Disc Disease Research Articles

Response to "Unnecessary spinal surgery"

Response to "Unnecessary spinal surgery"

Spine Abnormalities Depicted by Magnetic Resonance Imaging in Adolescent Rowers

Background: Most lesions of the spine of athletes, which often are detected incidentally, do not cause important symptoms or make the athletes discontinue their physical activities. To better understand the significance of these lesions, new imaging studies have been conducted with asymptomatic athletes in several sports, aiming to detect potentially deleterious and disabling abnormalities. Purpose: To compare the magnetic resonance imaging (MRI) lumbar spine findings in a group of asymptomatic adolescent rowers and in a control group of adolescents matched according to age and sex who do not practice any regular physical activity. Study Design: Cohort study (prevalence); Level of evidence, 3. Methods: Our study evaluated 44 asymptomatic adolescent boys distributed in 2 groups of 22 rowers and 22 control subjects. All the examinations were performed using a 0.35-T open-field MRI unit and evaluated by 2 experienced radiologists blinded to the study groups. Each MRI scan was analyzed for the presence of disc degeneration/desiccation, herniated or bulging disc, pars interarticularis stress reaction, and spondylolysis. The Student t test and the Fisher exact test were used for statistical analyses. Results: Nine rowers (40.9%) had at least 1 abnormality detected by MRI in the lumbar spine, whereas only 2 participants (9.1%) in the control group had at least 1 MRI abnormality (P = .03). Seven disc changes (31.8%) and 6 pars abnormalities (27.3%) were found in the group of elite rowers. In the control group, 3 disc changes (13.6%) and no pars abnormalities were found in the MR scans. The comparison between groups showed statistically significant differences in stress reaction of the pars articularis. Conclusion: Disc disease and pars interarticularis stress reaction are prevalent abnormalities of the lumbar spine of high-performance rowers.

Notochordal cell conditioned medium stimulates mesenchymal stem cell differentiation toward a young nucleus pulposus phenotype

IntroductionMesenchymal stem cells (MSCs) offer promise for intervertebral disc (IVD) repair and regeneration because they are easily isolated and expanded, and can differentiate into several mesenchymal tissues. Notochordal (NC) cells contribute to IVD development, incorporate into the nucleus pulposus (NP), and stimulate mature disc cells. However, there have been no studies investigating the effects of NC cells on adult stem cell differentiation. The premise of this study is that IVD regeneration is more similar to IVD development than to IVD maintenance, and we hypothesize that soluble factors from NC cells differentiate MSCs to a phenotype characteristic of nucleus pulposus (NP) cells during development. The eventual clinical goal would be to isolate or chemically/recombinantly produce the active agent to induce the therapeutic effects, and to use it as either an injectable therapy for early intervention on disc disease, or in developing appropriately pre-differentiated MSC cells in a tissue engineered NP construct.MethodsHuman MSCs from bone marrow were expanded and pelleted to form high-density cultures. MSC pellets were exposed to either control medium (CM), chondrogenic medium (CM with dexamethasone and transforming growth factor, (TGF)-β3) or notochordal cell conditioned medium (NCCM). NCCM was prepared from NC cells maintained in serum free medium for four days. After seven days culture, MSC pellets were analyzed for appearance, biochemical composition (glycosaminoglycans and DNA), and gene expression profile (sox-9, collagen types-II and III, laminin-β1 and TIMP1(tissue inhibitor of metalloproteinases-1)).ResultsSignificantly higher glycosaminoglycan accumulation was seen in NCCM treated pellets than in CM or TGFβ groups. With NCCM treatment, increased gene expression of collagen III, and a trend of increasing expression of laminin-β1 and decreased expression of sox-9 and collagen II relative to the TGFβ group was observed.ConclusionsTogether, results suggest NCCM stimulates mesenchymal stem cell differentiation toward a potentially NP-like phenotype with some characteristics of the developing IVD.

