rates of nutrients through the vertebral end-plates include end-plate calcification (506, 537, 538, 552,), the effects of changes in blood flow patterns secondary to arterial stenosis (522, 524-527), smoking, diabetes, and exposure to vibration (500, 517).
The Vicious Cycle of Degeneration:
This progressive loss of proteoglycan and dehydration begins to 'snowball' out of control. Not only because of the progressive loss of nutrients, but also because of the fact that decreased hydrostatic pressure also slows the production of proteoglycan by the disc cell (11). Here's what this vicious cycle looks like:
As the nutrient supply within the disc drops (because of blood vessel obliteration and later end-plate mineralization), the disc cells start to die. Because there are fewer available disc cells around to make proteoglycan, there is a drop in the amount of circulating proteoglycan aggrecan molecules. This decrease in the aggrecan molecule, (which is what holds water within the disc) results in both dehydration, and a decrease in hydrostatic pressure within the nucleus. The loss of hydrostatic pressure has two negative effects on the disc: a) it will cause a further decrease in the amount of circulating proteoglycan aggrecan molecules, for we know from the work of Handa et al. that disc cells need a constant hydrostatic pressure level of 3 atm to function normally (11). Any increase or decrease in hydrostatic pressure caused a reduction proteoglycan production, which in turn decreases hydrostatic pressure even more - hence the vicious cycle. b) Now, these biochemical changes begin to change the biomechanics of the disc: With the decrease of hydrostatic pressure the nucleus, like a deflating beach-ball, can no longer carry the full axial-load (weight) of the body. A 'shift' in the axial-load distribution begins to occur, with the periphery of the disc (outer anulus, ring apophysis, and zygapophyseal joints) taking on more and more of the load and stress. Experimentally, the anulus of a degenerated disc shows a very high 'stress-load' on the anulus and NOT the nucleus (17 ,12 ). We will later learn that this 'load-shift' can be greatly accelerated if the volume of the nucleus is increased by trauma-induced structural damage to either the end-plate (compression fracture) and/or tearing of the inner anulus.
2.) Non-Enzymatic Glycation & the aging process: Glycosylation (aka: Glycation)
Glycation (aka: Glycosylation, or non-enzymatic glycation) is a biochemical reaction which occurs when reduced sugars (like glucose) come in contact with proteins (like disc collagen) in an avascular environment. The more avascular the tissue, the more severe this reaction occurs. Since the disc is the largest avascular tissue in the body, the glycation process thrives within its substance and results in a slow but steady transformation of disc collagen into a thicker and more brittle substance. Specifically, this reaction occurs between the protein molecules within the collagen, and free floating glucose (reduced sugar). This reaction is called 'posttranslational protein modification' or simple Glycation. Here's how it work. In the absents of oxygen, reduced sugars start to 'rub against' (bind) the proteins within the collagen. The proteins can only take so much 'rubbing', and soon are transformed into what is called an 'Advanced Glycation End-Product' or AGE. These converted discal collagen strands (AGEs) become much more brittle and also much more 'sticky', i.e., they love to combine with their glycated neighbors in a process called 'cross-linking'. This 'cross-linking' phenomenon makes the disc thicker, more fibrous and more susceptible to the development of DDD (62). It also stains the discal tissue a distinct shade of brown (66).
Finally the unstable AGEs molecules, which produce another evil biochemical called the 'free radical', oxidize into a much more stable structure called a CML (N-Carboxymethyl-lysine). CML formation has been found to be an excellent indication of discal aging (15). In fact Andreas and Boos won the 1997 Volvo Award for their work in using the presents of CML-modified discal protein as an indicator for the various stages of aging (15). I'm not going to review this study for it's out of our scope, but for those of you who need-to-know, his paper is an excellent read.
That about does it for the natural aging process. Now lets learn how and why things 'go wrong' with this natural aging process.
DDD:
It seems that about 10% of us humans will develop chronic, life-long, back pain as a result of an accelerated form of natural disc aging which is to some degree, is traumatically induced. We may call this Degenerative Joint Disease (DDD), although keep in mind that many doctors use the term DDD and natural disc aging interchangeable. DDD includes all of the mechanisms of natural disc aging that we have discussed above but goes a step farther and includes often painful anular tears (216), disc protrusions (303) arrant nerve ingrowth (900), and stenosis.
