Investigating the Potential of Multilineage Differentiating Stress-Enduring Cells for Osteochondral Healing.

OBJECTIVE: Multilineage differentiating stress-enduring (Muse) cells, a pluripotent stem cell subset of mesenchymal stem cells (MSCs), have shown promise for various tissue repairs due to their stress tolerance and multipotent capabilities. We aimed to investigate the differentiation potential in vitro, the dynamics in vivo, and the reparative contribution of Muse cells to osteochondral lesions. DESIGN: Labeled MSCs were cultured and sorted into Muse and non-Muse (MSCs without Muse cells) groups. These cells were then formed into spheroids, and chondrogenic differentiation was assessed in vitro. Twenty-one immunocompromised mice were used as the in vivo models of osteochondral lesions. Live imaging, macroscopic evaluation, and histological and immunohistochemical analyses were conducted at the 4- and 8-week time points. RESULTS: Muse cell spheroids were formed, which were larger and stained more intensely with toluidine blue than non-Muse spheroids, indicating better chondrogenic differentiation. Live imaging confirmed luminescence in all 4-week model knees, but only in a few knees at 8 weeks, suggesting cell persistence. Macroscopically and histologically, no significant differences were observed between the Muse and non-Muse groups at 4 and 8 weeks; however, both groups showed better cartilage repair than that of the vehicle group at 8 weeks. No collagen type II generation was observed in the repaired tissues. CONCLUSION: The implantation of the spheroids of Muse and non-Muse cells resulted in better healing of osteochondral lesions than that of the controls, and Muse cells had a higher chondrogenic differentiation potential in vitro than non-Muse cells.

Number of intra-operative cyclic knee motion required to achieve stable graft tension in anterior cruciate ligament reconstruction; a prospective clinical study.

BACKGROUND: Applying pretension by cyclic knee motion immediately before graft fixation in anterior cruciate ligament (ACL) reconstruction surgery decreases graft elongation during the postoperative course. However, the expected change in graft tension caused by cyclic knee motion remains unclear. We measured graft tension changes caused by cyclic knee motion during double-bundle ACL reconstruction. METHODS: We included 39 patients undergoing primary anatomical double-bundle ACL reconstruction with autologous hamstrings as graft sources, at multiple centers between February 2021 and August 2022. After securing the anteromedial (AM) and posterolateral (PL) bundle grafts to the femoral cortex, they were initially tensioned to 40 N per bundle. After 10 cycles of knee extension and flexion motion, ranging from 0 to 90-110°, tension was re-measured and re-tensioned to 40 N if the graft tension had decreased. This was repeated thrice for 10 cycles on each graft. Every 10 cycles, we recorded graft tension changes (ΔGT) and compared the mean ΔGT in the AM and PL bundles. Furthermore, we assessed relationships between total ΔGT in each bundle, age, sex, and graft diameter. RESULTS: Twenty-five women and 14 men with a mean age of 27.4 ± 12.4 years were included. The mean ΔGT in AM and PL bundles after every 10 cycles were 6.6 ± 3.7 N, 3.0 ± 2.3 N, 1.4 ± 1.5 N, and 9.9 ± 3.8 N, 4.9 ± 2.6 N, and 2.5 ± 1.9 N, respectively. There were significant differences in ΔGT in both bundles after every 10 cycles (p < 0.01). ΔGT in the AM bundle was significantly lower than in the PM bundle at the same number of cycles (p < 0.01). No correlation was observed between ΔGT in either bundle and age, sex, or graft diameter. CONCLUSIONS: The initially applied graft tension decreased by intra-operative cyclic knee movement, and the changes in graft tension decreased after retention and repeated cycles. Three sets of 10 cycles knee motion may avoid initial tension loss of the hamstring autograft in the early phase after double-bundle ACL reconstruction.

Lateral meniscal injury without medial meniscal injury indicates the existence of the Segond fracture in ACL-deficient knees.