Herpes Zoster Radiculopathy Treated with Fluoroscopically-Guided Selective Nerve Root Injection

Background: Varicella-zoster virus, a member of the herpes virus family, is a neurotrophic virus that primarily affects afferent sensory neurons. Reactivation of latent virus within the dorsal root ganglion and axoplasmic transport to epithelial nerve terminals causes the segmental cutaneous rash and neuralgic pain characteristic of herpes zoster. Setting: Outpatient orthopedic practice. Case Description: A 75-year-old male developed a herpetic rash followed by burning pain in the right L5 distribution. The pain was exacerbated by standing or walking. Six weeks later, the rash had improved, but the patient developed a right foot drop requiring use of a molded ankle-foot orthosis. MRI of the lumbar spine revealed mild degenerative changes without evidence of significant spinal stenosis or disc disease. Electrodiagnostic studies confirmed the diagnosis of right L5 radiculopathy. Results: The patient had dramatic improvement of pain and weakness after undergoing a fluoroscopically guided right L5 selective nerve root block with Depo-Medrol and Lidocaine. He then began a course of physical therapy and, 6 weeks later, had only trace weakness of the ankle dorsiflexor group on the right side. The patient has continued without significant weakness or pain since the procedure and has returned to normal functioning. Discussion: This case demonstrates apparent treatment of a relatively uncommon phenomenon, herpes zoster radiculopathy, using selective nerve root block. Limitations: There is a limited amount of data regarding this disorder presently available regarding Herpes Zoster Radiculopathy. A second limitation would be an inability to exclude spinal pathology as an alternative etiology of this patient’s condition. Conclusion: Cases of herpes zoster-induced radiculopathy may become more frequent, as evidenced by the increasing number of cases of herpes zoster in the United States noted epidemiologically. Key words: Herpes zoster, shingles, lumbar radiculopathy, lumbar stenosis, dermatome, electrodiagnosis, selective nerve, root injection

DSC Study of Collagen in Disc Disease

Differential scanning calorimetry (DSC) has been used to estimate the effect of disc disease on the collagen helix-coil transition and morphology for tissue extracted from patients during surgical operation. Forty discs were obtained from patients with degenerative disc disease undergoing surgery for low back pain. The patients were in the age between 20 and 70 years old. The specimens were kept wet during DSC experiment. The data allow the comparison between thermal stability of collagen tissue from healthy patients and from patients suffering from disc disease. In the paper the comparison between thermal helix-coil transition for collagen fibers from patients suffering from disc disease and collagen fibers from healthy organisms has been discussed. The heating rate has an influence on the position on denaturation temperatures of collagen in disc tissues. Higher helix-coil transition temperature of collagen in degenerated disc suggests that additional intermolecular cross linking of collagen fibers occurs. Denaturation temperatures of collagen in degenerated male disc possess smaller values than in female ones. Disc disease induces changes in collagen structure and leads to formation of additional crosslinks between collagen fibers.

Increased intrathecal synthesis of fibronectin in bacterial and carcinomatous meningitis

Immunoreactive fibronectin (Fn) was quantified in paired cerebrospinal fluid (CSF) and serum samples from patients with bacterial meningitis (n = 46), tick-borne encephalitis (TBE) (n = 6), HIV infection (n = 6), Guillain-Barré syndrome (n = 5), carcinomatous meningitis (n = 11), multiple sclerosis (n = 15), disk disease (n = 11), and controls (n = 28). A highly significant elevation of CSF Fn was found in bacterial meningitis, TBE, and carcinomatous meningitis. There were no significant differences in serum Fn between any of the groups. An Fn index to estimate the rate of intrathecal Fn synthesis reached the highest value in bacterial meningitis. Our findings suggest that CSF Fn may be an indicator of adequate host reaction and tissue repair. For diagnostic purposes, the determination of CSF Fn probably does not add much to routine CSF laboratory tests.

Low back pain in neurosurgical outpatients: An audit

Low back pain is a common condition. This is a retrospective study of new referrals to neurosurgical outpatients at the Western Hospital, Victoria, Australia. Two hundred and fifteen histories were systematically reviewed. Statistical analysis was performed using univariate and multivariate analyses. Patients who had tried physiotherapy, epidural injection or had no pre-outpatient imaging were more likely to get MRI ( p < 0.02). Patients with clinical features of neurogenic claudication ( p < 0.01) or with neurological signs ( p = 0.02) were more likely to proceed to surgery. CT scan demonstrated significant correlation to MRI for lumbar canal stenosis, disc disease or the absence of disease ( p < 0.01). Referral guidelines for general practitioners regarding back pain are proposed. Recommendations are also made to facilitate the selected use of CT scan and MRI.