The Risk Factors:
There are two major risk factors that increase the chance of someone developing debilitating DDD: 1) Traumatically induced 'Structural Damage' to either the anulus fibrosus or the vertebral end-plate (12 ,59,16 ). 2) Inheritance and/or Poor Genetics, which research has demonstrated to be the single greatest risk-factor for DDD (505,411). Let's explore the major risk factors more in depth:
1) DDD induced by 'Structural Damage' to the Disc:
The 'Structural Damage Theory' (as I call it) of DDD, is based on the fact that any sudden loss of nuclear hydrostatic pressure (as a result of end-plate fracture/micro-fracture, and/or inner anular disruption) will result in a sudden and devastating 'axial-load-shift' (weight bearing shift) from the 'deflated' nucleus, onto the posterior anulus, ring apophysis, and zygapophyseal joints (12,59,16). This extra pressure upon the posterior anulus results in biochemical changes (MMP-3 secretion) which encourage the break down (degradation) and weakening of the anulus, hence encouraging painful anular tears (IDD) which may lead to disc herniation (19). Let's discuss this in more depth:
The Vertebral End-Plate: The Achilles' Heal of the disc.
The vertebral end-plates are definitely the 'Achilles' Heal' of the motion segment (16) (two vertebrae and the disc in-between), and are easily damaged by 'axial over-load injuries'; such as a fall on the buttock, lifting something that is way too heavy, or from repetitively lifting something moderately heavy (fatigue failure) (16). It has been repeatedly demonstrated that when the motion segment is experimentally compressed to point of 'failure', it's almost always the end-plates that 'breaks' first, NOT disc (30-33).
It's also known that it doesn't take much end-plate damage to trigger this 'axial load-shift'. Adams et al. has experimentally determined that only "minor compressive damage to a middle-age vertebra" will result in a "large and progressive" axial load-shift, that always upon the posterior anulus (16).
Abnormal Hydrostatic Pressure accelerates disc degeneration:
Both Handa et al. (11) as well as Ishihara (20) have concluded experimentally that disc cells are very picky about the amount of hydrostatic pressure that they can function in. They thrive at 3 atm of hydrostatic pressure, which just happens to be the normal pressure of a non-degenerated disc. Any variation in that pressure, EITHER higher (>30 atm) or especially lower (< 1 atm) will stop that disc from functioning (making proteoglycan which hold water within the disc).
Another Vicious Cycle:
When the vertebral end-plates or inner anulus become disrupted, the 'volume' of the nucleus is increased (the nucleus has gained extra space), which in turn causes an immediate and sudden drop in the hydrostatic pressure within that nucleus (23). In order to get that nuclear pressure back up, the disc cells would have to kick into 'over-drive' and make proteoglycan (which would suck up more water and resort hydrostatic pressure). Unfortunately, as noted in the above paragraph, the cells of the human the disc cells turn OFF in response to lowered hydrostatic pressure (< 1 atm) (11,20) instead of ON, so there is no chance to 'pump that nucleus back up'. To make matters even worse, since many disc cells are no longer making proteoglycan, the hydrostatic pressure falls even lower which turns off even more cells and a vicious cycle is born. This vicious cycle shifts more and more 'axial-load' onto the posterior anulus, hence worsening the degradation of the anulus even more.
2) Inheritance and Poor Genetic: The number 1 risk factor of DDD.
There are three areas of study in this sub-field of disc degeneration: Familial associations, unspecific genetic twin studies, and specific gene studies.
A) Familial Risk factors for DDD:
IF IT'S IN THE FAMILY WATCH OUT: There are two studies that strongly indicate that genes for DDD do exists and carry a significantly high risk factor for the passage of DDD and its evil end-phases (disc herniation in these studies) to the off-spring.
In 1998, Matsui L et al. (398) demonstrated for the first time that moderate to severe disc degeneration was strongly associated with a family history of past disc surgery. This study evaluated two groups of patients (gender and age matched) that were suffering from lower back pain and/or unilateral leg pain. The first group (study group) all had immediate family members (first degree) that had previously undergone lumbar disc surgery. The second group (control group) had no immediate family members that had under disc surgery. Both groups had the same level and duration of back/leg pain entering into the study. MRIs were performed on all the members of both groups. RESULTS: The 'study' group had a much higher incidence of moderate and severe disc degeneration (DDD) on MRI than the control group. Specifically, there was about a 50% greater chance of developing severe disc degeneration in the relatives of past disc surgery patients. Matsui concluded that paper by saying, "There may be a genetic factor and familial predisposition in the development of lumbar disc herniation as an expression of disc degeneration."
Other studies have found similar results (397,399) to that of Matsui. This same 50% increased chance of developing DDD was also seen in a study by Kellgren JH, et al. where they found first-degree relative are twice (50%) as likely as population-controls, to have generalized osteoarthritis involving many joints of the body (396).
So, if you have someone in your family who has crippling arthritis, or who has had back or neck surgery as the result of the end-phases of DDD, there is a chance that you may be at risk to suffer their fate as well.
B) Gene Mutations and DDD:
Even more striking than DDDs connection to familial factors, is that between certain gene mutations and DDD.