Background/Objective: The purpose of this study was to find factors indicating the occurrence of the Segond fracture, a specific type of anterolateral ligament injury. Methods: From January 2015 to December 2017, we retrospectively reviewed the medical records of patients diagnosed with acute anterior cruciate ligament (ACL) injury who underwent reconstruction within 90 days of injury. Diagnosis of the Segond fracture was determined either by magnetic resonance imaging or plain radiographs. Factors examined were: age at surgery, sex, body mass index (kg/m2), status of menisci, and activities led to ACL injury. After univariate screening, multivariate logistic regression analyses were performed. Patients were divided into four groups based on the presence of lateral meniscal (LM) and/or medial meniscal (MM) injuries and compared with respect to the occurrence of Segond fractures. Results: A total of 375 patients were included (163 males, 212 females), with mean age 25.8 years old. Among them, 22 of 375 (5.9 %) had a Segond fracture. We identified injured lateral menisci (adjusted odds ratio (aOR), 3.029; 95 % Confidence Interval (CI), 1.206-7.609; P = 0.018), intact medial menisci (aOR, 0.229; 95 % CI, 0.065-0.810; P = 0.022), and higher body mass index (aOR, 1.102; 95 % CI, 1.008-1.205; P = 0.034) as factors indicative of the occurrence of Segond fracture. LM injury without MM injury suggested the existence of a Segond fracture. Conclusion: LM injury without a MM injury indicated the occurrence of a Segond fracture. Higher body mass index also increased the risk for Segond fracture occurrence.

Differential Associations of Sports Participation With Self-Rated Health and Depressive Symptoms Among Japanese Adolescents.

INTRODUCTION: We aimed to evaluate the associations of sports participation with self-rated health and depressive symptoms in a nationally representative sample of Japanese adolescents. METHODS: A questionnaire survey was conducted with 1,658 adolescents aged between 12 and 21 years. Sports participation levels were divided into high-frequency, moderate-frequency, low-frequency, and no-participation groups. Self-rated health was evaluated using a four-grade scale. Depressive symptoms were assessed using the Japanese version of the Patient Health Questionnaire-8. Other lifestyle behaviors were also surveyed. The associations of sports participation with self-rated health and depressive symptoms were examined using multiple logistic regression analysis. RESULTS: The participants in the high- (odds ratio (OR), 0.45) and moderate-frequency (OR, 0.46) groups were less likely to self-report poor health than those in the non-participation group. By contrast, a U-shaped association was found between sports participation and depression, in which the participants in the moderate-frequency group (OR, 0.52) were less likely to have depressive symptoms. The OR for the high- (0.89) and low-frequency (0.91) groups were not significant. Furthermore, eating regular breakfasts, six or more days/week, and having shorter screen times of less than two hours/day were negatively associated with poor self-reported health and depressive symptoms. CONCLUSION: Moderate- to high-frequency sports activities are associated with a reduced risk of poor self-rated health among Japanese adolescents. However, only moderate-frequency activities were associated with a reduced risk of depression. Participation in optimal sports activities may effectively lower the risk of poor health in adolescents.

Referential values for lower limb flexibility in healthy children and adolescents in Japan: A five-year cross-sectional study.

BACKGROUND: Lower limb flexibility (LLF) is an essential motor function. However, assessing LLF during adolescence is difficult because of the influence of marked physical changes. We, therefore, assessed LLF and investigated the relationship between LLF and sex and age in healthy children and adolescents. METHODS: We conducted a five-year cross-sectional study with students aged 8-14 years at a single school in Japan. We evaluated the heel-buttock distance (HBD), straight leg raising angle (SLRA), and dorsiflexion angle of the ankle joint (DFA) at the beginning of each year. We conducted a comparative analysis on the performance of the HBD, SLRA, and DFA techniques, stratified by both sex and age. The statistical significance of observed differences was assessed through the application of Mann-Whitney U and Kruskal-Wallis tests. Furthermore, we analyzed the effects of sex, age, height, and weight on LLF using a multivariable linear regression model. RESULTS: Of the 4221 initial study participants, 3370 were analyzed. Mean HBD, SLRA, and DFA values were 1.6 cm, 77.0°, and 15.7°, respectively. Girls showed significantly higher HBD and lower SLRA and DFA values than boys and 14-year-olds (p < 0.01). Median HBD value for girls was 0 cm, whereas for boys, it exceeded 0 cm after age 13. The median SLRA value for girls was 80-85°, while for boys, it was 70-75°. The median DFA value for girls was 15-19°, and for boys, it was 12-15°. A multivariable linear regression model indicated that boys had significantly greater tightness than girls (p < 0.01). CONCLUSIONS: The reference values of HBD, SLRA, and DFA differed according to age and sex. Furthermore, we showed that sex differences were significantly associated with LLF. Data in this study provide the reference value for assessing LLF in children and adolescents.

