Biological treatment strategies for disc degeneration: potentials and shortcomings

Recent advances in molecular biology, cell biology and material sciences have opened a new emerging field of techniques for the treatment of musculoskeletal disorders. These new treatment modalities aim for biological repair of the affected tissues by introducing cell-based tissue replacements, genetic modifications of resident cells or a combination thereof. So far, these techniques have been successfully applied to various tissues such as bone and cartilage. However, application of these treatment modalities to cure intervertebral disc degeneration is in its very early stages and mostly limited to experimental studies in vitro or in animal studies. We will discuss the potential and possible shortcomings of current approaches to biologically cure disc degeneration by gene therapy or tissue engineering. Despite the increasing number of studies examining the therapeutic potential of biological treatment strategies, a practicable solution to routinely cure disc degeneration might not be available in the near future. However, knowledge gained from these attempts might be applied in a foreseeable future to cure the low back pain that often accompanies disc degeneration and therefore be beneficial for the patien

Matrix metalloproteinase expression levels suggest distinct enzyme roles during lumbar disc herniation and degeneration

The disruption of the extracellular disc matrix is a major hallmark of disc degeneration. This has previously been shown to be associated with an up-regulation of major matrix metalloproteinase (MMP) expression and activity. However, until now hardly any data are available for MMP/TIMP regulation and thereby no concept exists as to which MMP/TIMP plays a major role in disc degeneration. The objective of this study was, therefore, to identify and quantify the putative up-regulation of MMPs/TIMPs on the mRNA and protein level and their activity in disc material in relation to clinical data and histological evidence for disc degeneration. A quantitative molecular analysis of the mRNA expression levels for the MMPs (MMPs-1, -2, -3, -7, -8, -9, -13) and the MMP inhibitors (TIMPs-1 and -2) was performed on 37 disc specimens obtained from symptomatic disc herniation or degeneration. In addition, disc specimens from patients without disc degeneration/herniation (=controls) were analyzed. Expression of MMPs-1, -2, -3, -7, -8, -9, -13 and TIMPs-1, -2 was analyzed using quantitative RT-PCR, normalized to the expression level of a house keeping gene (GAPDH). Gene expression patterns were correlated with MMP activity (in situ zymography), protein expression patterns (immunohistochemistry), degeneration score (routine histology) and clinical data. MMP-3 mRNA levels were consistently and substantially up-regulated in samples with histological evidence for disc degeneration. A similar but less pronounced up-regulation was observed for MMP-8. This up-regulation was paralleled by the expression of TIMP-1 and to a lesser extent TIMP-2. In general, these findings could be confirmed with regard to protein expression and enzyme activity. This study provides data on the gene and protein level, which highlights the key role of MMP-3 in the degenerative cascade leading to symptomatic disc degeneration and herniation. Control of the proteolytic activity of MMP-3 may, therefore, come into the focus when aiming to develop new treatment options for early disc degeneratio

Outcome assessment in low back pain: how low can you go?

The present study examined the psychometric characteristics of a "core-set” of six individual questions (on pain, function, symptom-specific well-being, work disability, social disability and satisfaction) for use in low back pain (LBP) outcome assessment. A questionnaire booklet was administered to 277 German-speaking LBP patients with a range of common diagnoses, before and 6months after surgical (N=187) or conservative (N=90) treatment. The core-set items were embedded in the booklet alongside validated ‘reference' questionnaires: Likert scales for back/leg pain; Roland and Morris disability scale; WHO Quality of Life scale; Psychological General Well-Being Index. A further 45 patients with chronic LBP completed the booklet twice in 1-2weeks. The minimal reliability (similar to Cronbach's alpha) for each core item was 0.42-0.78, increasing to 0.84 for a composite index score comprising all items plus an additional question on general well-being (‘quality of life'). Floor or ceiling effects of 20-50% were observed for some items before surgery (function, symptom-specific well-being) and some items after it (disability, function). The intraclass correlation coefficient (ICC) ("test-retest reliability”) was moderate to excellent (ICC, 0.67-0.95) for the individual core items and excellent (ICC, 0.91) for the composite index score. With the exception of "symptom-specific well-being”, the correlations between each core item and its corresponding reference questionnaire ("validity”) were between 0.61 and 0.79. Both the composite index and the individual items differentiated (P<0.001) between the severity of the back problem in surgical and conservative patients (validity). The composite index score had an effect size (sensitivity to change) of 0.95, which was larger than most of the reference questionnaires (0.47-1.01); for individual core items, the effect sizes were 0.52-0.87. The core items provide a simple, practical, reliable, valid and sensitive assessment of outcome in LBP patients. We recommend the widespread and consistent use of the core-set items and their composite score index to promote standardisation of outcome measurements in clinical trials, multicentre studies, routine quality management and surgical registry system