Based on a fairly recent, 'Volvo Award Winning' Twin study, 'inheritance' has been determined to be the largest single 'risk-factor' of a person developing DDD (403) and this inheritance is at least partly genetic in nature (413a). It now seem likely that there may well be 'genetic weaknesses' in the collagen framework of the disc and/or genetic influences on blood supply and disc metabolism (413a). There may also be 'genetic susceptibility' that may indirectly lead to DDD such as genetically small discs, a heavy torso, or small internal levers. The latter factors may all over-whelm the disc and lead to DDD.
Gene mutations occurring within the structural make-up of the disc have also been recently discovered. Here are some of these recent and exciting mutations:
Two mutations (polymorphisms) have been found within the genes that produce discal collagen (type IX collagen). These gene mutations have been named COL9A2 and COL9A3. Although the occurrence of this type of gene mutation is rare, when it does occur, the association with disc degeneration and sciatica are extremely strong (406,407, 408).
Another gene mutation has been associated with the discal proteoglycan aggrecan molecule (409, 410). You remember how important aggrecan molecules are right? Remember that they attract and hold water within the disc, which disc the disc high hydrostatic pressure. This particular devastating gene mutation produces a non-water absorbing aggrecan! Yikes! This gene ultimately results in severe disc dehydration and greatly increases the chance for IDD, and disc herniation (409, 410).
Recently, a mutation within the Vitamin D receptor gene has been associated with DD although the mechanism is still not clear (411a, 412, 413,414).
Other gene mutations have been strongly associated with disc bulging, anular tearing (IDD) and osteophytosis (412, 417).
I'm sure we will hear a lot more about this fascinating research area in the near future. In future there may a blood test that will warn you if your susceptible for the development of DDD and its 'evil end-phases'. This could help you chose a line of work that was conducive to the strength of you discs and maybe help prevent a middle aged catastrophe!
C. Other Risk Factors of DDD:
Occupation:
In 2000, Luoma et al. (201) conducted an excellent study on the relationship between DDD, pain, and occupation. They found that occupation type was strongly related to lower back pain and sciatica, however, DDD was only somewhat associate with these pains. Here's the study in a 'nut-shell':
A moderate sized (50 - 60) group of construction workers [heavy lifting], heavy equipment operators [vibration & prolonged sitting], and office workers [sit & stand light work] were followed for four years via questionnaire & nurse interview. At the end of the four years a MRI, interview, and final questionnaire was done on each participant. Results: Over the last year, and over the last four years the heavy equipment operators has about 50% more sciatica (nonspecific) than the construction workers, and 66% more sciatica than the office worker. The office workers did the best and had about 25 to 30% less back/leg pain over the four year period. Interesting, despite all this sciatica (over 50% of the heavy equipment operators had complained of leg pain) there were NO disc herniation found in any of the groups! So, lower back pain and leg pain does seem to be related to occupation. DDD (defined at disc bulging and a black nucleus on T2-weighted MRI) was also associated with back pain and sciatica not nearly as strongly as was occupation was.
Cigarette Smoking:
Cigarette smoking with a disc condition is just a bad idea! In 1991, Battie et al. (28) won the Volvo Award for her discovery that smoking increased spinal disc degeneration (across all discs!) by nearly 20%! She did this by using twin pairs that were discordant (one twin smoked with the other twin didn't) for smoking. I personally know several spinal surgeons who will NOT perform surgery unless the patient is 'smoke-free' for at least three months. It has been theorized that smoking damages the already compromised capillary beds (which reduces nutrient supply to the disc and dehydrates the disc) above the vertebral end-plates.
The 'Evil' End-Phases of DDD:
As I've mentioned back at the beginning of this paper, it's not the beginning phases of DDD that are painful. The pain begins when the intervertebral disc becomes disrupted and disorganized. Let's discuss some of the possible 'end-phases' of DDD:
#1) Internal Disc Disruption (IDD) and Disc Herniations:
The outer 1/3 of the disc and perianuluar tissue is filled with tiny pain-sensitive nerve fiber (701-705). Because of the 'vicious cycle' of DDD that was discussed above (here) clefts and fissures begin to form in the nucleus and anulus of the disc. With time these may grow into larger anular fissures that eventually may completely rip through the disc. is 'structural disruption' of the disc, or Internal Disc Disruption (IDD) (aka: radial anular tear). Because of the structural disruption within the anulus fibrosus (via genetics, trauma, and the 'axial-load shift), nuclear material is force outward, through anuluar fissures and into the pain sensitive outer 1/3 of the anulus. This scenario may well cause extreme lower back pain, and even sciatic (discogenic sciatica). I've got three pages on the subject of IDD, and anular tears for you to further study.
Disc herniations are born when the final layers of the anulus rupture and allow nuclear material to either collect behind the posterior longitudinal ligament (PLL) (this would be called a 'contained herniation' or 'protrusion'), or extrude into the peridural space (this would be called an extrusion or non-contained herniation) and compress the sensitive posterior nerve roots, dura of the cauda equina, dorsal root ganglion (DRG), and/or spinal nerve root. Now, the patient may develop 'true' radicular pain (true sciatica) which is often worse than the lower back pain. These topics will be covered separately on another page.