Concentrations of Acute‐Phase Proteins in Dogs with Steroid Responsive Meningitis‐Arteritis

Measurement of concentrations of acute-phase proteins (APPs) is used as an aid in the diagnosis of a variety of diseases in animals. To determine the concentration of APPs in dogs with steroid responsive meningitis-arteritis (SRMA) and other neurologic diseases. One hundred and thirty-three dogs with neurologic diseases, 6 dogs with sepsis, and 8 healthy dogs were included in the study. Thirty-six dogs had SRMA (31 of which had monitoring), 14 dogs had other meningoencephalitides (ME), 32 had disk disease (IVDD/DLSS), 26 had tumors affecting the central nervous system (TCNS), and 25 had idiopathic epilepsy (IE). Prospective, observational study: C-reactive protein (CRP), alpha(2)-macroglobulin (AMG), and albumin concentrations were determined in the serum or plasma. CRP was also measured in the cerebrospinal fluid. Serum CRP was significantly higher in dogs with SRMA (x=142 microg/mL+/-75) and sepsis (x=114 microg/mL+/-67) in comparison with dogs with other neurologic diseases (x=2.3-21 microg/mL; P< .001). There was no significant difference detected in AMG between groups. Serum albumin concentration was significantly lower (P< .01) in dogs with SRMA (x=3.2 g/dL+/-0.41) than in other groups (x=3.6-3.9 g/dL). Serum CRP concentration of SRMA dogs correlated with alkaline phosphatase levels (r=0.515, P= .003). CRP concentrations in serum are useful in diagnosis of dogs with SRMA. Serum CRP could be used as a monitoring parameter in treatment management of these dogs.

DISEASES OF THE NERVE ROOTS

ABSTRACT Disorders of spinal nerve roots can give rise to disabling pain and weakness. Damage to nerve roots resulting from disc disease and spondylosis can be localized by attention to anatomic principles and with appropriate testing. Management strategies vary, depending on the clinical situation. Autoimmune, infectious, diabetic, infiltrative, degenerative, and hereditary disorders are also causes of nerve root disease. Other neurologic conditions can masquerade as nerve root disease.

Apoptosis and gene expression of collagenases but not gelatinases in rabbit disc fragment cultures

The object of this study was to characterize the biological response of isolated intervertebral disc fragments to in vitro culture conditions with respect to cell death and inflammatory and catabolic changes. The acquired data could help to gain a better understanding of the biological reaction of disc tissue when exposed to environmental changes along with altered nutritional and osmotic conditions, as are encountered in different in vitro disc models or disc diseases in vivo. Intervertebral disc anulus fragments were isolated from Burgundy rabbits and cultured in standard media for 3 days. The disc fragments were analyzed for their swelling properties, proteoglycan loss on histological studies, lactate dehydrogenase activity, apoptosis, gene expression of collagenases and gelatinases, and for proinflammatory (MCP-1, IL-8, and IL-6) and apoptosis-associated (TNF-alpha, Fas-L, and caspase 3) genes. The results demonstrate that disc specimens were swelling, and a loss of proteoglycans with disarrangement of anulus architecture was observed. The disc cells underwent rapid apoptosis with upregulation of various proinflammatory genes. Both collagenases, matrix metalloproteinase (MMP)-1 and MMP-13, were increasingly transcribed, whereas the gelatinases MMP-2 and MMP-9 did not respond or were downregulated. Cultured disc fragments swell and undergo necrotic and apoptotic cell death combined with a catabolic gene response and gene expression of proinflammatory and chemoattractant proteins. Some of these findings have been demonstrated before in various spinal disorders. In addition, disc fragments are not suitable for long-term culture if a stable disc metabolism is desired, and the described changes have to be considered when using isolated disc material for in vitro cultures.

Evidence for Skeletal Progenitor Cells in the Degenerate Human Intervertebral Disc

