Yasunobu Sawaji

Regulation of nerve growth factor by anti-inflammatory drugs, a steroid, and a selective cyclooxygenase 2 inhibitor in human intervertebral disc cells stimulated with interleukin-1.

Study Design. Regulation of nerve growth factor (NGF) by 2 different anti-inflammatory drugs was investigated in vitro using isolated human intervertebral disc (IVD) cells stimulated with the proinflammatory cytokine interleukin-1 (IL-1). Objective. To investigate the regulation of NGF by a synthetic steroid and a selective cyclooxygenase-2 (COX-2) inhibitor and to clarify the biological role of prostaglandin E2 (PGE2) in this process. Summary of Background Data. NGF is known to play an important role in pain, including low back pain, and to be induced by proinflammatory cytokines in IVD cells. However, the effect of clinically used drugs for managing low back pain on the regulation of NGF is unclear. Methods. Isolated human IVD cells were stimulated with interleukin-1 (IL-1) in the presence or absence of dexamethasone or a selective COX-2 inhibitor (NS-398). NGF expression and release were determined by real-time polymerase chain reaction and enzyme-linked immuno sorbent assay, respectively. Inhibition of PGE2 release was determined by enzyme-linked immuno sorbent assay. The effects of exogenous PGE2 and its receptor (E-series prostanoid receptors [EPs] 1–4) agonists were also tested for NGF regulation. Results. IL-1 transiently induced, in a dose-dependent manner, the induction of NGF in human IVD cells. Pretreatment with dexamethasone strongly inhibited the NGF expression, whereas NS-398 significantly enhanced it at the concentration at which PGE2 release was substantially inhibited. Exogenous PGE2 inhibited IL-1 induction of NGF and this effect was mimicked when EP2 and EP4, but not EP1 and EP3, agonists were supplemented to the culture. Conclusion. Although selective COX-2 inhibitors have been shown to be effective for acute low back pain by inhibiting PGE2 release, our findings suggest that it may have a limited efficacy because it exaggerated NGF expression, whereas dexamethasone inhibited it. On the other hand, PGE2 had an inhibitory function for NGF induction by mediating EP2/4 in human IVD cells. Further studies are needed to clarify whether these observations could take place in vivo. Level of Evidence: N/A

Relationship among cervical, thoracic, and lumbopelvic sagittal alignment in healthy adults

Purpose. To evaluate the association between cervical sagittal alignment and thoracic/lumbopelvic sagittal alignment in healthy Japanese adults. Methods. 30 male and 22 female healthy adults aged 22 to 50 years were recruited. Spinal parameters were measured on radiographs, including the cervical sagittal vertical axis, sagittal vertical axis, C7 tilt angle, Ishihara index for cervical lordosis, thoracic kyphosis, lumbar lordosis, sacral slope, pelvic tilt, and pelvic incidence. Results. The C7 tilt angle positively correlated with the Ishihara index (r=0.52, p<0.0001) and thoracic kyphosis (r=0.53, p<0.0001). The Ishihara index positively correlated with thoracic kyphosis (r=0.34, p=0.01) and C7 tilt angle (r=0.52, p<0.0001). Pelvic incidence positively correlated with sacral slope (r=0.45, p=0.001), lumbar lordosis (r=0.26, p=0.07), and pelvic tilt (r=0.29, p=0.03). Compared with men, women had a smaller Ishihara index (0.07 vs. 0.001, p=0.03), thoracic kyphosis (30.5° vs 24.1°, p=0.02), and C7 tilt angle (23.1° vs. 16.8°, p=0.02). Women had less cervical lordosis and thoracic kyphosis, that is, a straighter cervico-thoracic sagittal alignment. Conclusion. In healthy Japanese adults, cervical sagittal alignment is associated with thoracic sagittal alignment but not with lumbopelvic alignment.