Foot morphology and correlation with lower extremity pain in Japanese children: A cross-sectional study of the foot posture Index-6.

BACKGROUND: Abnormal foot morphology in children and adolescents is a possible risk factor for lower extremity pain. Foot posture index-6 (FPI-6) is a valid and reliable tool to assess foot morphology. However, the normative data on the age distribution for FPI-6 in Asian children and adolescents are still minimal. Further, the correlation of FPI-6 with lower extremity pain is poorly understood. We aimed to investigate the normative distribution for FPI-6 and the relationship between FPI-6 scores and knee and heel pain in Japanese children. METHODS: We included 2569 Japanese children, aged 9-15 years, at a single school from 2016 to 2018. We summarized the age distribution of children and their mean bilateral FPI-6 scores. Additionally, we assessed the tenderness at the apophysis or tendon insertions at the knee and heel. We performed a cross-sectional analysis to investigate the correlations between FPI-6 scores and sex, age, and knee and heel pain for the data obtained each year. RESULTS: The mean FPI-6 score was 3.1 ± 2.4, 3.4 ± 2.0, and 3.2 ± 1.9 for the left foot and 3.0 ± 2.4, 3.2 ± 1.9, and 3.1 ± 1.9 for the right foot in 2016, 2017, and 2018, respectively. Boys tended to have higher scores than girls, and the FPI-6 score of the left foot was significantly higher than that of the right foot (p < 0.05). There was no correlation between FPI-6 scores and knee and heel pain. CONCLUSION: Children and adolescents between 9 and 15 years of age have neutral to slightly pronated foot morphology and an average FPI-6 score of 3.0-3.4. In addition, there was no relationship between foot morphology and knee and heel pain. This normative distribution for FPI-6 in Japanese children could serve as a reference value for future research and clinical evaluation.

The influence of COVID-19 pandemic on the incidence of knee pain and physical activity level in children and adolescents in Japan: A prospective observation study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a profound impact on children's lifestyles. Some studies have reported psychological changes in children after the pandemic, but information on musculoskeletal problems is scarce. This study aimed to investigate the incidence of knee pain and changes in physical activity after the spread of COVID-19 among elementary and junior high school students in Japan. METHODS: Knee pain and amount of physical activity were recorded on a monthly basis between August 2019 and February 2021 in children aged 8-14 years using a self-administered questionnaire. The amount of physical activity was scored using the Hospital for Special Surgery Pediatric Functional Activity Brief Scale (HSS Pedi-FABS). The period until February 2020 was defined as "Before pandemic," and the period from March 2020 was defined as "After pandemic." The incidences of knee pain and HSS Pedi-FABS scores before and after the COVID-19 pandemic were compared. Additionally, we compared the prevalence of knee pain and HSS Pedi-FABS scores according to sex and age. RESULTS: We enrolled 886 and 881 participants before and after the pandemic, respectively. The prevalence of knee pain among the participants before and after the pandemic was 6.7% and 7.9%, respectively (p = 0.032). The mean HSS Pedi-FABS scores before and after the pandemic were 14.8 and 14.5, respectively (p = 0.005). Participants aged 14 years had a significantly lower incidence of knee pain (p = 0.013) and significantly higher HSS Pedi-FABS scores (p < 0.001) after the spread of COVID-19. CONCLUSIONS: In elementary and junior high school students, increase in the incidence of knee pain and decrease in the amount of physical activity after the spread of COVID-19 were observed.

