Masaomi Yamashita

Associations between proinflammatory cytokines in the synovial fluid and radiographic grading and pain-related scores in 47 consecutive patients with osteoarthritis of the knee

BackgroundOne of the sources of knee pain in osteoarthritis (OA) is believed to be related to local chronic inflammation of the knee joints, which involves the production of inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin (IL)-6, and nerve growth factor (NGF) in the synovial membrane, and these cytokines are believed to promote pathological OA. In the present study, correlations between proinflammatory cytokines in knee synovial fluid and radiographic changes and functional scores and pain scores among OA patients were examined.MethodsSynovial fluid was harvested from the knees of 47 consecutive OA patients, and the levels of TNFα, IL-6, and NGF were measured using enzyme-linked immunosorbent assays. Osteoarthritic knees were classified using Kellgren-Lawrence (KL) grading (1-4). The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) was used to assess self-reported physical function, pain, and stiffness.ResultsTNFα and IL-6 were detectable in knee synovial, whereas NGF was not. TNFα was not correlated with the KL grade, whereas IL-6 had a significantly negative correlation. We observed differences in the correlations between TNFα and IL-6 with WOMAC scores and their subscales (pain, stiffness, and physical function). TNFα exhibited a significant correlation with the total score and its 3 subscales, whereas IL-6 exhibited a moderately significant negative correlation only with the subscale of stiffness.ConclusionsThe present study demonstrated that the concentrations of proinflammatory cytokines are correlated with KL grades and WOMAC scores in patients with knee OA. Although TNFα did not have a significant correlation with the radiographic grading, it was significantly associated with the WOMAC score. IL-6 had a significant negative correlation with the KL grading, whereas it had only a weakly significant correlation with the subscore of stiffness. The results suggest that these cytokines play a role in the pathogenesis of synovitis in osteoarthritic knees in different ways: TNFα is correlated with pain, whereas IL-6 is correlated with joint function.

Existence of a Neuropathic Pain Component in Patients with Osteoarthritis of the Knee

Purpose Pain from osteoarthritis (OA) is generally classified as nociceptive (inflammatory). Animal models of knee OA have shown that sensory nerve fibers innervating the knee are significantly damaged with destruction of subchondral bone junction, and induce neuropathic pain (NP). Our objective was to examine NP in the knees of OA patients using painDETECT (an NP questionnaire) and to evaluate the relationship between NP, pain intensity, and stage of OA. Materials and Methods Ninety-two knee OA patients were evaluated in this study. Pain scores using Visual Analogue Scales (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), painDETECT, duration of symptoms, severity of OA using the Kellgren-Lawrence (KL) system, and amount of joint fluid were evaluated and compared using a Spearmans correlation coefficient by rank test. Results Our study identified at least 5.4% of our knee OA patients as likely to have NP and 15.2% as possibly having NP. The painDETECT score was significantly correlated with the VAS and WOMAC pain severity. Compared with the painDETECT score, there was a tendency for positive correlation with the KL grade, and tendency for negative correlation with the existence and amount of joint fluid, but these correlations were not significant. Conclusion PainDETECT scores classified 5.4% of pain from knee OA as NP. NP tended to be seen in patients with less joint fluid and increased KL grade, both of which corresponded to late stages of OA. It is important to consider the existence of NP in the treatment of knee OA pain.

Tumor Necrosis Factor-alpha in the Nucleus Pulposus Mediates Radicular Pain, but Not Increase of Inflammatory Peptide, Associated With Nerve Damage in Mice

Study Design. Changes in behavior and the immunohistochemistry of dorsal root ganglion (DRG) neurons were examined using a mouse model of radicular pain. Objective. To examine the effects of TNF-α in the nucleus pulposus (NP) on nerve roots. Summary of Background Data. Radicular pain is induced by mechanical compression and inflammation of nerve roots. Many authors have reported that following disc herniation, producing TNF-α plays a major role in neuropathic pain. Their findings suggest that TNF-α contained in the NP is significant in the development of pain and nerve root degeneration, but it has not been clearly demonstrated. Methods. Wild-type NPs or TNF-KO NPs, which were harvested from C57BL/6 mice (wild-type NP) or TNF-knock-out mice (TNF-KO NP), were applied to the left sciatic nerves of 30 wild-type mice, and the nerves were pinched. Production of hind paw mechanical allodynia, activating transcription factor 3, and calcitonin gene- related peptide (CGRP) were assessed. Results. Animals receiving a NP application demonstrated significant mechanical allodynia compared to the pinch-only and the control groups. The degree of mechanical allodynia was greater in the wild-type than in the TNF-KO group. The number of activating transcription factor 3 immunoreactive neurons was significantly higher in the wild-type than in the TNF-KO group. The number of CGRP-immunoreactive neurons was higher in the wild-type and TNF-KO than in the control groups. However, no significant difference in activity was observed between both CGRP positive groups. Conclusion. In this study TNF-α contained in the NP was important for the production of radicular pain accompanied by long-lasting degeneration of DRG neurons. However, other cytokines in the NP and nerve compression may also play important roles in pain transmission. In this model system, TNF-α in the NP appears to mediate pain, but not cause an increase in CGRP in the DRG neurons.