Limited efficacy of COX-2 inhibitors on nerve growth factor and metalloproteinases expressions in human synovial fibroblasts

BACKGROUND Nerve growth factor (NGF) is associated with arthritic pain and metalloproteinases are implicated in collagen and aggrecan degradation. Although selective COX-2 inhibitors are recommended for the treatment of arthritic diseases, their effects on NGF and metalloproteinases remain unclear. This study investigated the regulations of NGF and metalloproteinases by selective COX-2 inhibitors in isolated human synovial cells. METHODS The isolated human synovial cells were stimulated with IL-1β in the presence of selective COX-2 inhibitors (NS-398 or celecoxib) with or without exogenous PGE2 or its receptor (EP1-4) agonists. The expressions of NGF, MMP-1, -3, -13, ADAMTS-4, and -5 were quantified by real-time PCR and their proteins were determined by Western blotting. The amount of PGE2 released was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS The IL-1β inductions of NGF and MMP-1 and MMP-13 were augmented by the COX-2 inhibitors, whereas the inductions of ADAMTS-4 and ADAMTS-5 were inhibited. These actions were reversed by supplementing PGE2 or the EP4 agonist exogenously. CONCLUSION Our comprehensive analysis revealed that COX-2 inhibitors may be beneficial for suppressing aggrecan degradation and for reducing inflammatory pain by inhibiting PGE2 release, although they may have limited efficacy in suppressing collagen degradation and nerve growth. This study suggests the feedback roles of PGE2 in the negative regulation of NGF and MMP-1 and MMP-13 and the positive regulation of ADAMTS-4 and ADAMTS-5.

A case of rapidly-progressing cervical spine subependymoma with atypical features

This was a study of the case of a 60-year-old woman who presented with a six-month history of headache and numbness radiating to the right arm. MRI revealed a fusiform intramedullary spinal tumor spanning C2 to C5 at the hospital where she first presented. As her right upper limb weakness had presented gradually, she visited our hospital after one and a half years. Neurological examination revealed muscle weakness in the right deltoid, but no sensory disturbance. The patient underwent a C2-C6 total laminectomy and posterior midline myelotomy from the posterior median fissure of the spinal cord. The intraoperative histological diagnosis was glioma. Pathological findings in low magnification demonstrated clusters of small uniform nuclei embedded in a dense and fibrillary matrix in hematoxylin-eosin staining (H.E.). On immunohistochemical staining, the tumor cells were weakly positive for glial fibrillary acidic protein (GFAP), but negative for the epithelial membrane antigen (EMA). The histopathological findings were consistent with the diagnosis of a subependymoma. However, the MIB-1 labeling index was of moderately high level up to approximately 8%. In this case, we performed total resection because the tumor had rapidly increased in size and was of atypical form in histological findings. It should be minded that some of subependymomas have a possibility of rapidly increasing in size with progressing neurological deficits.

Radiographic Assessment of Spinopelvic Sagittal Alignment from Sitting to Standing Position

Introduction Most people in modern societies spend the majority of their time sitting. However, sagittal spinal alignment is usually analyzed in the standing position. For understanding the symptoms associated with postural changes, this alignment is better to be analyzed in various positions. The purpose of this study was to investigate lumbo-pelvic relationships between standing up and sitting (sit-to-stand) motion. Methods The study subjects were 25 healthy young adult volunteers without any spinal symptoms. The following parameters were measured, namely, intervertebral range of motion (IV ROM), lumbar lordotic angle (L1L5), sacral slope (SS), pelvic tilt (PT), and pelvic incidence (PI), on lateral whole-spine radiographs while sitting upright, sitting anterior flexed (anteflexed), standing anteflexed, and standing upright. Results The measurements of spinopelvic parameters during sit-to-stand motion (sitting upright, sitting anteflexed, standing anteflexed, standing upright, respectively) were as follows: L1L5 (7.9, −4.4, 3.1, 31.9) and PT (31.5, 26.5, 11.9, 7.7). Regarding IV ROM, the lumbar segmental ROM after seat-off was wider than before seat-off (sitting anteflexed). In particular, the L4-L5 segments had a wide ROM from standing anteflexed to standing upright. Conclusions The pelvis was retroverted in the sitting upright position and gradually anteverted during sit-to-stand motion. Lumbar lordosis decreased in the sitting upright position, temporarily decreased further (sitting anteflexed), and then increased in the standing position (standing anteflexed and standing upright). The mechanical loads on lumbosacral segments were greater after seat-off due to the reverse movement between upper lumbar and pelvic segments.