Nuclear receptor subfamily 1 group D member 1 in the pathology of obesity-induced osteoarthritis progression.

Mechanical overload and chemical factors are both related to obesity-induced progression of knee osteoarthritis. The circadian rhythm is related to the development of metabolic syndrome and the progression of osteoarthritis, and the core clock genes nuclear receptor subfamily 1 group D member 1 (NR1D1) and brain and muscle arnt-like protein 1 (BMAL1) are dysregulated in cartilage from patients with osteoarthritis. Here, we focused on NR1D1 and investigated osteoarthritis-related changes and gene expression in a mouse model of diet-induced obesity. A high-fat diet was provided to C57BL6/J mice, and changes in body weight, blood lipids, and gene expression were investigated. Destabilization of the medial meniscus or sham surgery was performed on mice fed a high-fat diet or normal diet, and histological osteoarthritis-related changes and NR1D1 expression were investigated. The effects of the NR1D1 agonist SR9009 were also assessed. Mice fed a high-fat diet developed significant obesity and dyslipidemia. Nr1d1 and Bmal1 gene expression levels decreased in the liver and knee joints. Moreover, increased osteoarthritis progression and decreased NR1D1 protein expression were observed in high-fat diet-fed mice after surgical osteoarthritis induction. SR9009 decreased the progression of obesity, dyslipidemia, and osteoarthritis. Overall, obesity and dyslipidemia induced by the high-fat diet led to osteoarthritis progression and decreased NR1D1 expression. Thus, NR1D1 may play an important role in obesity-induced osteoarthritis.

Risk factors for the occurrence and protraction of patellar and patellar tendon pain in children and adolescents: a prospective cohort study of 3 years.

BACKGROUND: Patellar and patellar tendon pain is a common limitation to children's participation in social and physical activities. Some factors have been implicated in the occurrence and protraction of knee pain, but the causal relationship is unknown. The purpose of this study was to investigate whether participants' physical characteristics and activity level are risk factors for the occurrence and protraction of patellar and patellar tendon pain in children and adolescents. METHODS: A three-year prospective cohort study was conducted with healthy students who were aged 8-14 years old, in Japan. Height, weight, heel-buttock distance, straight leg raising angle, and dorsiflexion angle of the ankle joint were collected as individual physical factors at the beginning of each year. The presence of self-reported patellar and patellar tendon pain and the Hospital for Special Surgery Pediatric Functional Activity Brief Scale (HSS Pedi-FABS) was collected every month. Protraction was defined as either (1) pain lasting for more than three continuous months or (2) recurrent pain after more than three months of complete recovery. Participants who did not have any pain at the beginning of the observation period were included in the analysis. We analyzed the odds ratio (OR) of pain occurrence within a year of registration and protraction throughout the study period for all physical factors and HSS Pedi-FABS. RESULTS: We included 1133 participants in the analysis and 252 participants developed knee pain within a year. 34.8% of participants with pain experienced protraction during the follow-up period. A high HSS Pedi-FABS significantly predicted knee pain occurrence (OR 1.03, 95% confidence interval [CI] 1.01-1.05) and protraction (OR 1.03, 95% CI 1.00-1.05). In addition, younger children and girls were at a significantly higher risk of patellar and patellar tendon pain protraction (age, OR 0.81, 95% CI, 0.73-0.90; sex, OR 1.69, 95% CI, 1.09-2.64). Other physical factors did not significantly predict the occurrence or protraction of knee pain. CONCLUSIONS: This study showed that a greater physical activity level was a risk factor for the occurrence and protraction of patellar and patellar tendon pain in childhood. In addition, younger age and female sex predicted higher risk of protraction of pain.

Detecting Distal Radial Fractures from Wrist Radiographs Using a Deep Convolutional Neural Network with an Accuracy Comparable to Hand Orthopedic Surgeons.