Nerve In-growth:
There is mounting evidence that a diseased disc (DDD) may be generating pain from deep within its own tissue (900,904,905,906)! For years it's been taught that the nucleus, inner and central anulus are completely avascular and aneural (have no blood or nerves), and that only the very outer layers of the posterior and anterolateral anulus contain nerve fiber (701-705). There is now strong evidence that pain carrying nerve fibers can grow inward, deep into the middle anulus and even nucleus in some cases!
These nerve fibers have now been liked with chronic discogenic pain and must be considered when making a diagnosis.
IDD is so important that I have devoted a several pages to it. I'll just briefly say here that natural disc aging (dehydration, stiffening, and brittleness) will predispose the to 'tearing'. Traumatic injury, and/or repetitive trauma to the spine over prolonged periods of time (strenuous occupation) can cause the disc to tear open from the inside out, which in turn may allow nuclear material to be forced
Stenosis as a result of DDD:
The extra axial load which is placed upon the outer structures of the disc, not only affects the anulus but also affects facet joints, especially when/if the disc begins to thin (12, 13). Human bone, as in the facet joints, responds to mechanical stress (i.e., the extra weight bearing duty) by making more bone in the areas of highest stress. This bony thickening is called hypertrophy. Stress induced hypertrophy is a good thing, for it makes the bone stronger and less apt to break under any newly imposed stress. Unfortunately, the facet joints just happen to form the posterior boarder a bony tunnel called the intervertebral foramen (IVF), in which the delicate and sensitive spinal nerve roots reside. IF our over-stressed facet joints just happen to hypertrophy (thicken) too much, and in the anterior direction, a narrowing (aka: encroachment) of the already narrow IVF will occur. The sensitive spinal nerves will slowly be crushed by the thickening facet, which leads to back pain, leg pain, and a decrease in the muscle power (motor power) in the lower limbs. This syndrome of facet joint hypertrophy into the IVF is called 'Stenosis', (lateral stenosis to be exact) and is a major concern for the elderly, i.e., it's the number one disabling spinal disorder in people over 65 (1).
Bony thickening may also occur within the posterior ring apophysis, and if severe, may compress the front portion of the spinal cord (cauda equina). This type of stenosis is called 'central stenosis', and can also cause pain, motor loss, and bowel and bladder dysfunction (cauda equina syndrome).
Stenosis often does very poorly with conservative care and may ultimately force the person into decompressive surgery.
Now lets answer some commonly asked questions about disc degeneration:
Can the disc degeneration process be stopped or reversed?
No! Once the 'train leaves the station' it is on its way; meaning that once the process of disc desiccation (dehydration) begins, there is no way to stop its progression! To understand this we need to go over some simple disc physiology; its time to get technical!!
The future: Biological therapies to the rescue? NOT
Researchers are futilely working on all sorts of ways to rejuvenate the dying disc via both biological based therapy and gene related therapy - based on tissue engineering (21 ,24,25,47 ). I'm not even going to bother to go into all of the theories, for their efforts will at best, only buy some additional time for the disc. The reason for my blanket condemnation? Any new implanted modified disc tissue or any gene injected to create new disc tissue, will immediately be starved for food, dehydrate, and die; just as the original disc cells did! Doh!! THERE NOT PAYING ATTENTION TO FACT THAT THE DISC CAN'T GET FOOD THROUGH THE NOW DISCOMBOBULATED VERTEBRAL END-PLATES. If you don't feed things, they die!