Diffusion magnetic resonance imaging to differentiate degenerative from infectious endplate abnormalities in the lumbar spine.

Study Design. A retrospective observational study of healthy volunteers and patients with degenerative and infectious endplate abnormalities in the lumbar spine. Objectives. Our purpose was to evaluate the usefulness of diffusion-weighted imaging (DWI) for the differentiation of degenerative and infectious endplate abnormalities using 1.5-T magnetic resonance imaging (MRI). Summary of Background Data. DWI can provide valuable structural information about tissues that may be useful for clinical applications in differentiation between degenerative and infectious endplate abnormalities. Methods. Sixteen consecutive patients with endplate abnormalities that was detected by MRI of the lumbar spine, and 15 healthy volunteers were studied. DWI was performed using whole-body imaging with background body signal suppression with a b value of 1000 s/mm2. Apparent diffusion coefficient values of normal and abnormal vertebral bone marrow were calculated. Results. Twenty-nine vertebral abnormalities were found in 16 patients. Nine vertebral abnormalities in 5 patients were because of infections and 20 vertebral abnormalities in 11 patients were because of degenerative changes; 7 levels were classified as Modic type 1, 7 levels as type 2, and 6 levels as type 3. DWI showed hyperintensity in all patients with infection, similar to that used in positron emission tomography, but not in the intervertebral spaces of any patients with degenerative disease. Apparent diffusion coefficient values of infectious bone marrowwere significantly higher than normal and degenerative bone marrow. Conclusion. DWI is useful for differentiation of degenerative and infectious endplate abnormalities. Moreover, MRI is widely used clinically because of the lack of ionizing radiation, low cost, and fast imaging time as compared with positron emission tomography. Therefore, DWI has the potential to be used as a screening tool.

TNF-alpha in nucleus pulposus induces sensory nerve growth: a study of the mechanism of discogenic low back pain using TNF-alpha-deficient mice.

Study Design. We used retrograde neurotracing with fluoro-gold to investigate the relationship between tumor necrosis factor (TNF-á) and nerve growth into the nucleus pulposus (NP) of wild-type and TNF-&agr;-deficient mice. Objective. To clarify mechanisms underlying nerve growth into the NP and the role of TNF-á in this process. Summary of Background Data. Degeneration of lumbar intervertebral discs is a cause of low back pain. Pathogenesis may involve sensory nerve ingrowth into the inner layers and NP of degenerating discs. We hypothesized that TNF-á in the NP is a major inducer of nerve ingrowth and investigated this hypothesis in vivo using wild-type and TNF-á-deficient mice. Methods. NP was harvested at the L4/5 level from 10 wild-type and 10 TNF-deficient mice. These 20 samples of wild-type NP or TNF-deficient NP were mixed with fluoro-gold and injected into the left quadriceps muscle of 20 other wild-type mice (1 sample per mouse). Five control mice underwent sham operations in which they received similar injections of NP-free fluoro-gold into their left quadriceps muscles to detect whether neurons innervating the muscle establish contact with injected NP. Seven and 14 days after surgery, left L4 dorsal root ganglions were removed and incubated with antibodies against growth-associated protein 43 (GAP43), a marker of axonal growth. We evaluated fluoro-gold-labeled and GAP43-immunoreactive dorsal root ganglions neurons. Results. Within the set of fluoro-gold-labeled neurons, 10% were positive for GAP43 in sham-operated animals, 22% positive in the TNF-deficient NP group, and 38% positive in the wild-type NP group. These intergroup differences in the percentage of GAP43-positive neurons were statistically significant (sham vs. TNF-deficient NP group: P = 0.009; TNF-deficient NP group vs wild-type NP group: P = 0.026). Conclusion. The percentage of fluoro-gold–labeled GAP43-immunoreactive neurons significantly increased after injections of NP harvested from both mouse types. Furthermore, the percentage of GAP43-immunoreactive neurons was significantly higher in mice receiving wild-type NP compared with mice receiving TNF-deficient NP. These findings suggest that TNF-&agr; acts as an inducer of axonal growth into degenerated discs, as evidenced by decreased GAP-43 immunoreactivity in mice receiving TNF-deficient NP injections and even lower GAP-43 immunoreactivity in control mice receiving NP-free fluoro-gold injections.