In recent years, fracture image diagnosis using a convolutional neural network (CNN) has been reported. The purpose of the present study was to evaluate the ability of CNN to diagnose distal radius fractures (DRFs) using frontal and lateral wrist radiographs. We included 503 cases of DRF diagnosed by plain radiographs and 289 cases without fracture. We implemented the CNN model using Keras and Tensorflow. Frontal and lateral views of wrist radiographs were manually cropped and trained separately. Fine-tuning was performed using EfficientNets. The diagnostic ability of CNN was evaluated using 150 images with and without fractures from anteroposterior and lateral radiographs. The CNN model diagnosed DRF based on three views: frontal view, lateral view, and both frontal and lateral view. We determined the sensitivity, specificity, and accuracy of the CNN model, plotted a receiver operating characteristic (ROC) curve, and calculated the area under the ROC curve (AUC). We further compared performances between the CNN and three hand orthopedic surgeons. EfficientNet-B2 in the frontal view and EfficientNet-B4 in the lateral view showed highest accuracy on the validation dataset, and these models were used for combined views. The accuracy, sensitivity, and specificity of the CNN based on both anteroposterior and lateral radiographs were 99.3, 98.7, and 100, respectively. The accuracy of the CNN was equal to or better than that of three orthopedic surgeons. The AUC of the CNN on the combined views was 0.993. The CNN model exhibited high accuracy in the diagnosis of distal radius fracture with a plain radiograph.

Effect of Systemic Administration of Granulocyte Colony-Stimulating Factor on a Chronic Partial-Thickness Cartilage Defect in a Rabbit Knee Joint.

OBJECTIVE: Cartilage lesions in the knee joint can lead to joint mechanics changes and cause knee pain. Bone marrow stimulation (BMS) promotes cartilage regeneration by perforating the subchondral bone just below the injury and inducing bone marrow cells. This study aimed to investigate whether systemic administration of granulocyte colony-stimulating factor (G-CSF) with BMS improves repair of chronic partial-thickness cartilage defects (PTCDs). DESIGN: Eighteen 6-month-old New Zealand white rabbits were divided into 3 groups: control (C, n = 6), BMS alone (n = 6), and BMS + G-CSF (n = 6). Partial cartilage defects with 5 mm diameter were created in the trochlear region of both knees; after 4 weeks, the BMS alone and BMS + G-CSF groups underwent BMS; G-CSF (50 µg/kg) or saline was administered subcutaneously for 5 days starting from 3 days before BMS. At 8 and 16 weeks after cartilage defect creation, the area of cartilage defects was macroscopically and histologically evaluated. RESULTS: International Cartilage Repair Society (ICRS) grades for macroscopic assessment were 0, 0.7, and 0.7 at 8 weeks and 0, 1.2, and 1.3 at 16 weeks in the C, BMS, and BMS + G-CSF groups, respectively. Wakitani scores for histological assessment were 9.8, 8.7, and 8.2 at 8 weeks and 9.5, 9, and 8.2 at 16 weeks in the C, BMS, and BMS + G-CSF groups, respectively. The BMS + G-CSF group showed significantly more repair than the C group, but there was no difference from the BMS group. CONCLUSIONS: The effect of BMS and G-CSF on chronic PTCDs in mature rabbit knees was limited.

Lumbopelvic Fixation for Sacral Insufficiency Fracture Presenting with Sphincter Dysfunction.

Sacral insufficiency fractures (SIFs) are common in the elderly. In patients with SIF, objective neurological abnormalities such as sphincter dysfunction or leg paresthesia are uncommon. We present a case of SIF accompanied by spinopelvic dissociation with late neurological compromise treated by spinopelvic fixation. A 61-year-old woman presented to our hospital with low back pain without obvious trauma history. She had a past history of eosinophilic granulomatosis with polyangiitis and treatment with steroids. Her low back pain became worse, and she started to have radiating left posterior thigh pain and motor weakness in the left ankle and both great toes with symptoms of stress urinary incontinence, constipation, and loss of anal sensation. Magnetic resonance imaging revealed an H-shaped sacrum fracture. We attributed the neurological symptoms to unstable SIF and performed lumbopelvic fixation. After the surgery, her leg pain and symptoms of stress urinary incontinence improved markedly, as did anal sensation. At a 6-month follow-up, the patient reported no low back pain and she was walking independently without pelvic complaints. CT showed bone union was achieved. Even minimally displaced SIF in patients with osteoporosis can be a cause of bowel and bladder disturbance. Lumbopelvic fixation is a treatment option for SIF with spinopelvic dissociation presenting neurological deficit.