It's not just me who believes their work is in vain. Famed researcher, author and multi-timed Volvo Award Winner, Dr. Norbert Boos, also politely insinuates that this line of research is 'doomed for failure' and advices the researchers to focus their efforts on ways of "tackling the discal inflammatory reactions (which seem to be the real 'ignition switch' of back and leg pain) at a molecular level instead of attempting tissue repair." (6)
References:
1) Spivak J, "Degenerative Spinal Stenosis" J Bone Joint Surg - 1998; 80:1053-1066
2) Gruber, H.E. and Hanley, E.N., Jr. (1998) Analysis of aging and degeneration of the human intervertebral disc. Comparison of surgical specimens with normal controls. Spine 1998; 23(7):751-7
3) Sward L, et al. "Disc Degeneration and associated abnormalities of the spine in elite gymnasts; a MRI study." Spine, 1991 ;16:437 -43
4) Salminen JJ, et al. "Recurrent low back pain and early disc degeneration in the young." Spine 1999; 24: 1316-21
5) Horner HA, Urban JPG, "Effects of Nutrient Supply on the Viability of Cells from the Nucleus Pulposus of the Intervertebral Disc: 2001 Volvo Award in Basic Science." Spine 2001; 26(23):2543-2549
6) Boos N, et al. " Classification of Age-Related Changes in Lumbar Intervertebral Discs 2002 Volvo Award in Basic Science" Spine 2002; Volume 27, Number 23, pp 2631-2644
7) Vernon-Roberts B, "Age-related and degenerative pathology of intervertebral discs and apophyseal joints. In: Jayson MIV, ed The lumbar Spine and back Pain. Edinburgh , Scotland : Churchill Livingstone, 1992: 17-41
8) Vernon-Roberts B, "Disc pathology and disc states." In : Gosh P, ed. The Biology of the intervertebral disc. Boca Raton , FL : CRC Press, 1988: 73-119
9) Hall AC, Urban, JPG, "The effects of hydrostatic pressure on matrix synthesis in articular cartilage." J Orthop Res 1991 ;9:1 -10
10) Parkkinen JJ, et al. "Altered Golgi apparatus in hydrostatically loaded articular cartilage chondrocytes." Ann Rheum Dis 1993 ;52:192-8
11) Handa T, et al. "Effects of hydrostatic pressure on Matrix Synthesis and MMP production in the human lumbar intervertebral disc." Spine 1997 ;22:1085 -1091
12) Adams MA, et al. "Stress distributions inside intervertebral discs: The effects of age and degeneration. J Bone Joint Surg [Br] 1996 ;78:965 -72
13) Dunlop RB, Adams MA, et al. "Disc space narrowing and the lumbar fact joints. J Bone Joint Surg [Br] 1984 ;66:706 -10
14) Buckwalter JA, "Aging and degeneration of the human intervertebral disc." Spine 1995; 20:1307-1314
15) Nerlich AG, Boos N, et al. "Volvo Award Winner 1997: Immunohistologic Markers for Age-Related Changes of Human Lumbar Intervertebral Discs." Spine 1997; 22(24):2781-2795
16) Adams MA, Freeman BJC, et al. "mechanical initiation of intervertebral disc degeneration." Spine 2000; 25(13):1625-1636
17) Adams MA, et al. "the stages of disc degeneration as revealed by discograms." J Bone Joint Surg Br 1986:68:36-41
18) Adams MA, Hutton WC, "The effect of posture on the fluid content of lumbar intervertebral discs." Spine 1983; 8:665-71
19) Adams MA, et al. "Abnormal stress concentrations in lumbar intervertebral discs following damage to the vertebral body: A cause of disc failure." Eur Spine J 1993 1:214-21
20) Ishihara H, Urban JPG, et al. "Effects of hydrostatic pressure on matrix synthesis in different regions of the intervertebral disk." J Appl Physiol 1996; 80: 839-46
21) Moon SH, et al. (2000) "Human Intervertebral disc cells are genetically modifiable by adenovirus mediated gene transfer:" Spine - 2000; 25:2573-9
24) Nishida K, et al. (1999) "Modulation of the biologic activity of the rabbit IVD by gene therapy" Spine - 1999; 24:2419-25
23) Brinckmann P, Grootenboer H. "Change of disc height, radial disc bulge, and intradiscal pressure from discectomy: An in vitro investigation on human lumbar discs." Spine 1991; 16:641-6
25) Nishida K, et al. (1998) "Adenovirus-mediated gene transfer to nucleus pulposus cells:" Spine 1998; 23:2437-42
26) Buckwalter JA. "Spine update: Aging and degeneration of the human intervertebral disc." Spine 1995; 20:1307-14
27) Modic MT et al. "Imaging of degenerative disc disease." Radiology 1988 ;177 -86
28) Battie MC, et al. " 1991 Volvo Award in clinical sciences. Smoking and lumbar intervertebral disc degeneration: an MRI study of identical twins." Spine 1991 ;16:1015 -21
30) Brinckmann P, et al. "Fatigue fracture of human lumbar vertebrae." Con Biomech 1988 ;3 ( Suppl 1)
31) Brinckmann P, et al. "Prediction of the compressive strength of human lumbar vertebrae." Clin Biomech 1989; 4( Suppl 2)
