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Background Context: Chemonucleolysis has been proposed as a less invasive technique than surgery for patients with lumbar disc herniation. Once chymopapain had been approved as a chemonucleolysis drug, it was withdrawn because of serious complications. A novel agent with fewer complications would be desirable., Purpose: The purpose of this study was to investigate the effects of recombinant human matrix metalloproteinase 7 (rhMMP-7) in experimental chemonucleolysis in vitro and in vivo and examine its effects on tissue damage., Study Design: The study design is the experimental study using human herniated discs and enzyme substrates in vitro and dogs in vivo., Methods: The effects of rhMMP-7 on the degradation of human herniated discs were examined by measuring the wet weight in vitro. The correlations between the decrease in wet weight by rhMMP-7 and the conditions associated with herniated discs were also analyzed. The effects of rhMMP-7 on the proteoglycan and water contents were respectively examined with alcian blue staining and T2-weighted magnetic resonance imaging at 7 days after intradiscal injection in dogs. The distribution of [125I]-labeled rhMMP-7 was investigated by autoradioluminography at 7 days after intradiscal injection in dogs. An epidural injection study with rhMMP-7 was performed to evaluate the effects on the tissue damage around the discs at 1 and 13 weeks after the treatment in dogs. The Type 1 and 2 collagen cleavage rates were measured and compared with those of aggrecan in vitro., Results: Recombinant human matrix metalloproteinase 7 concentration dependently decreased the wet weight of herniated discs in vitro. The decrease in wet weight of the discs by rhMMP-7 did not significantly correlate with the conditions associated with herniated discs. Intradiscal injection of rhMMP-7 reduced the proteoglycan and water contents, with an increase in the serum keratan sulfate levels. Radioactivity of [125I]-labeled rhMMP-7 was detected in the nucleus pulposus and annulus fibrosus but not in the muscle. Epidural injection of rhMMP-7 had no effect on the injection site or the nerve tissues. The Type 1 and 2 collagen cleavage rates of rhMMP-7 were 1,000-fold weaker than those of aggrecan., Conclusions: This study demonstrated experimental chemonucleolysis with rhMMP-7 in vitro and in vivo. The effects of rhMMP-7 were not affected by the conditions associated with herniated discs. The epidural injection study together with the autoradioluminography and in vitro enzyme assay suggests that intradiscal injection of rhMMP-7 may not induce tissue damage around the discs because of its distribution and substrate selectivity. Recombinant human matrix metalloproteinase 7 may be a novel and promising chemonucleolysis agent., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The authors describe 2 cases of thoracic disc herniation, resulting in acute myelopathy without bladder dysfunction or progressive muscular weakness; the herniated disc apparently resorbed without surgical intervention. Thoracic disc herniations are less frequent than cervical or lumbar disc herniations and are usually associated with severe neurological deficits. In these 2 cases, the herniated discs exhibited marked decreases in size, corresponding to a favorable clinical outcome within a few months after the initiation of conservative treatment with prostaglandin E(1) and/or steroids in conjunction with physical therapy. The authors conclude that thoracic herniated discs are capable of undergoing natural resorption and that conservative treatment could be indicated, even in the presence of moderate myelopathy, when the myelopathy is not accompanied by bladder dysfunction or progressive muscular weakness.

Purpose: Recently, MMP-7 and MMP-3 have been found to play a crucial role in the natural resorption process of herniated discs. We therefore examined the role of these recombinant human matrix metalloproteinases (rh MMPs) in the treatment of herniated discs., Methods: (a) Surgical samples of herniated disc were cultured in the presence or absence of rh MMPs, and wet weight was measured 24h later. (b) The rh MMPs were administered into normal rabbit intervertebral discs, and after 1 week spine samples were stained with Safranin O. (c) The rh MMPs were administered into canine herniated discs in vivo. Myelography and MRI were performed prior to and 1 week after administration. Spine samples were examined histologically. Whole disc tissue was collected, total protein was extracted, and Western blot analysis was performed., Results: (a) Proteoglycan degradation was found in MMP-7, MMP-3, and chymopapain-treated samples. MMP-7 and chymopapain-treated samples displayed a significant loss in wet weight (p<0.01). (b) Normal disc tissues after administration of rh MMP-7, MMP-3, and chymopapain showed an extensive loss of Safranin O staining. (c) The rh MMP-7-treated discs had a marked decrease in protruded herniation by MRI. Herniated discs after administration of MMP-7 and chymopapain showed a significant decrease in protruded mass 7 days after administration compared with saline-treated discs when evaluated by myelography (p<0.01). The rh MMP-7-treated discs displayed a clear loss of Safranin O staining in the nucleus pulposus. Proteoglycan expression was barely detectable in disc tissues after MMP-7 administration, whereas obvious expression was obtained in saline-treated or untreated disc tissues., Conclusions: Exposure to rh MMP-7 resulted in promising proteoglycan loss in human surgical samples, normal rabbit intervertebral discs, and natural canine herniated discs. Administration of rh MMP-7 may facilitate the resorption process of herniated discs.