Cervical Kyphotic Deformity after Laminoplasty in Patients with Cervical Ossification of Posterior Longitudinal Ligament with Normal Sagittal Spinal Alignment

Background Preoperative cervico-thoracic kyphosis and cervical regional positive imbalance are the risk factors for postoperative cervical kyphosis after expansive laminoplasty (ELAP). However, the relationship between preoperative global sagittal spinal alignment and postoperative cervical kyphosis in patients with cervical ossification of the posterior longitudinal ligament (OPLL) is unclear. The purpose of this study was to investigate the relationship between the onset of postoperative cervical kyphosis after ELAP and the preoperative global spinal sagittal alignment in patients with OPLL with normal sagittal spinal alignment. Methods Sixty-nine consecutive patients without preoperative cervical kyphosis who underwent ELAP for OPLL and cervical spondylotic myelopathy (CSM) were enrolled. The global sagittal alignment radiography preoperatively and 1 year postoperatively were examined. The subjects were divided into a postoperative cervical lordosis group (LG) or a kyphosis group (KG) at 1 year postoperatively. The preoperative global sagittal spinal alignment between LG and KG in CSM and OPLL was compared. Results The occurrence of cervical kyphosis after ELAP was 7 of 27 cases (25.9%) in OPLL and 13 of 42 cases (31.0%) in CSM. In patients with CSM in the KG, C7 the sagittal vertical axis (SVA) was smaller than in the LG. In patients with cervical OPLL in the KG, C2-C7 angle, C2-C7 SVA, and thoracic kyphosis (TK) were smaller than those in the LG. In OPLL, the age of the KG was younger than that of LG; however, this was not a significant difference in CSM. Conclusion In patients with cervical OPLL without preoperative global spinal sagittal imbalance, preoperative small C2-C7 angle, C2-C7 SVA, TK, and younger age were typical characteristics of postoperative cervical kyphosis after ELAP.

Factors associated with bone metabolism in patients with cervical ossification of the posterior longitudinal ligament accompanied with diffuse idiopathic skeletal hyperostosis

Introduction: Diffuse idiopathic skeletal hyperostosis (DISH) and ossification of the posterior longitudinal ligament (OPLL) are both characterized as ossification in paravertebral ligaments and sometimes present simultaneously, however, the bone metabolism in patients with cervical OPLL accompanying/not accompanying DISH has not well been studied. Thus, a retrospective analysis was performed to understand any differences in bone metabolism in these patients. Methods: Male patients who underwent surgery for OPLL were divided into two groups based on the presence or absence of DISH (OD and O group, respectively). Patients with cervical spondylosis comprised the control group (CS group). Bone mineral density (BMD) and bone metabolism factors were compared among the groups. Results: The OD and O groups had significantly higher body mass indexes (BMIs) than did the CS group. Morphologically, the number of continuous type of OPLL was high in the OD group whereas that of segmental type was higher in the O group. The OD and O group had greater BMD than the CS group. Both TRACP-5b and P1NP were tended to be lower in the OD group whereas Ca and P concentrations were similar level among the groups. Intact parathyroid hormone in OD group was significantly higher than CS group. Discussion: Patients with OPLL accompanying DISH had significantly higher BMD whereas they tend to be lower in bone turnover. Significantly higher i-PTH levels was found in the OD group and would be the characteristic blood marker, but further research on the relationship between DISH and PTH was necessary.