32) Brinckmann P, et al. "A laboratory model of lumbar disc protrusion." Spine 1994; 19:228-35
33) Perry O. "Fracture of the Vertebral End-plate: A biomechanical investigation." Acta Orthop Scand 1957; ( Suppl 25)
36) Gunzburg R, Moore R, et al. "A cadaveric study comparing discography, MRI, histology, and mechanical behaviour of the human lumbar disc. Spine 1992; 17:417-23
37) Tanaka M, et al. "A pathologic study of discs in the elderly." Spine 1993; 18:1456-62
47) Wehling P, et al. (1997) "Transfer of genes to chondrocytic cells of the lumbar spine:" Spine 1997; 22:1092-7
59) Bogduk N, Adams M, et al. "The Biomechanics of back pain." Churchill Livingstone - 2002; London : 1 st edition: 62-71
60) Moneta GB, et al. "Reported pain during lumbar discography as a function of anular ruptures and disc degeneration." Spine 1994; 19:1968-74
62) Banks RA, et al. "Ageing and zonal variation in post-translational modification of collagen in normal human articular cartilage." Biochem J 1998; 330:345-51
64) Nachemson A. "In vivo discomety in lumbar discs with irregular nucleograms." Acta Orthop Scand 1965; 36:418-34
66) Nerlich AG, Boos N, " Immunohistologic markers for age-related changes of human lumbar intervertebral discs." Spine 1997; 22:2781-95
81) Vernon-Roberts B. "Disc pathology and disease states." In: Ghosh P, ed . The Biology of the Intervertebral Disc. Vol II. Boca Raton , Fl: CRC Press, 1988:73-119
100) Jensen MC, et al. "MRI imaging of the lumbar spine in people without back pain." N Engl J Med - 1994; 331:369-373
101) Boden SD et al. "Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects." J Bone Joint Surg - 1990; 72A:403-407
102) Weishaupt D et al. "MRI of the lumbar spine: Prevalence of intervertebral disc extrusion and sequestration, nerve root compression and plate abnormalities, and osteoarthritis of the fact joints in Asymptomatic Volunteers." Radiology - 1998; 209:661-666
103) Boos N, et al. "1995 Volvo Award in clinical science: The diagnostic accuracy of MRI, work perception, and psychosocial factors in identifying symptomatic disc herniations." Spine - 1995; 20:2613-2625
104) Powell MC, et al. "Prevalence of lumbar disc degeneration observed by magnetic resonance in symptomless women." Lancer - 1986; 2:1366-7
105) Boos N, et al. "Natural history of individuals with asymptomatic disc abnormalities in MRI: Predictors of low back pain-related medical consultation and work incapacity." Spine 2000 ; 25:1484
106) Borenstein G, et al. "The value of magnetic resonance imaging of the lumbar spine to predict low-back pain in asymptomatic individuals: A 7-year follow-up study. J Bone Joint [am] 2001; 83:320-34
151) Buckwalter JA, "Fine structural studies of the human intervertebral disc." In: White AA, et al. Idiopathic Low Back pain. St. Louis : CV Mosby , 1982:108-43.
152) Buckwalter JA, et al. Soft tissue aging and musculoskeletal function. J Bone Joint Surg [Am] 1993; 75:1533-48
200) Urban JPG, Roberts S, (2003) "Degeneration of the intervertebral disc" Arthritis Res Ther - 2003; 5:120-130
201) Luoma K, et al. "Low back pain in relation to lumbar disc degeneration". Spine - 2000; 25(4):487-492
203) Aprill C, Bogduk N, "High-intensity zone: A diagnostic sign of painful lumbar disc on MRI." Br J Radiol 1992 ;65:361 -9
202) Boden SD et al. "Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects." J Bone Joint Surg - 1990; 72A:403-407
206) Erkintalo MO et al. "Development of degenerative changes in the lumbar intervertebral disc: Results of a prospective MR imaging study in adolescents with and without low-back pain." Radiology - 1995; 196:529-33
209) Horton WC, Daftari TK, "Which disc as visualized by MRI is actually a source of pain? A correlation between MRI and discography." Spine 1992 ;17:S164 -71
215) Modic MT , et al, "Magnetic resonance imaging of intervertebral disk disease: Clinical and pulse sequence considerations." Radiology 1984; 152:103-11
216) Moneta GB, et al, "Reported pain during lumbar discography as a function of anular ruptures and disc degeneration: A re-analysis of 833 discograms." Spine 1994 ;19:1968 -74
219) Paajanen H, et al. "Magnetic resonance study of disc degeneration in young low-back pain patients. Spine 1989; 14:982-5
226) Tertti M, et al. "Disc degeneration in magnetic resonance imaging: A comparative biochemical, histologic and radiologic study in cadaver spines." Spine 1991; 16:629-34
227) Tertti M, et al. "Low-back pain and disc degeneration in children: A case - control MRI study." Radiology 1991; 180:503-7
231) Vanharanta H, et al. "The relationship of pain provocation to lumbar disc deterioration as seen by CT/discography." Spine 1987 ;12:295 -298