Intervertebral disc herniation (HD) is one of the most common orthopaedic conditions. MRI analysis of HD has revealed a spontaneous resorption mechanism related with neo-vascularization. It appears that the interaction of activated macrophages with disc tissues leads to the generation of inflammatory cytokines. Moreover, inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) is required for the induction of angiogenesis inducing factors such as vascular endothelial growth factor (VEGF) or matrix degrading enzymes such as MMP-3, MMP-7 and plasmin. We hypothesized that these molecules play a crucial role during spontaneous HD resorption. In this study, we have examined the sequential expression of these molecules using a co-culture system which is composed of the interaction of activated macrophages and disc tissues as a model of the acute response of inflammation occurred in HD. We have also considered the mechanism of activating latent MMPs during HD resorption process. Current our results indicate that upregulation of both TNF-alpha mRNA and protein expressions occur first in the inflammation induced by HD. VEGF upregulation follows the increased level of TNF-alpha expression. Both plasmin and MMP-3 are upregulated at later time points. We also demonstrate that both TNF-alpha and VEGF induce upregulated expression of urokinase-type plasminogen activator (u-PA). Our previous work has demonstrated that TNF-alpha could upregulate the expression of VEGF, MMP-3 and MMP-7 in the co-culture system. It has been reported that plasmin could affect to activate latent MMPs. Based on these findings, we suggest that TNF-alpha acts as the initiator of inflammation following contact between macrophages and disc chondrocytes and that plasmin and u-PA play a crucial role in activation of MMPs. We propose a spontaneous HD resorption cascade. Further understanding of the resorption process may provide future novel therapies for HD.

Intervertebral disc herniation is a major cause of low back pain and sciatica. Spontaneous resorption of herniated disc (HD) is frrequently detected by magnetic resonance imaging (MRI). Marked infiltration by macrophages and neo-vascularization are observed upon histogical examination of HD. In addition, enhanced MRI studies suggest that HD resorption occurs more frequently in those completely exposed to the epidural space and that this correlates with their degree of vascularization. We have postulated that the angiogenic factor, vascular endothelial growth factor (VEGF), may be implicated in the neo-vascularization of HD tissues. Here we demonstrate that VEGF and its receptors VEGFR-1 and VEGFR-2 are expressed in human surgical samples of HD. Using a co-culture system comprised of murine peritoneal macrophages and intervertebral disc tissue as a model of the acute phase of HD developed previously, an increase in macrophage VEGF protein and mRNA expression was observed upon exposure to disc tissue. Tumor necrosis factor alpha (TNF-alpha) was required for this induction of VEGF. Use of a novel angiogenesis assay revealed that addition of the conditioned media from the co-culture system resulted in an increase of vascular tubule formation. This effect was strongly inhibited by anti-VEGF antibody, but augmented by recombinant VEGF. We conclude that VEGF induction, under the co-culture conditions tested can result in neo-vascularization of intervertebral disc tissue and may thus play a role in the resorption of HD.

This study was designed to determine the prognostic factors in unilateral lumbar radiculopathy due to herniated nucleus pulposus (HNP); this was done by prospectively investigating the clinical course of consecutive patients with HNP. The study population consisted of 131 patients who complained primarily of unilateral leg pain, and who were examined by magnetic resonance imaging (MRI) to establish a definite diagnosis. Patients with a questionable diagnosis were excluded. The initial assessment was done within the first 2 months of presentation, according to conventional surgical indications. Surgery was performed only in patients who gave their informed consent for the procedure. Questionnaires were sent to patients twice, in 1994 and 1996, to assess the clinical outcome in those patients who did not meet the surgical indications and in those who met the indications, but who refused surgery. Clinical outcomes were classified into three categories based on the patients' own assessment. Fifty patients met the surgical indication criteria, and 25 were actually operated on. Neither these patients' profiles nor their MRI findings correlated with the results of the initial assessment. Patient age was significantly correlated with outcome only at the time of the first follow-up. The type of HNP and the result of the initial assessment were correlated with outcome at the times of both follow-ups, but the significance of these correlations had decreased at the second follow-up. In conclusion, initial assessment and type of HNP on MRI are major prognostic factors. However, the conventional manner of treatment selection is inadequate for the appropriate management of lumbar disc herniation.

