Tumor necrosis factor-alpha modulates matrix production and catabolism in nucleus pulposus tissue.
BioEngineering of Skeletal Tissues Team, Mount Sinai Hospital, Ontario, Canada. Spine
(Impact Factor: 2.3).
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.
Available from: Abbie Binch
- "The roles of cytokines within IVD degeneration have been profusely studied, and their actions have been well documented over the past decade or so. Native cells of the NP in both non-degenerate and degenerate IVDs produce cytokines, in particular interleukin-1 (IL-1β) and tumour necrosis factor (TNFα)[7,171819202122. Numerous studies by Le Maitre and colleagues localised all members of the IL-1 family (IL-1α, IL-1β, IL-1RI, ICE, IL-1Ra) in IVD tissue, yet it was only the natural inhibitor of IL-1, IL-1 receptor antagonist (IL-1Ra) that did not increase with severity of degeneration[18,23]. These cytokines are known to contribute to the ECM degradation by mediating increased expression of catabolicof the IVD. "
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ABSTRACT: The ECM of the intervertebral disc and articular cartilage contain a highly organised network of collagens and proteoglycans which resist compressive forces applied to these tissues. A pathological hallmark of the intervertebral disc is the imbalance between production of anabolic and catabolic factors by the resident cells. This process is thought to be mediated by pro-inflammatory cytokines, predominantly TNF-α and IL-1β, which upregulate expression of matrix degrading enzymes such as MMPs and ADAMTSs. This imbalance ultimately results in tissue degeneration causing failure of the biomechanical function of the tissues. A similar cascade of events is thought to occur in articular cartilage during development of osteoarthritis. Within these skeletal tissues a small, cell surface heparan sulphate proteoglycan; syndecan-4 (SDC4) has been implicated in maintaining physiological functions. However in the degenerating niche of the intervertebral disc and cartilage, dysregulated activities of this molecule may exacerbate pathological changes. Studies in recent years have elucidated a role for SDC4 in mediating matrix degradation in both intervertebral discs and cartilage by controlling ADAMTS-5 function and MMP3 expression. Discourse presented in this review highlights the potential of SDC4 as possible therapeutic target in slowing the progression of ECM degradation in both degenerative disc disease and osteoarthritis.
Available from: Theodoor Henri Smit
- "ADAMTS 5, MMP 13 and 14, IL 1 and 8). These could be potential therapeutic targets for the prevention and/or treatment of (load-induced) DDD , , . We anticipate that treatments blocking the activity of pro-inflammatory or remodeling enzymes could show efficacy on the delay or attenuation of load-induced disc degeneration –. "
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ABSTRACT: Mechanical overloading of the spine is associated with low back pain and intervertebral disc (IVD) degeneration. How excessive loading elicits degenerative changes in the IVD is poorly understood. Comprehensive knowledge of the interaction between mechanical loading, cell responses and changes in the extracellular matrix of the disc is needed in order to successfully intervene in this process. The purpose of the current study was to investigate whether dynamic and static overloading affect caprine lumbar discs differently and what mechanisms lead to mechanically induced IVD degeneration. Lumbar caprine IVDs (n = 175) were cultured 7, 14 and 21 days under simulated-physiological loading (control), high dynamic or high static loading. Axial deformation and stiffness were continuously measured. Cell viability, cell density, and gene expression were assessed in the nucleus, inner- and outer annulus. The extracellular matrix (ECM) was analyzed for water, glycosaminoglycan and collagen content. IVD height loss and changes in axial deformation were gradual with dynamic and acute with static overloading. Dynamic overloading caused cell death in all IVD regions, whereas static overloading mostly affected the outer annulus. IVDs expression of catabolic and inflammation-related genes was up-regulated directly, whereas loss of water and glycosaminoglycan were significant only after 21 days. Static and dynamic overloading both induced pathological changes to caprine lumbar IVDs within 21 days. The mechanism by which they inflict biomechanical, cellular, and extracellular changes to the nucleus and annulus differed. The described cascades provide leads for the development of new pharmacological and rehabilitative therapies to halt the progression of DDD.
- "Prolapsed disc is a condition of the spine, when there is a tear in the outer annulus fibrosus of an intervertebral disc, allowing the soft central gelatinous nucleus pulposus to bulge out beyond the vertebral body margins posteriorly. This could cause pain directly through compression of a nerve root, and/or the tear may cause release of inflammatory chemical mediators, for example tumour necrotic factor (TNF).12345 Tears are almost always postero-lateral, since the posterior longitudinal ligament protects the postero-medial area. Prolapsed disc could be due to wear and tear from certain jobs that require constant sitting, like driving; recreational activities including rowing, skiing, weight lifting, jogging, walking, etc.167 Genetics, height, age and smoking could also influence the occurrence of this lesion.16789101112131415 "
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ABSTRACT: The pattern of distribution of surgically treated symptomatic prolapsed lumbar and sacral intervertebral discs has been published, though scantily, especially in males. We decided to look at our own series, compare and contrast ours with some of those published.
We treated 88 locations of this lesion in 68 males. The clinical features were those of lower back pains, with or without radiation into the lower extremities, sensory loss and paresis of the limbs. There was a case of loss of urinary bladder and ano-rectal control. All lesions were confirmed through cauda-equinograms and treated under general anaesthesia in knee-chest position (MECCA position). The patients were followed up for 3-6 months post-operatively.
There were 88 locations in 68 males of 21-70 years of age, with 29 prolapses occurring during the age range 31-40 years, while 54 locations were on the left and 48 at L4/5. The procedures were well tolerated by all patients and there were no post-operative complications.
This lesion in our series occurred mostly on the left, at the L4/5 level and peaked at 31-40 years age range. The predictability of occurrence of this disease, using side, level and age is still not feasible in males from our series.
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