Sema3A regulates bone-mass accrual through sensory innervations.

Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance. Previous studies have demonstrated that Sema3a(-/-) mice have multiple developmental defects due to abnormal neuronal innervations. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3a(-/-) mice had a low bone mass due to decreased bone formation. However, osteoblast-specific Sema3A-deficient mice (Sema3acol1(-/-) and Sema3aosx(-/-) mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons (Sema3asynapsin(-/-) and Sema3anestin(-/-) mice) had low bone mass, similar to Sema3a(-/-) mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin(-/-) mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin(-/-) mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a(-/-) mice, such as olfactory development, were identified in Sema3asynasin(-/-) mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a(-/-) mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. This study demonstrates that Sema3A regulates bone remodelling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts.

Long-term results of a prospective study of anterior decompression with fusion and posterior decompression with laminoplasty for treatment of cervical spondylotic myelopathy.

BACKGROUND: There have been no prospective studies comparing anterior surgery and posterior method in terms of long-term outcomes. The purposes of this study is to clarify whether there is any difference in long-term clinical and radiologic outcomes of anterior decompression with fusion (ADF) and laminoplasty (LAMP) for the treatment of cervical spondylotic myelopathy (CSM). METHODS: Ninety-five patients were prospectively treated with ADF or LAMP for CSM in our hospital from 1996 through 2003. On alternate years, patients were enrolled to receive ADF (1997, 1999, 2001, and 2003: ADF group, n = 45) or LAMP (1996, 1998, 2000, and 2002: LAMP group, n = 50). We excluded 19 patients who died during follow-up, and 25 who were lost to follow-up. Clinical outcomes were evaluated by the recovery rate of the Japanese Orthopaedic Association (JOA) score between the two groups. Sagittal alignment of the C2-7 lordotic angle and range of motion (ROM) in flexion and extension on plain X-ray were measured. RESULTS: Mean age at the time of surgery was 58.3 years in the ADF group and 57.9 years in the LAMP group. Mean preoperative JOA score was 10.0 and 10.5, respectively. Mean recovery rate of the JOA score at 3-5 years postoperatively was significantly higher in the ADF group (p < 0.05). Reoperation was required in 1 patient for pseudarthrosis and in 1 patient for recurrence of myelopathy in the ADF group; no patient in the LAMP group underwent a second surgery. There was a significant difference in maintenance of the lordotic angle in the ADF group compared with the LAMP group (p < 0.05), but not in ROM. CONCLUSIONS: Both ADF and LAMP provided similar good outcomes at 10-year time-point whereas ADF could achieve more satisfactory outcomes and better sagittal alignment at the middle-term. However, the incidence of reoperation and complication in the ADF group were higher than those in the LAMP group. STUDY DESIGN: A prospective comparative study (not randomized).

Impact of the surgical treatment for degenerative cervical myelopathy on the preoperative cervical sagittal balance: a review of prospective comparative cohort between anterior decompression with fusion and laminoplasty.

PURPOSE: Cervical sagittal balance has received increased attention as an important determinant of radiological and clinical outcomes. However, no prospective studies have compared the impact of cervical sagittal balance between anterior and posterior surgeries. We previously conducted a prospective study comparing anterior decompression with fusion (ADF) and laminoplasty (LAMP) for degenerative cervical myelopathy (DCM) and reported; however, analysis of cervical alignment within the concept of sagittal balance has yet to be performed, because that concept has recently been proposed. This study aimed to review this prospective cohort, specifically focusing on cervical sagittal balance. METHODS: We prospectively performed ADF or LAMP for DCM patients based on the year of enrollment: ADF was performed in odd-numbered years and LAMP in even-numbered years. Cervical lateral X-ray images taken in the neutral standing position were evaluated preoperatively and at a 1-year follow-up. The radiographic measurements included the following: (1) CL (cervical lordosis: C2-7 lordotic angle), (2) CGH (center of gravity of the head)-C7 SVA (sagittal vertical axis), and (3) C7 slope. The clinical results were evaluated using the Japanese Orthopedic Association scoring system for cervical myelopathy (C-JOA score). RESULTS: We analyzed the data for 66 patients (ADF n = 28, LAMP n = 38). While the CL and CGH-C7 SVA in the ADF were unchanged after the operation, those in the LAMP group worsened, especially in patients with preoperative cervical sagittal imbalance. The C7 slopes were not affected by the operation in either group. The postoperative decreases in the CL in the LAMP group correlated with the preoperative CGH-C7 SVA (r = 0.618, P < 0.01), but those in ADF group did not. In patients with preoperative cervical sagittal imbalance (CGH-C7 SVA ≥40 mm), the recovery rate of the C-JOA score in the ADF group was superior to that in the LAMP group (67.3 vs. 39.8 %). In contrast, for patients without cervical sagittal imbalance, the recovery rate of the C-JOA score showed no significant difference between the ADF and LAMP groups (64.5 vs. 58.7 %). CONCLUSIONS: Postoperative cervical sagittal alignment and balance were maintained after ADF but deteriorated following LAMP, especially in patients with preoperative CGH-C7 SVA ≥40 mm. In these patients, neurological recovery after LAMP was unsatisfactory. LAMP is not suitable for degenerative cervical myelopathy patients with preoperative cervical sagittal imbalance.