To identify and characterize endogenous progenitor cell population from intervertebral disc. To determine if progenitor cells exist in degenerate human discs. Back pain, a significant source of morbidity in our society, is directly linked to the pathology of the intervertebral disc. Because disc disease is accompanied by a loss of cellularity, there is considerable interest in regeneration of cells of both the anulus fibrosus (AF) and nucleus pulposus (NP). To determine if skeletal progenitor cells are present in the disc, samples were obtained from the degenerate AF and NP of 5 patients (Thompson grade 2 and 3, mean age 34 +/- 7.6 years) undergoing anterior cervical discectomy and fusion procedures as well as adult rat lumbar spine. Cells isolated from degenerate human tissues expressed CD105, CD166, CD63, CD49a, CD90, CD73, p75 low affinity nerve growth factor receptor, and CD133/1, proteins that are characteristic of marrow mesenchymal stem cells. In osteogenic media, there was an induction of alkaline phosphatase activity and expression of alkaline phosphatase, osteocalcin, and Runx-2 mRNA. When maintained in adipogenic media, a small percentage of cells displayed evidence of adipogenic differentiation: accumulation of cytosolic lipid droplets and increased expression of peroxisome proliferator-activated receptor-gamma2 and lipoprotein lipase mRNA. AF- and NP-derived cells also evidenced chondrogenic differentiation. CD133 (+) cells in the AF were able to commit to either the chondrogenic or adipogenic lineages. The results of the human disc studies were confirmed using cell derived from the NP and AF tissue of the mature rat disc. The analytical data indicated that the pathologically degenerate human disc contained populations of skeletal progenitor cells. These findings suggest that these endogenous progenitors may be used to orchestrate the repair of the intervertebral disc.

Investigation of nano-mechanical properties of annulus fibrosus using atomic force microscopy

We describe the use of atomic force microscopy (AFM) to investigate the nanomechanical properties of annulus fibrosus (AF)—the outer fibrous layer of an intervertebral disc (IVD) encapsulating the inner jelly-like mass known as the nucleus pulposus (NP). Disk disease, degenerated discs, slipped discs, and herniated discs are common terms often linked to back pain and are caused due to degeneration of IVD. Due to the variations in the structure and biochemical composition of the IVD, studies of macromechanical properties in the motion segment or AF may lack all significant nanomechanical responses or behaviors. Existing studies do not report the micro or nano level of mechanics of IVD components and whether the nanomechanics of this tissue mimic its macromechanical behavior is not known. Our studies used AFM to investigate the regional micromechanical properties of the AF that have been otherwise difficult due to small sample size of the tissue. Five different zones including peripheral and central were tested mechanically as well as biochemically. Qualitative biochemical staining and quantitative values of nanomechanical properties of different zones are compared and discussed in detail. The results of nanomechanical investigations described in this study not only reveal its mimic at macroscopic level, they represent an important step towards establishing a framework for testing and comparing tissue engineered IVD replacements with native tissues.

Cervicogenic Headache Caused by Myofascial Trigger Points in the Sternocleidomastoid: A Case Report

Disturbances in the integrity of the upper cervical spine are now well known to be associated with head pain and can give rise to chronic daily headaches (1–3). Head pain that derives from cervical dysfunctions or disease is now contained under the category of cervicogenic headaches (4), which describes a heterogeneous group of disorders that commonly refer pain from structures in the cervical spine region (e.g. joints, muscle, nerve) to various regions in the head. The mechanisms that underlie head pain referred from the neck are not entirely understood. There is general consensus that the trigeminocervical complex, which is located in the lower brainstem and upper three cervical spinal segments and receives multiple afferent inputs from both the trigeminal nerve and cervical peripheral afferents, serves as the centre of convergence for the projection of perceived pain in the head that originates from cervical pain generators (1). However, this model may not explain all forms of cervicogenic pain, in particular myogenic referred head pain that derives from myofascial trigger points (MTrPs) of the cervical and upper back musculature (5, 6). An accurate diagnosis of the aetiology of cervicogenic headache can be challenging for the clinician due, in part, to the overlap of pain and associated symptoms between cervicogenic headache and primary headache (3, 7, 8) and the multiple abnormalities of the cervical spine and musculature that can be a primary source of head pain (9–12). Several authors have emphasized the role of anaesthetic nerve blockade, particularly directed to the occipital nerve and C2 spinal level, as the primary criterion for the diagnosis of cervicogenic headache (1, 3, 13). The increasing attention to anaesthetic blockade as a diagnostic tool has paralleled the expansion of the use of interventional procedures for the treatment of chronic cervicogenic headache (14–16). Interventional diagnostic measures tend to follow from abnormal radiographic findings, such as spondylosis, disk disease or facet arthropathy (1,9), and rely on patient report of diminished pain to anaesthetic challenge as a guide to diagnosis. Increasing reliance on nerve blockade as a diagnostic tool may encourage de-emphasis on the clinical examination of the musculature. Reliance on an interventional approach to the diagnosis of cervicogenic headache that targets joint arthropathies or possible nerve involvement tend to ignore the potential contribution of MTrPs or intersegmental motion restrictions as primary causes of cervicogenic headache (10, 17–19). Identification of the musculoskeletal dysfunctions requires a careful and informed clinical examination. Lack of familiarity with the characteristic myofascial referred pain patterns frequently leads to misdiagnosis and ineffectual headache interventions (10). We report a case of a male with a 25-year history of chronic headaches despite an extensive course of medical evaluations and treatment. After a recent hospitalization and further interventional procedures to identify a cause of his pain, a careful physical examination of the cervical musculature identified MTrPs in the sternocleidomastoid (SCM) muscle as a primary source of his head pain. Physical therapy that focused on reducing the myofascial dysfunction and addressing perpetuating factors felt to be maintaining his MTrP activity brought about dramatic reduction in his pain within 6 weeks, which was maintained at 6 months.