Postoperative Radiographic Early-Onset Adjacent Segment Degeneration after Single-Level L4–L5 Posterior Lumbar Interbody Fusion in Patients without Preoperative Severe Sagittal Spinal Imbalance

Study Design Retrospective study. Purpose To investigate the relationship between preoperative total spinal sagittal alignment and the early onset of adjacent segment degeneration (ASD) after single-level posterior lumbar interbody fusion (PLIF) in patients with normal sagittal spinal alignment. Overview of Literature Postoperative early-onset ASD is one of the complications after L4–L5 PLIF, a common surgical procedure for lumbar degenerative disease in patents without severe sagittal imbalance. A better understanding of the preoperative characteristics of total spinal sagittal alignment associated with early-onset ASD could help prevent the condition. Methods The study included 70 consecutive patients diagnosed with lumbar degenerative disease who underwent single-level L4–L5 PLIF between 2011 and 2015. They were divided into two groups based on the radiographic progression of L3–L4 degeneration after 1-year follow-up: the ASD and the non-ASD (NASD) group. The following radiographic parameters were preoperatively and postoperatively measured: sagittal vertebral axis (SVA), thoracic kyphosis (TK), lumbar lordosis, pelvic tilt, and pelvic incidence (PI). Results Eight of the 70 patients (11%) experienced ASD after PLIF (three males and five females; age, 64.4±7.7 years). The NASD group comprised 20 males and 42 females (age, 67.7±9.3 years). Six patients of the ASD group showed decreased L3–L4 disc height, one had L3–L4 local kyphosis, and one showed both changes. Preoperative SVA, PI, and TK were significantly smaller in the ASD group than in the NASD group (p <0.05). Conclusions A preoperative small SVA and TK with small PI were the characteristic alignments for the risk of early-onset ASD in patients without preoperative severe sagittal spinal imbalance undergoing L4–L5 single-level PLIF.

PGE1 Attenuates IL-1β-induced NGF Expression in Human Intervertebral Disc Cells.

Study Design. In vitro study using isolated human intervertebral disc (IVD) cells. Objective. To investigate the effects of prostaglandin (PG)E1 and its orally available derivative limaprost on the regulation of nerve growth factor (NGF) expression and to compare their actions with other prostanoids using interleukin (IL)-1-stimulated human IVD cells. Summary of Background Data. We previously reported that a selective COX-2 inhibitor enhanced, whereas PGE2 suppressed the induction of NGF by IL-1 in human IVD cells, and proposed that PGE2 can suppress NGF expression by a negative feedback mechanism. Methods. Isolated human IVD cells were stimulated with IL-1 in the presence or absence of increasing concentrations of PGE2, PGE1, limaprost, PGI2, PGD2, or PGF2&agr; (10–10,000 nM). For some experiments, an E-series prostanoid receptor (EP)4 antagonist (L-161,982) was added prior to the stimulation. NGF expression was determined by real-time polymerase chain reaction and its protein level was quantified by enzyme-linked immunosorbent assay. Results. PGE2, PGE1, and limaprost inhibited the IL-1-mediated induction of NGF in a concentration-dependent manner, with IC50 values of 9.9, 10.6, and 70.9 nM, respectively. PGI2 also suppressed NGF expression but to a much less extent. PGD2, on the other hand, significantly enhanced NGF expression, whereas PGF2&agr; had no effect. Protein expression levels of NGF mirrored its mRNA levels. The suppression of NGF expression by PGE2 and PGE1 was partly reversed by L-161,982. Conclusion. PGE1 and limaprost exhibited a novel pharmacological action that suppresses NGF expression in human IVD cells, and other prostanoids differentially regulated NGF expression. Limaprost has been used to treat patients with lumbar spinal stenosis in Japan and was proved to be effective in relieving symptoms. Our in vitro results may explain, in part, the mechanism of action of limaprost for low back pain. Level of Evidence: N/A