Longitudinal validation of the Fear-Avoidance Beliefs Questionnaire (FABQ) in a Swiss-German sample of low back pain patients

Work and activity-specific fear-avoidance beliefs have been identified as important predictor variables in relation to the development of, and treatment outcome for, chronic low back pain. The objective of this study was to provide a cross-cultural German adaptation of the Fear-Avoidance Beliefs Questionnaire (FABQ) and to investigate its psychometric properties (reliability, validity) and predictive power in a sample of Swiss-German low back pain patients. Questionnaires from 388 operatively and non-operatively treated patients were administered before and 6months after treatment to assess: socio-demographic data, disability (Roland and Morris), pain severity, fear-avoidance beliefs, depression (ZUNG) and heightened somatic awareness (MSPQ). Complete baseline and follow-up questionnaires were available from 255 participants. The corrected item-total correlations, coefficients of test-retest reliability and internal consistencies of the two scales of the questionnaire were highly satisfactory. In a confirmatory factor analysis (CFA), all items loaded on the appropriate factor with minor loadings on the other. Cross-sectional regression analysis with disability and work loss as the dependent variables yielded results that were highly comparable with those reported for the original version. Prognostic regression analysis replicated the findings for work loss. The cross-cultural German adaptation of the FABQ was very successful and yielded psychometric properties and predictive power of the scales similar to the original version. The inclusion of fear-avoidance beliefs as predictor variables in studies of low back pain is highly recommended, as they appear to have unique predictive power in analyses of disability and work los

Improved 6-year overall survival in AT/RT - results of the registry study Rhabdoid 2007

Atypical teratoid rhabdoid tumors (AT/RT) are characterized by mutations and subsequent inactivation of SMARCB1 (INI1, hSNF5), a predilection for very young children and an unfavorable outcome. The European Registry for rhabdoid tumors (EU-RHAB) was established to generate a common European database and to establish a standardized treatment regimen as the basis for phase I/II trials. Thus, genetic analyses, neuropathologic and radiologic diagnoses, and a consensus treatment regimen were prospectively evaluated. From 2005 to 2009, 31 patients with AT/RT from four countries were recruited into the registry study Rhabdoid 2007 and treated with systemic and intraventricular chemotherapy. Eight patients received high-dose chemotherapy, 23 radiotherapy, and 17 maintenance therapy. Reference evaluations were performed in 64% (genetic analyses, FISH, MLPA, sequencing) up to 97% (neuropathology, INI1 stain). Germ-line mutations (GLM) were detected in 6/21 patients. Prolonged overall survival was associated with age above 3years, radiotherapy and achievement of a complete remission. 6-year overall and event-free survival rates were 46% (+/- 0.10) and 45% (+/- 0.09), respectively. Serious adverse events and one treatment-related death due to insufficiency of a ventriculo peritoneal shunt (VP-shunt) and consecutive herniation were noted. Acquisition of standardized data including reference diagnosis and a standard treatment schedule improved data quality along with a survival benefit. Treatment was feasible with significant but manageable toxicity. Although our analysis is biased due to heterogeneous adherence to therapy, EU-RHAB provides the best available basis for phase I/II clinical trials