Proinflammatory Cytokines Stimulate the Expression of Nerve Growth Factor by Human Intervertebral Disc Cells

In vitro studies of the effects of proinflammatory cytokines on the production of nerve growth factor (NGF) by human intervertebral disc (IVD) cells. To determine the constitutive expression and production of NGF and the effect of cytokines on the expression of NGF by human IVD cells. NGF may play a role in the collateral sprouting of sensory axons, neural survival, and regulation of nociceptive sensory neurons. NGF is known to be up-regulated by proinflammatory cytokines. The presence of NGF protein was analyzed by immunohistochemistry using human IVD cells obtained from cadaveric human spines with no known disc disease (MRI Thompson grades 2-4). The effects of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) on NGF production and mRNA expression of NGF by IVD cells were examined. The expression of NGF receptors, trkA and p75, was also assessed immunohistochemically. Cadaveric anulus fibrosus (AF) and nucleus pulposus (NP) cells cultured in vitro in monolayer and in alginate beads positively stained with an anti-NGF antibody. The constitutive production of NGF protein in IVD cells was low (NP) or not detectable (AF). The expression of NGF mRNA was detectable in both cell types. IL-1beta and TNF-alpha up-regulated the NGF mRNA expression and the secretion of NGF protein into the media. TrkA was immunolocalized in AF and NP cells. Our results demonstrate, for the first time, that human AF and NP cells constitutively express NGF protein and mRNA, and that the proinflammatory cytokines IL-1beta and TNF-alpha stimulate the production of NGF. The precise role of NGF produced by IVD cells in the generation of discogenic pain or on the metabolism of IVD cells, especially under certain physiologic conditions in which cytokines are up-regulated, needs to be clarified in future experimentation.

Cervical spine magnetic resonance imaging in primary care consulters with shoulder pain: a case–control study

Objectives:To investigate the association between shoulder region pain presenting in primary care and cervical spine magnetic resonance imaging (MRI) abnormalities.Methods:A matched case–control study of 48 pairs of participants. Patients had...

Difficult medical problems: On explanatory models and a pragmatic alternative

Despite the significant improvements in the treatment of many pathologic processes witnessed over the past century, some particularly difficult medical problems persist. Some of these problems, perhaps best exemplified by chronic low back pain/degenerative disc disease, are characterized by unclear underlying etiologies and less than desirable outcomes of treatment in spite of considerable intellectual and financial investment. Faced with these disorders, many physicians rely on 'explanatory models', such as the traditional Biomedical model or the Biopsychosocial model, to provide a perspective from which to aim research, diagnosis, and treatment programs. The strength of the Biomedical model is its proven success as a roadmap for diagnosis and treatment of a multitude of diseases over the past two centuries. Its weakness lies in its failure to fully include psychosocial factors which have proven to be powerful co-factors of disease in modern society. The Biopsychosocial model has filled this void, but carries with it the potential to blur more straightforward biomedical models of causation (and their straight-forward treatments), questions about whether it is a falsifiable scientific theory, and whether it further 'medicalizes' those being treated. In this paper, we expand and detail the strengths and weaknesses of using these explanatory models and conclude by presenting a 'pragmatic alternative' hypothesis.