Existence of nerve growth factor receptors, tyrosine kinase a and p75 neurotrophin receptors in intervertebral discs and on dorsal root ganglion neurons innervating intervertebral discs in rats.

Study Design. We evaluated 2 types of nerve growth factor (NGF) receptors on dorsal root ganglion (DRG) cells and nerve fibers innervating rat lumbar intervertebral discs. Objective. To examine the NGF receptors, tyrosine kinase A (TrkA) and p75 neurotrophin receptor (p75NTR) on DRG cells and nerve fibers innervating rat lumbar intervertebral discs using immunohistochemistry and a retrograde neurotracing method. Summary of Background Data. Nerve innervation of intervertebral discs is thought to be a pathology of discogenic low back pain. NGF is also important for mediating inflammatory pain from intervertebral discs via the high affinity receptor, TrkA. Recent research has also revealed that the low affinity NGF receptor, p75NTR plays an important role in inflammatory pain. However, the presence of TrkA and p75NTR-immunoreactive (NTR-IR) DRG neurons innervating the rat L5/6 intervertebral disc, and p75NTR-IR nerve fibers in rat intervertebral discs, has not been explored. Methods. The Fluoro-gold neurotracer was applied to rat L5/6 intervertebral discs to determine the DRG neurons innervating the discs (n = 20). Fourteen days after surgery, bilateral DRG from the L1–L6 levels were harvested, sectioned, and immunostained for TrkA and p75NTR. The percentages of TrkA and p75NTR-IR DRG neurons were counted, and p75NTR-IR nerve fibers in L5/6 discs evaluated. Results. p75NTR-IR nerve fibers were found in superficial layers in the annulus fibrosus in L5/6 intervertebral discs. Fluoro-gold-labeled neurons innervating the L5/6 discs were distributed throughout DRG from the L1–L6 levels. The percentage of TrkA-immunoreactive (TrkA-IR) neurons was 75.1% ± 3.9% (mean ± SE) and that of p75NTR-IR neurons was 75.8% ± 5.1%. These percentages were similar for each level. Conclusion. Rat L5/6 intervertebral discs were innervated by multisegmental levels of DRG. Most DRG neurons innervating the discs were positive for 2 types of NGF receptors.

Surgical versus nonsurgical treatment of selected patients with discogenic low back pain: a small-sized randomized trial.

Low back pain (LBP) is a common clinical problem and is of major socioeconomic importance. Although any of the spinal structures (intervertebral discs, facet joints, vertebral bodies, ligaments, and muscles) may be a source of LBP, the most likely cause is a lumbar intervertebral disc.1–3 Many autho

Evaluation of low back pain using the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire for lumbar spinal disease in a multicenter study: differences in scores based on age, sex, and type of disease

BackgroundThe Japanese Orthopaedic Association (JOA) has investigated the JOA Back Pain Evaluation Questionnaire (JOABPEQ) to evaluate several aspects of low back pain in patients. The score includes five categories (25 items) selected from the Roland Morris Disability Questionnaire and Short Form 36, and a visual analogue scale. Japanese physicians have recently used these scores to evaluate back pain; however, the efficacy has not been fully explored in large-scale studies. In the current study, we used the JOABPEQ to evaluate lumbar spinal disease in 555 patients (with lumbar disc herniation, lumbar spinal stenosis, and lumbar disc degeneration/spondylosis) in multiple spine centers and compared the results based on age, sex, and type of disease.MethodsA total of 555 patients who had low back or leg pain were selected in 22 hospitals in Chiba Prefecture. Spine surgeons diagnosed their disease type based on symptoms, physical examination, radiography images, and magnetic resonance imaging. In all, 486 patients were diagnosed with spinal stenosis (239 patients), disc degeneration/spondylosis (143 patients), or disc herniation (104 patients). The other 69 patients were diagnosed with spondylolysis (16 patients) or other diseases (53 patients). The pain score in all patients was evaluated using the JOABPEQ (from 0 to 100, with 0 indicating the worst pain).ResultsThe age of the patients was 56.1 ± 13.3 years (mean ± SD); the age of patients in the disc herniation and disc degeneration/spondylosis group was significantly lower than that in the spinal stenosis group. The average JOABPEQ scores in all patients were, for low back pain, 47.1; lumbar function, 53.6; walking ability, 54.8; social life function, 48.7; and mental health, 48.3. The low back pain score in men was significantly worse than that in women. In contrast, the mental health score in women was significantly higher than that in men. The low back pain score in patients <40 years old and the walking ability score in patients >65 years old were significantly lower than those scores in other patients. Based on the disease type, low back pain, lumbar function, social life function, and mental health scores for patients with disc herniation were significantly worse than for those with spinal stenosis.ConclusionJOABPEQ scores were evaluated for several lumbar diseases. The average of five categories of JOABPEQ scores in all patients was similarly distributed. However, the average scores in the five categories were significantly different depending on age, sex, and type of disease. Compared with prior mass data (baseline data on the observational cohort of the Spine Patient Outcomes Research Trial in the United States), many data were similar based on the type of disease in the current study. Furthermore, the JOABPEQ is easy to use compared with the SF-36. Hence, we concluded that the JOABPEQ could be used worldwide as a tool for evaluating low back pain.