241) Urban JPG, McMullin JF, "Swelling pressure of the lumbar intervertebral discs: influence of age, spinal level, composition and degeneration." Spine 1988, 13:179-187
250) Maniadakis N, Gray A, "The economic burden of back pain in the UK ." Pain 2000; 84:95-103
251 ) ) Luoma k, (2000) "Low back pain in relation to lumbar disc degeneration" Spine - 2000; 25(4):487-492
252) Nachemson AL, Egon J, "Neck and back pain: The scientific evidence of causes, diagnosis, and treatment." Lippincott Williams & Wilkins - 2000; Philadelphia , PA
253) SCB ( statistiska centralbyran [Statistics Sweden]). Undersokningar av levnadsforhallanden , ULF [National household surveys]. Stockholm :SCB , 1996
300) Jensen MC, et al. "MRI imaging of the lumbar spine in people without back pain." N Engl J Med - 1994; 331:369-373
301) Boden SD et al. "Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects." J Bone Joint Surg - 1990; 72A:403-407
302) Weishaupt D et al. "MRI of the lumbar spine: Prevalence of intervertebral disc extrusion and sequestration, nerve root compression and plate abnormalities, and osteoarthritis of the fact joints in Asymptomatic Volunteers." Radiology - 1998; 209:661-666
303) Boos N, et al. "1995 Volvo Award in clinical science: The diagnostic accuracy of MRI, work perception, and psychosocial factors in identifying symptomatic disc herniations." Spine - 1995; 20:2613-2625
304) Powell MC, et al. "Prevalence of lumbar disc degeneration observed by magnetic resonance in symptomless women." Lancer - 1986; 2:1366-7
305) Boos N, et al. "Natural history of individuals with asymptomatic disc abnormalities in MRI: Predictors of low back pain-related medical consultation and work incapacity." Spine 2000 ; 25:1484
306) Borenstein G, et al. "The value of magnetic resonance imaging of the lumbar spine to predict low-back pain in asymptomatic individuals: A 7-year follow-up study. J Bone Joint [am] 2001; 83:320-34
321) Trout JJ, Buckwalter JA, Moore KC, "Ultrastructure of the human intervertebral disc: II. Cells of the nucleus pulposus." Anat Rec 1982; 204:307-314
324) Johnstone B, Bayliss MT , "The large proteoglycans of the human intervertebral disc: Changes in their biosynthesis and structure with age, topography, and pathology. Spine 1995; 20:674-684
325) Urban JP, et al. "Swelling pressures of proteoglycans at the concentration found in cartilaginous tissues." Biorheology 1979; 16:447-464
333) Lyons G, et al. "Biochemical changes in intervertebral disc degeneration." Biochim Biophys Acta 1981; 673:443-453
365) Nachemson A, et al. "In vitro diffusion of dye through the end-plates and annulus fibrosus of human lumbar intervertebral discs." Acta Orthop Scand 1970; 41:589-607
396) Kellgren JH, et al. "Genetic factors in generalized osteoarthritis." Ann Rheum Dis , 1963 ;22:237 -55
397) Heikkila JK, et al. "Genetic and environmental factors in sciatica. Evidence from a nationwide panel of 9365 adult twin pairs." Ann Med 1989; 21:393-398
398) Matsui H, Kanamori M, et al. " Familial predisposition for lumbar degenerative disc disease. A case-control study." Spine 1998; 23:1029-1034
399) Varlotta GP, et al. "Familial predisposition for herniation of a lumbar disc in patients who are less than twenty-one years old." J Bone Joint Surg Am 1991; 73:124-128
400) Heikkila JK, et al. "Genetic and environmental factors in sciatica. Evidence from a nationwide panel of 9365 adult twin pairs." Ann Med 1989, 21:393-398
401) Matsui H, et al. "Familial predisposition for lumbar degenerative disc disease. A case-control study." Spine - 1998; 23:1029-1034
402) Variotta GP, et al. "Familial predisposition for herniation of a lumbar disc in patients who are less than twenty-one years old. J Bone Joint Surg AM 1991; 73:124-128
403) Battie MC, et al. "1995 Volvo Award: Determinants of lumbar disc degeneration. A study relating lifetime exposures and MRI findings in identical twins." Spine 1995; 20:2601-2612
404) Sambrook PN, et al. "Genetic influences on cervical and lumbar disc degeneration: a MRI study in twins." Arthritis Rheum 1999; 42:366-372
405) Battie MC, et al. "Similarities in degenerative findings on MRI of the lumbar spines of identical twins." J Bone Joint Surg AM 1995; 77:1662-1670
406) Ala- Kokko L, "Genetic risk factors for lumbar disc disease." Ann Med 2002; 34:42-47
407) Annunen S, et al. "An allele of COL9A2 associated with intervertebral disc disease." Science - 1999; 285:409-12
408) Paassilta P, et al. "Identification of a novel common genetic risk factor for lumbar disc disease." JAMA 2001 ;285:1843 -9