Lower Extremity Nerve Function in Patients With Lower Extremity Ischemia

We determined whether lower extremity ischemia, as measured by the ankle brachial index (ABI), is associated with impaired lower extremity nerve function. Participants included 478 persons with peripheral arterial disease (PAD) identified from noninvasive vascular laboratories and 292 persons without PAD identified from a general medicine practice and noninvasive vascular laboratories. Peripheral arterial disease was defined as an ABI lower than 0.90 (mild PAD: ABI, 0.70 to <0.90; moderate PAD: ABI, 0.50 to <0.70; and severe PAD: ABI, <0.50). The ABI and electrophysiologic measures of the peroneal, sural, and ulnar nerves were obtained. Among 546 participants without diabetes, PAD participants had significantly impaired peripheral nerve function in the upper and lower extremities compared with non-PAD participants. After adjusting for age, sex, race, smoking, height, body mass index, recruitment source, alcohol use, disk disease, spinal stenosis, cardiac disease, and cerebrovascular disease, these associations were not statistically significant. After adjusting for confounders among nondiabetic participants, those with severe PAD (ABI, <0.50) had poorer peroneal nerve conduction velocity (NCV) compared with participants without PAD (42.6 vs 44.8 m/s; P = .003) and poorer peroneal NCV compared with participants with mild PAD (42.6 vs 45.0 m/s; P = .001) or moderate PAD (42.6 vs 44.1 m/s; P = .03). Among 224 participants with diabetes, after adjusting for confounders, PAD was associated with poorer peroneal NCV (40.8 vs 43.5 m/s; P = .01), sural nerve amplitude (3.1 vs 4.8 muV; P = .045), and ulnar NCV (47.6 vs 50.2 m/s; P = .03) compared with those without PAD. Our findings suggest that leg ischemia impairs peroneal nerve function. This association is less strong in patients with diabetes, perhaps because of the overriding influence of diabetes on peripheral nerve function. Clinicians should consider screening for PAD in patients with idiopathic peroneal nerve dysfunction. Peripheral arterial disease-associated nerve dysfunction may contribute to PAD-associated functional impairment.

Bertolotti’s syndrome

Bertolotti’s syndrome is characterised by anomalous enlargement of the transverse process(es) of the most caudal lumbar vertebra which may articulate or fuse with the sacrum or ilium and cause isolated L4/5 disc disease. We analysed the elective MR scans of the lumbosacral spine of 769 consecutive patients with low back pain taken between July 2003 and November 2004. Of these 568 showed disc degeneration. Bertolotti’s syndrome was present in 35 patients with a mean age of 32.7 years (15 to 60). This was a younger age than that of patients with multiple disc degeneration, single-level disease and isolated disc degeneration at the L4/5 level (p ≤ 0.05). The overall incidence of Bertolotti’s syndrome in our study was 4.6% (35 of 769). It was present in 11.4% (20 patients) of the under-30 age group. Our findings suggest that Bertolotti’s syndrome must form part of a list of differential diagnoses in the investigation of low back pain in young people.

Back Pain and Disc Disease in Adolescents

Back Pain and Disc Disease in Adolescents

Tumor Necrosis Factorα Modulates Matrix Production and Catabolism in Nucleus Pulposus Tissue

This study examines changes in the production of extracellular matrix molecules as well as the induction of tissue degradation in in vitro formed nucleus pulposus (NP) tissues following incubation with tumor necrosis factor (TNF)alpha. To characterize the response of NP cells to TNF-alpha, a proinflammatory cytokine present in herniated NP tissues. TNF-alpha is a proinflammatory cytokine expressed by NP cells of degenerate intervertebral discs. It is implicated in the pain associated with disc herniation, although its role in intervertebral disc degeneration remains poorly understood. In vitro formed NP tissues were treated with TNF-alpha (up to 50 ng/mL) over 48 hours. Tissues were assessed for histologic appearance, proteoglycan and collagen contents, as well as proteoglycan and collagen synthesis. Reverse transcriptase polymerase chain reaction was used to determine the effect of TNF-alpha on NP cell gene expression. Proteoglycan degradation was assessed by immunoblot analysis. At doses of 1-5 ng/mL, TNF-alpha induced multiple cellular responses, including: decreased expression of both aggrecan and type II collagen genes; decreases in the accumulation and overall synthesis of aggrecan and collagen; increased expression of MMP-1, MMP-3, MMP-13, ADAM-TS4, and ADAM-TS5; and induction of ADAM-TS dependent proteoglycan degradation. Within 48 hours, these cellular responses resulted in NP tissue with only 25% of its original proteoglycan content. Because low levels of TNF-alpha, comparable to those present physiologically, induced NP tissue degradation, this suggests that TNF-alpha may contribute to the degenerative changes that occur in disc disease.