Expression and regulation of toll-like receptors (TLRs) in human intervertebral disc cells

Purpose: Although inflammatory processes play an essential role in painful intervertebral disc (IVD) degeneration, the underlying regulatory mechanisms are not well understood. This study was designed to investigate the expression, regulation and importance of specific toll-like receptors (TLRs)—which have been shown to play an essential role e.g. in osteoarthritis—during degenerative disc disease. Methods: The expression of TLRs in human IVDs was measured in isolated cells as well as in normal or degenerated IVD tissue. The role of IL-1β or TNF-α in regulating TLRs (expression/activation) as well as in regulating activity of down-stream pathways (NF-κB) and expression of inflammation-related genes (IL-6, IL-8, HSP60, HSP70, HMGB1) was analyzed. Results: Expression of TLR1/2/3/4/5/6/9/10 was detected in isolated human IVD cells, with TLR1/2/4/6 being dependent on the degree of IVD degeneration. Stimulation with IL-1β or TNF-α moderately increased TLR1/TLR4 mRNA expression (TNF-α only), and strongly increased TLR2 mRNA expression (IL-1β/TNF-α), with the latter being confirmed on the protein level. Stimulation with IL-1β, TNF-α or Pam3CSK4 (a TLR2-ligand) stimulated IL-6 and IL-8, which was inhibited by a TLR2 neutralizing antibody for Pam3CSK4; IL-1β and TNF-α caused NF-κB activation. HSP60, HSP70 and HMGB1 did not increase IL-6 or IL-8 and were not regulated by IL-1β/TNF-α. Conclusion: We provide evidence that several TLRs are expressed in human IVD cells, with TLR2 possibly playing the most crucial role. As TLRs mediate catabolic and inflammatory processes, increased levels of TLRs may lead to aggravated disc degeneration, chronic inflammation and pain development. Especially with the identification of more endogenous TLR ligands, targeting these receptors may hold therapeutic promise

Expression and regulation of toll-like receptors (TLRs) in human intervertebral disc cells

PURPOSE Although inflammatory processes play an essential role in painful intervertebral disc (IVD) degeneration, the underlying regulatory mechanisms are not well understood. This study was designed to investigate the expression, regulation and importance of specific toll-like receptors (TLRs)-which have been shown to play an essential role e.g. in osteoarthritis-during degenerative disc disease. METHODS The expression of TLRs in human IVDs was measured in isolated cells as well as in normal or degenerated IVD tissue. The role of IL-1β or TNF-α in regulating TLRs (expression/activation) as well as in regulating activity of down-stream pathways (NF-κB) and expression of inflammation-related genes (IL-6, IL-8, HSP60, HSP70, HMGB1) was analyzed. RESULTS Expression of TLR1/2/3/4/5/6/9/10 was detected in isolated human IVD cells, with TLR1/2/4/6 being dependent on the degree of IVD degeneration. Stimulation with IL-1β or TNF-α moderately increased TLR1/TLR4 mRNA expression (TNF-α only), and strongly increased TLR2 mRNA expression (IL-1β/TNF-α), with the latter being confirmed on the protein level. Stimulation with IL-1β, TNF-α or Pam3CSK4 (a TLR2-ligand) stimulated IL-6 and IL-8, which was inhibited by a TLR2 neutralizing antibody for Pam3CSK4; IL-1β and TNF-α caused NF-κB activation. HSP60, HSP70 and HMGB1 did not increase IL-6 or IL-8 and were not regulated by IL-1β/TNF-α. CONCLUSION We provide evidence that several TLRs are expressed in human IVD cells, with TLR2 possibly playing the most crucial role. As TLRs mediate catabolic and inflammatory processes, increased levels of TLRs may lead to aggravated disc degeneration, chronic inflammation and pain development. Especially with the identification of more endogenous TLR ligands, targeting these receptors may hold therapeutic promise