Occipital Condyle Fracture: A Case Report of a Typically Stable Fracture That Required Surgical Treatment.

An occipital condyle fracture (OCF) is a relatively rare trauma that is now increasingly diagnosed because of the wide availability of computed tomography. For nondisplaced OCFs, conservative treatment is generally recommended, and there is no previous report of a nondisplaced OCF requiring surgery. We report a patient who had a nondisplaced OCF with craniocervical misalignment (a condyle-C1 interval > 2.0 mm) and C1-C2 translation treated with a halo vest and occipitocervical fusion surgery. An 87-year-old Asian woman fell from a 4-meter height and hit her head. She was transferred to our emergency room. Computed tomography revealed a nondisplaced impaction OCF with a 2.5 mm occipital condyle-C1 interval and a 5 mm C1-C2 translation. The fracture pattern was considered stable. However, since craniocervical misalignment and C1-C2 translation were present, the patient was placed in a halo device, and we reduced the occipitoatlantoaxial joint, adjusting the halo ring position preoperatively. Confirming reduction of the atlantooccipital facet joint and the atlantoaxial joint by computed tomography, we performed an occipitocervical fusion. This is the first report of a nondisplaced OCF with craniocervical misalignment and C1-C2 translation that required surgical treatment. Clinicians should be aware of craniocervical misalignment and atlantoaxial instability even in Tuli type 1 OCFs.

Direct application of the tumor necrosis factor-α inhibitor, etanercept, into a punctured intervertebral disc decreases calcitonin gene-related peptide expression in rat dorsal root ganglion neurons.

STUDY DESIGN: retrograde neurotracing and immunohistochemistry were used to investigate the effect of the tumor necrosis factor (TNF)-α inhibitor, etanercept, on calcitonin gene-related peptide (CGRP) expression in dorsal root ganglion (DRG) neurons innervating intervertebral discs in rats. OBJECTIVE: to clarify the action of a TNF-α inhibitor on a sensory neuropeptide in DRG neurons innervating intervertebral discs. SUMMARY OF BACKGROUND DATA: degeneration of lumbar intervertebral discs is a cause of low back pain. TNF-α in the intervertebral disc is a major contributor to discogenie pain. Effects of TNF-α inhibition on CGRP expression in DRG neurons were evaluated. METHODS: the neurotracer FluoroGold was applied to the surfaces of L4/5 discs to label their innervating DRG neurons (n = 30). Of 30 rats, 10 were in a nonpunctured disc sham surgery control group, whereas the other 20 were in experimental groups in which intervertebral discs were punctured with a 23-gauge needle. Etanercept or saline was applied into the punctured discs (n = 10 each treatment). After 14 days of surgery, DRGs from L1 to L6 were harvested, sectioned, and immunostained for CGRP. The proportion of FluoroGold-labeled CGRP-immunoreactive DRG neurons was evaluated in all groups. RESULTS: FluoroGold-labeled neurons innervating the L4/5 disc were distributed throughout L1-L6 DRGs in all groups. Of the FluoroGold-labeled neurons, the proportion of CGRP-immunoreactive neurons was 21% ± 4% in the sham surgery control group, 32% ± 7% in the puncture + saline group, and 23% ± 4% in the puncture + etanercept group. The proportion of CGRP-immunoreactive neurons was significantly greater in the puncture + saline group compared with the sham control and puncture + etanercept groups (P < 0.01). CONCLUSION: in this model, CGRP was upregulated in DRG neurons innervating damaged discs. However, direct intradiscal application of etanercept immediately after disc puncture suppressed CGRP expression in DRG neurons innervating injured discs. This finding may further elucidate the mechanism for the effectiveness of etanercept in upregulation of neuropeptide in DRG neurons innervating intervertebral discs.

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 (p75(NTR)), 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-p75(NTR) 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-p75(NTR) 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 p75(NTR) antagonism induced the most profound suppression.