Study Design: A retrospective study of cervical disc herniation using results of repeated magnetic resonance imaging examinations., Objectives: To clarify the cervical disc herniation morphological changes over time in order to establish a strategy for treatment., Summary of Background Data: In the authors' previous magnetic resonance imaging follow-up study of patients with lumbar disc herniation, spontaneous regression was observed in the sequestration-type lesions, and it was found that the tendency toward regression differed based on the anatomic position of extruded disc material., Methods: Thirty-eight patients with cervical disc herniation who underwent repeated magnetic resonance imaging examinations were studied. The changes over time in herniated disc size were evaluated using this imaging technique. Evaluation showed the characteristics of those in whom spontaneous regression was found, such as extrusion pattern, and the clinical outcome was evaluated by symptoms., Results: In 15 patients (40%), the volume of herniated material was decreased. The interval from onset of symptoms to the initial examination was significantly shorter in the regression group than in the group that showed no change in disc herniation. By extrusion pattern, cervical disc herniation, which was divided into migration type on sagittal view and lateral type on axial view, most frequently exhibited spontaneous regression. All of the patients with radicular pain and upper limb amyotrophy were treated successfully with conservative therapy., Conclusion: Although the possibility of the combination of hemorrhage and disc material could not be denied, active resorption of herniated material probably occurred during the acute phase. Extruded material exposed to the epidural space may be resorbed more quickly than that beneath the ligament. Vascular supply probably plays a role in the mechanism of resorption. The phase and position of extrusion were the significant factors affecting cervical disc herniation resorption. It was demonstrated that examination performed during the acute phase using magnetic resonance imaging is necessary for elucidation of the pathogenesis of cervical disc herniation, and that migrating, lateral-type herniations regress so frequently that conservative treatment should be chosen not only for patients with radicular pain, but also for those with upper limb amyotrophy.

Study Design: This study was designed to investigate the morphologic changes in contrast-enhanced magnetic resonance imaging that occur during conservative treatment of patients with unilateral leg pain resulting from herniated nucleus pulposus without significant lumbar canal stenosis., Objectives: To compare the morphologic results with clinical outcomes to ascertain whether enhanced magnetic resonance imaging contributes to the management of lumbar disc herniation., Summary of Background Data: Contrast-enhanced magnetic resonance imaging has already been reported to be useful in the postoperative examination of the lumbar spine and in visualization of symptomatic nerve roots. However, there have been few reports about its usefulness in the conservative management of herniated nucleus pulposus or about the correlation between herniated nucleus pulposus regression and enhanced effect. The study population consisted of 48 patients with radiculopathy. All patients primarily reported unilateral leg pain, and 94% had positive tension signs. Additionally, 38% exhibited muscle weakness corresponding to the symptomatic nerve root., Methods: All patients were studied twice or more using gadolinium-magnetic resonance imaging during conservative therapy, at a mean interval of 191 days. Changes in the size of the herniated nucleus pulposus on precontrast images fell into four categories, with changes in enhancement on postcontrast images classified into two categories: "enlargement" and "no change.", Results: In all cases of migrating type herniated nucleus pulposus, circular enhancement was seen on postcontrast images. In 17 of 22 cases, the enhanced area gradually thickened and intruded into the migrated disc materials as the size of the herniated nucleus pulposus decreased; the herniated nucleus pulposus disappeared in nine cases and showed a marked decrease in seven cases. These cases showed good clinical courses of sciatica. In the other five patients, in whom there were no changes in the enhanced area, there was less of a tendency for the herniated nucleus pulposus to decrease in size, and there were poorer clinical results. In six cases of extruding-type herniated nucleus pulposus, no enhanced effects were observed throughout the follow-up period. The other 20 cases showed enhancement that was relatively weaker than that of migrating disc herniation. Extension or expansion of the enhanced area was observed in the follow-up images of 15 cases, though only four showed obvious changes in the size of the herniated nucleus pulposus. These 15 cases had better clinical results than the other cases, in which enhanced effects did not change or were not observed., Conclusion: Contrast-enhanced magnetic resonance imaging is a useful prognostic parameter, and multiple use contributes to the proper management of lumbar disc herniation.