Efficacy and safety of porous hydroxyapatite/type 1 collagen composite implantation for bone regeneration: A randomized controlled study.

BACKGROUND: Porous hydroxyapatite/collagen composite (HAp/Col) is a bioresorbable bone substitute composed of nano-scale HAp and porcine type 1 collagen. In this study, the efficacy and safety were assessed in comparison to commercially available porous ß-tricalcium phosphate (ß-TCP). METHODS: Patients with bone defects caused by benign bone tumors, fractures, or harvesting of autografts were randomly allocated for implantation of porous HAp/Col (n = 63) or porous ß-TCP (n = 63). X-ray images were scored and used to evaluate the efficacy of the implantation until 24 weeks after surgery. Blood tests and observation of the surgical site were also performed to evaluate the safety of the implants. In total, 59 and 60 cases were analyzed in the porous HAp/Col and ß-TCP groups, respectively. RESULTS: At 18 and 24 weeks after surgery, the highest grade of bone regeneration was more frequent in the porous HAp/Col group than in the porous ß-TCP group (p = 0.0004 and 0.0254 respectively). Wilcoxon's rank sum test confirmed the superiority of porous HAp/Col from early time points onward (p = 0.0084, 4 w; p = 0.0037, 8 w; p = 0.0030, 12 w; p < 0.0001, 18 w; and p = 0.0316, 24 w). The incidence of adverse effects was higher in the porous HAp/Col group than in the ß-TCP group. However, no serious adverse events were reported and no cases needed to drop out of the clinical trial. CONCLUSIONS: The superiority of porous HAp/Col for bone regeneration in comparison to an established porous ß-TCP was confirmed. Although the incidence of side effects associated with the porous HAp/Col implant was higher than that in the ß-TCP group, no serious adverse events occurred that resulted in rejection of the implants.

Intrathecal AAV serotype 9-mediated delivery of shRNA against TRPV1 attenuates thermal hyperalgesia in a mouse model of peripheral nerve injury.

Gene therapy for neuropathic pain requires efficient gene delivery to both central and peripheral nervous systems. We previously showed that an adenoassociated virus serotype 9 (AAV9) vector expressing short-hairpin RNA (shRNA) could suppress target molecule expression in the dorsal root ganglia (DRG) and spinal cord upon intrathecal injection. To evaluate the therapeutic potential of this approach, we constructed an AAV9 vector encoding shRNA against vanilloid receptor 1 (TRPV1), which is an important target gene for acute pain, but its role in chronic neuropathic pain remains unclear. We intrathecally injected it into the subarachnoid space at the upper lumbar spine of mice 3 weeks after spared nerve injury (SNI). Delivered shTRPV1 effectively suppressed mRNA and protein expression of TRPV1 in the DRG and spinal cord, and it attenuated nerve injury-induced thermal allodynia 10-28 days after treatment. Our study provides important evidence for the contribution of TRPV1 to thermal hypersensitivity in neuropathic pain and thus establishes intrathecal AAV9-mediated gene delivery as an investigative and potentially therapeutic platform for the nervous system.

Central control of bone remodeling by neuromedin U.

Bone remodeling, the function affected in osteoporosis, the most common of bone diseases, comprises two phases: bone formation by matrix-producing osteoblasts and bone resorption by osteoclasts. The demonstration that the anorexigenic hormone leptin inhibits bone formation through a hypothalamic relay suggests that other molecules that affect energy metabolism in the hypothalamus could also modulate bone mass. Neuromedin U (NMU) is an anorexigenic neuropeptide that acts independently of leptin through poorly defined mechanisms. Here we show that Nmu-deficient (Nmu-/-) mice have high bone mass owing to an increase in bone formation; this is more prominent in male mice than female mice. Physiological and cell-based assays indicate that NMU acts in the central nervous system, rather than directly on bone cells, to regulate bone remodeling. Notably, leptin- or sympathetic nervous system-mediated inhibition of bone formation was abolished in Nmu-/- mice, which show an altered bone expression of molecular clock genes (mediators of the inhibition of bone formation by leptin). Moreover, treatment of wild-type mice with a natural agonist for the NMU receptor decreased bone mass. Collectively, these results suggest that NMU may be the first central mediator of leptin-dependent regulation of bone mass identified to date. Given the existence of inhibitors and activators of NMU action, our results may influence the treatment of diseases involving low bone mass, such as osteoporosis.

Runx1 and Runx2 cooperate during sternal morphogenesis.