Inhibiting Nerve Growth Factor or Its Receptors Downregulates Calcitonin Gene-Related Peptide Expression in Rat Lumbar Dorsal Root Ganglia Innervating injured Intervertebral Discs

Nerve growth factor (NGF) and its dual structurally unrelated receptors, tropomyosin‐related kinase A (TrkA) or p75 neurotrophin receptor (p75NTR), cause the pathogenesis of discogenic pain. To investigate the sensory innervation of injured rat lumbar intervertebral disc (IVD), we examined the expression of neuropeptides such as calcitonin gene‐related peptide (CGRP) at dorsal root ganglia (DRG) by inhibiting NGF or its dual receptors. Sprague–Dawley rats with multiply punctured L5–L6 IVD were used. Six experimental groups were prepared: naïve, sham control, and four agent‐treated groups with punctured IVD (vehicle, anti‐NGF antibody, anti‐TrkA antibody, and anti‐p75NTR antibody). Retrograde neurotracer Fluoro‐Gold (FG) was applied together except for the naïve group. Their lumbar DRG were harvested and immunolabeled for CGRP. FG‐labeled DRG neurons were most prevalent at L1 and L2 DRG, and the proportion of FG‐labeled CGRP‐immunoreactive DRG neurons in the vehicle group was significantly elevated (p < 0.05) compared with the sham group, while those of antibody‐treated groups, especially in the anti‐p75NTR group, significantly decreased compared with the vehicle group (p < 0.05). Direct intradiscal application of antibody to NGF or its receptors suppressed CGRP expression, and p75NTR antagonism induced the most profound suppression.

The effects of risedronate and exercise on osteoporotic lumbar rat vertebrae and their sensory innervation.

Study Design. Investigation of sensory innervation of rat osteoporotic lumbar vertebrae using in vitro and in vivo models. Objective. To investigate (1) sensory innervation of osteoporotic rat vertebrae, (2) effects of risedronate on sensory neurons, (3) effects of osteoporosis treatment on bone mineral densities (BMDs) and the sensory innervation. Summary of Background Data. Osteoporotic patients without fractures sometimes experience vague low back pain of unknown origin. The mechanisms of osteoporosis treatments against the pain are unclear. Methods. (1) The expression of calcitonin gene-related peptide (CGRP) immunoreactive (-ir) or transient receptor potential vanilloid 1 (TRPV1)-ir nerve fibers in vertebrae and dorsal root ganglions (DRG) innervating L3 vertebrae of Sprague Dawley rats labeled with neurotracer were examined in control, sham, and ovariectomized (OVX) rats. (2) Cultured rat neonate DRG neurons in media containing different concentrations of risedronate were immunostained for CGRP, and we measured its activity using axonal length and proportion of CGRP-ir neurons. (3) BMDs and CGRP expression in DRG neurons innervating L3 vertebrae were examined in the following 5 groups: sham (treated with saline), OVX (saline), OVX+EXE (treadmill exercise), OVX+RIS (risedronate), and OVX+RIS+EXE (risedronate and exercise). Results. (1) A few CGRP-ir or TRPV1-ir nerve fibers were observed in the bone marrow. CGRP or TRPV1 expression in DRG was elevated in the OVX group (P < 0.05). (2) The axonal length and proportion of CGRP-ir neurons were dose-dependently suppressed (P < 0.05). (3) BMDs improved and the CGRP expression decreased in the risedronate-treated groups (P < 0.05), especially in the OVX+RIS+EXE group. Conclusion. Sensory innervation of osteoporotic rat vertebrae showed increased expression of CGRP and TRPV1 in DRG neurons. Risedronate suppressed activity of CGRP-ir neurons in vitro, improved BMD, and decreased CGRP expression, especially together with exercise in vivo.