We previously demonstrated that the granulation tissues of herniated nucleus pulposus are composed of a marked infiltration of macrophages that strongly express monocyte chemotactic protein-1. Monocyte chemotactic protein-1 is a chemotactic cytokine that contributes to the activation and recruitment of macrophages. Relatively little is known about its role in the resorption process of herniated nucleus pulposus. To clarify the sequential dynamics of expression of monocyte chemotactic protein-1 in the granulation tissues of herniated nucleus pulposus, we introduced a rat autologous transplantation model of nuclear materials onto its lumbar dura mater and performed immunohistological analysis and competitive polymerase chain reaction assay using the grafted samples. Immunohistological analysis demonstrated that the majority of infiltrating mononuclear cells expressed monocyte chemotactic protein-1. Monocyte chemotactic protein-1 mRNA was expressed in the first 3 weeks after the procedure and was significantly and maximally upregulated at 1 week. To determine whether human recombinant monocyte chemotactic protein-1 facilitates the resorption process of herniated nucleus pulposus, we introduced another model of autologous transplantation, wherein the nuclear materials were grafted to the abdominal subcutaneous tissues and recombinant monocyte chemotactic protein-1 was subsequently applied to these materials. When monocyte chemotactic protein-1 was injected into the murine nucleus pulposus tissues, they reduced in size more rapidly than in the control group. These findings suggest that monocyte chemotactic protein-1 plays an important role in the recruitment of macrophages in the early phase of the resorption process of herniated nucleus pulposus and that its application may physiologically facilitate the resorption process of the nucleus pulposus.

Study Design: Immunohistologic analysis was performed on surgically removed samples of herniated nucleus pulposus to examine the expression of stromelysin-1. We performed in vitro and in vivo experiments to determine whether recombinant human (rh) stromelysin-1 is capable of degrading nucleus pulposus., Objective: To analyze the production of stromelysin-1 in various types of herniated nucleus pulposus, and to examine the effects of this recombinant protein on nucleus pulposus tissues., Summary of Background Data: The authors previously demonstrated a progressive decrease in herniated nucleus pulposus size in some of the transligamentous and sequestration types of herniated nucleus pulposus using magnetic resonance imaging. An increased production of stromelysin-1, a cartilage proteoglycan degrading enzyme, in herniated nucleus pulposus was reported recently. The authors speculated that if stromelysin-1 is involved in the degradation of herniated nucleus pulposus, stromelysin-1 itself may be used as a chemonucleolytic agent., Methods: Immunohistologic analysis using streptoavidin-biotin method was performed on 20 herniated nucleus pulposus samples to investigate the expression of stromelysin-1. Five herniated nucleus pulposus samples were incubated in a tissue culture medium in the presence or absence of rh stromelysin-1. After 24 hours of incubation, their weight changes were measured, and the loss of proteoglycan was assessed by Safranin O staining. Rat nucleus pulposus tissues were obtained from coccygeal intervertebral discs, and autologous subcutaneous transplantation was performed. Rh stromelysin-1 was injected into the grafted materials, and the reduction in size was followed by two-dimensional measurements from the skin surface, using engineer's calipers., Results: Immunohistologic analysis demonstrated the production of stromelysin-1 in the granulation tissues of herniated nucleus pulposus. When stromelysin-1 was injected into the murine nucleus pulposus tissues, they reduced in size more rapidly than the control group. In addition, human herniated nucleus pulposus materials obtained at surgery showed significant weight loss when treated with stromelysin-1 in an organ culture system. Safranin O staining revealed extensive depletion of proteoglycan in these herniated nucleus pulposus samples., Conclusions: Stromelysin-1 is a possible key enzyme in herniated nucleus pulposus resorption, and stromelysin-1 may be a good candidate for use in chemonucleolysis. Administration of human stromelysin-1 may physiologically facilitate the resorption process of herniated nucleus pulposus, increase the healing rate and decrease complications after chemonucleolysis.