409) Kawaguchi Y, et al. "Association between an aggrecan gene polymorphism and lumbar disc degeneration." Spine - 1999; 24:2456-60
410) Takahashi M, et al. "The association of degeneration of the intervetebral disc with 5a/6a polymorphism in the promoter of the human matrix metalloproteinase-3 gene." J Bone Joint Surg [Br] 2001; 83-B :491 -5
411) Videman T, et al. "1998 Volvo Award winner: Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration." Spine - 1998; 23:2477-85
411a) Kawaguchi Y, et al. "The association of lumbar disc disease with vitamin-D receptor gene polymorphism. J Bone Joint Surg Am 2002; 84-A :2022 -2028
412) Videman T, et al. "The relative roles of intragenic polymorphisms of the vitamin D receptor gene in lumbar spine degeneration and bone density." Spine 2001, 26:E7-E12
413) Videman T, et al. "1998 Volvo Award winner: Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration." Spine - 1998; 23:2477-85
413a) Videman T, et al. "Iatrogenic polymorphisms of the Vitamin D Receptor Gene Associated with intervertebral disc degeneration." Presented to the International Society for the study of the lumbar spine, Brussels , June 9-13, 1998
414) Jones G, et al. "Allelic variation in the vitamin D receptor, lifestyle factors and lumbar spinal degenerative disease." Ann Rheum Dis 1998, 57:94-99
417) Sambrook PN, et al. "Genetic influences on cervical and lumbar disc degeneration: a MRI study in twins." Arthritis Rheum 1999, 42:366-372
450) Luoma k, (2000) "Low back pain in relation to lumbar disc degeneration" Spine - 2002; 25(4):487-492
451) Allan DB, Wadell G , " An historical perspective on low back pain and disability." Acta Orthop Scand Suppl - 1989; 234:1-23
452) Lotz JC et al. "1998 Volvo Award Winner in biomechanical studies: Compression-induced degeneration of the intervertebral disc: An in vivo mouse model and finite-element study.
453) Eck JC, et al. "Adjacent-segment degeneration after lumbar fusion: a review of clinical, biomechanical, and radiologic studies." Am J Orthop 1999, 28:336- 340
454) Heliovaara M: Risk factors for low back pain and sciatica." Ann Med 1989, 21:257-264
500) Horner HA, Urban JPG, "Effects of Nutrient Supply on the Viability of Cells from the Nucleus Pulposus of the Intervertebral Disc: 2001 Volvo Award in Basic Science." Spine 2001; 26(23):2543-2549
505) Battie MC, et al. "Volvo Award in clinical sciences. Determinants of lumbar disc degeneration: a study relating lifetime exposures and magnetic resonance imaging findings in identical twins." Spine 1995; 20:2601-12
506) Bernick S, Sailliet R. "Vertebral endplate changes with aging of human vertebrae." Spine 1982; 7:97-102
517) Homs S, Nachemson A. "Nutrition of the intervertebral disc: acute effects of cigarette smoking. An experimental animal study. Ups J Med Sci 1988; 93:91-9
524) Kauppila LI. "Prevalence of stenotic changes in arteries supplying the lumbar spine: a post mortem angiographic study on 140 subjects." Ann Rheum Dis 1997; 56:591-5
526) Kauppila LI, et al. "Lumbar disc degeneration and atherosclerosis of the abdominal aorta." Spine 1994; 19:923-9
537) Roberts S, et al. "The cartilage endplate and intervertebral disc in scoliosis: calcification and other sequelae." J Orthopo Res 1993; 11:747-57
538) Roberts S, Urban J, et al. "Transport properties of the human cartilage endplate in relation to its composition and calcification." Spine 1996; 21:415-20
552) Urban MR, Fairbanks JCT, et al. "Electrochemical measurement of transport into scoliotic intervertebral discs in vivo using nitrous oxide as a tracer." Spine 2001; 26:984-90
600) Modic MT , Masaryk TJ, Ross JS, et al. Imaging of degenerative disk disease. Radiology 1988; 168: 177-86
601) Pearce RH, Thompson JP, Bebault GM, et al. Magnetic resonance imaging reflects the chemical changes of aging degeneration in the human intervertebral disk. J Rheumatol Suppl 1991; 27: 42-3.
602) Sether LA, Yu S, Haughton VM, et al. Intervertebral disk: normal age-related changes in MR signal intensity. Radiology 1990; 177: 385-8.
604) Pfirrmann CWA, Boos N et al. " Magnetic Resonance Classification of Lumbar Intervertebral Disc Degeneration" SPINE 2001 ;26:1873 -1878
900) Freemont AJ, et al " Nerve growth factor expression and innervation of the painful intervertebral disc." J Pathol 2002 ;197:286 -292
904) Freemont AJ, et al. "nerve in-growth into the diseased intervertebral disc in chronic back pain. Lancet, 1997 ;350:178 -81
905) Palmgren T, et al. " Imminohistochemical demonstration of sensory and autonomic nerve terminals in herniated lumbar disc tissue." Spine 1996; 21:1301-1306
906) Coppes MH, et al. "Innervation of 'painful' lumbar discs." Spine 1997; 22:2342-2349