Study Design: Immunohistologic examination was performed on surgically removed samples of herniated nucleus pulposus., Objectives: To determine what cell types predominate in the granulation tissues of herniated nucleus pulposus, and to elucidate whether chemokines are involved in the resorption process of herniated nucleus pulposus. SUMMARY OF BACKGROUND DATA. The study population consisted of 30 patients suffering from herniated nucleus pulposus. Five macroscopically normal discs were obtained from spinal cord tumor and spinal cord injury managed with anterior discectomy (age range, 27-63 years) as a healthy control group., Methods: Immunohistochemical analysis was used to analyze the expression of chemokines., Results: A marked infiltration of macrophage and vascular proliferation was identified with a T lymphocyte infiltration of mild degree in the granulation tissues. This tendency was more prominent in the exposed group compared with the nonexposed group. Infiltrating macrophages, fibroblasts, and endothelial cells in the granulation tissues strongly expressed monocyte chemotactic protein-1 and macrophage inflammatory protein-1 alpha. Statistical analysis demonstrated that the exposed group was more abundant in Factor VIII, monocyte chemotactic protein-1, and macrophage inflammatory protein-1 alpha positive cells than the unexposed group., Conclusions: Inflammatory cells and their positivity for chemokines, such as monocyte chemotactic protein-1 and macrophage inflammatory protein-1 alpha, are associated with blood vessels. Chemokines, such as monocyte chemotactic protein-1 and macrophage inflammatory protein-1 alpha, were overexpressed in macrophages, fibroblasts, and endothelial cells, suggesting that these chemokines contribute to activation and recruitment of macrophages in a paracrine or autocrine fashion.

Study Design: The present study retrospectively investigated the morphologic changes that occurred during conservative treatment of patients with unilateral leg pain resulting from herniated nucleus pulposus without significant lumbar canal stenosis., Objectives: The results were correlated with clinical outcomes and extruding forms to determine which type of herniated nucleus pulposus had the greatest capacity for spontaneous regression and how rapidly such regression might occur., Summary of Background Data: The study population consisted of 77 patients with radiculopathy., Methods: All patients complained primarily of unilateral leg pain, and 94% had positive tension signs. Additionally, 32% exhibited muscle weakness corresponding to the symptomatic nerve root. All patients were studied more than twice using magnetic resonance imaging during conservative therapy at a mean interval of 150 days. Morphologic changes on magnetic resonance imaging fell into four categories, with herniated nucleus pulposus classified into three types using T1-weighted sagittal views. Each patient was reexamined on the same scanner; 53 patients were examined twice, and 24 patients were examined more than three times., Results: Morphologic changes, with the exception of 13 false-negative cases, basically corresponded to clinical outcome. In half of the cases that showed some improvement at follow-up evaluation, improvement of clinical findings were seen before those observed on magnetic resonance imaging. Migrating herniated nucleus pulposus frequently presented an obvious decrease in size, and even disappearance in seven cases. The further the herniated nucleus pulposus migrated, the more decrease in size could be observed. The cases apparently corresponding to "protrusion" showed little or no change on follow-up magnetic resonance imaging. Regarding the mechanism of herniated nucleus pulposus disappearance, exposure to the vascular supply undoubtedly took a part, although many factors were suspected to have some influence., Conclusion: Morphologic changes on magnetic resonance imaging mainly corresponded to clinical outcomes but tended to lag behind improvement of leg pain. Disappearance of herniate nucleus pulposus was seen frequently in the cases of migrating disc herniation, and it was presumed that exposure to the vascular supply had a lot to do with this phenomenon.

Dissociated motor loss due to cervical spondylosis and disc herniation was evaluated in 10 patients who presented with left deltoid paresis in the absence of sensory deficits or myelopathy. All of these cases underwent cervical anterior decompression. Based on magnetic resonance imaging, computed tomography myelography, and computed tomography discography, patients were divided into two pathologic types: The first showed focal bony spur and disc herniation with axial cord rotation and nerve root compression, and the second demonstrated ventral cord flattening. Electrophysiologic studies included evoked spinal potentials, motor evoked potentials, and evoked muscle action potentials. Motor evoked potentials, recorded epidurally from the ventral aspect of the thecal sac and the nerve root within the anterior discectomy or vertebrectomy sites, proved clinically most useful. Combining the latest available neuroradiologic and electrophysiologic information, 4 types of neural injury associated with deltoid pareses were identified in the 10 patients. The first included isolated C5 nerve root lesions; the second, C6 nerve root lesions; the third, both C5 and C6 nerve root lesions, and finally, intrinsic cord pathology.