Chondrocyte differentiation is strictly regulated by various transcription factors, including Runx2 and Runx3; however, the physiological role of Runx1 in chondrocyte differentiation remains unknown. To examine the role of Runx1, we generated mesenchymal-cell-specific and chondrocyte-specific Runx1-deficient mice [Prx1 Runx1(f/f) mice and alpha1(II) Runx1(f/f) mice, respectively] to circumvent the embryonic lethality of Runx1-deficient mice. We then mated these mice with Runx2 mutant mice to obtain mesenchymal-cell-specific or chondrocyte-specific Runx1; Runx2 double-mutant mice [Prx1 DKO mice and alpha1(II) DKO mice, respectively]. Prx1 Runx1(f/f) mice displayed a delay in sternal development and Prx1 DKO mice completely lacked a sternum. By contrast, alpha1(II) Runx1(f/f) mice and alpha1(II) DKO mice did not show any abnormal sternal morphogenesis or chondrocyte differentiation. Notably, Runx1, Runx2 and the Prx1-Cre transgene were co-expressed specifically in the sternum, which explains the observation that the abnormalities were limited to the sternum. Histologically, mesenchymal cells condensed normally in the prospective sternum of Prx1 DKO mice; however, commitment to the chondrocyte lineage, which follows mesenchymal condensation, was significantly impaired. In situ hybridization analyses demonstrated that the expression of alpha1(II) collagen (Col2a1 - Mouse Genome Informatics), Sox5 and Sox6 in the prospective sternum of Prx1 DKO mice was severely attenuated, whereas Sox9 expression was unchanged. Molecular analyses revealed that Runx1 and Runx2 induce the expression of Sox5 and Sox6, which leads to the induction of alpha1(II) collagen expression via the direct regulation of promoter activity. Collectively, these results show that Runx1 and Runx2 cooperatively regulate sternal morphogenesis and the commitment of mesenchymal cells to become chondrocytes through the induction of Sox5 and Sox6.

The effects of risedronate administered in combination with a proton pump inhibitor for the treatment of osteoporosis.

This study was performed to investigate the effects of the co-administration of proton pump inhibitor (PPI) on the efficacy of bisphosphonate (BP) treatment for osteoporosis. A total of 180 women with low bone mineral density were randomly divided into four groups, one in which sodium risedronate was administered with sodium rabeprazole and one in which only risedronate was administered (BP + PPI and BP groups, respectively). The biomarkers were measured at the baseline and every 3 months, inlcuding: N-terminal telopeptide of type I collagen corrected for creatinine, bone-specific alkaline phosphatase (BAP), parathyroid hormone, bone mineral density (BMD) of the lumbar spine and physical parameters evaluated according to the SF-36v2™ Health Survey. Statistical comparisons of these parameters were performed after 9 months. Data were available for a total of 137 patients (62 in the BP group and 75 in the BP + PPI group). The Δ % value of increase in BMD and improvement of physical functioning in the BP + PPI group were significantly larger, and its decrease in BAP in the BP + PPI group was significantly smaller than that in the BP group. It is expected that risedronate administration in combination with a PPI may be more effective not only for treating osteoporosis but also improving physical fitness than treatment with risedronate alone.

Usefulness of multi-channels in intraoperative spinal cord monitoring: multi-center study by the Monitoring Committee of the Japanese Society for Spine Surgery and Related Research.

OBJECT: The purpose of this study is to analyze the data in terms of the number of channels employed to examine the usefulness of multi-channels in intraoperative spinal cord monitoring. METHODS: The prerequisites for inclusion in the baseline data were as follows: (1) cases in which only CMAP monitoring was conducted; (2) cases in which monitoring was conducted under the same stimulation condition and the recording condition. Cases where inhalation anesthesia was used or muscle relaxants were used as maintenance anesthesia was excluded from the baseline data. Of the 6,887 cases, 884 cases met the criteria. The items examined for each of the different numbers of channels were the sensitivity and specificity, the false positive rate, the false negative rate, and the coverage rate of postoperative motor deficit muscles. RESULT: To examine these two items in terms of the number of channels, the 4-channel group had lower sensitivity and specificity scores compared with the 8- and 16-channel groups (4 channels 73/93 %, 8 channels 100/97 %, 16 channels 100/95 %). Only four channels were derived for these cases and the coverage of postoperative motor deficit muscles was 38 % with only 30 out of the 80 postoperative motor deficit muscles in total being monitored. In the 8-channel group, it was 60 % with 12 of the 20 postoperative motor deficit muscles being monitored. The 16-channel group had 100 % coverage rate of postoperative motor deficit muscles. CONCLUSION: We suggest that multi-channel monitoring of at least eight channels is desirable for intraoperative spinal cord monitoring.

A microRNA regulatory mechanism of osteoblast differentiation.

Growing evidence shows that microRNAs (miRNAs) regulate various developmental and homeostatic events in vertebrates and invertebrates. Osteoblast differentiation is a key step in proper skeletal development and acquisition of bone mass; however, the physiological role of non-coding small RNAs, especially miRNAs, in osteoblast differentiation remains elusive. Here, through comprehensive analysis of miRNAs expression during osteoblast differentiation, we show that miR-206, previously viewed as a muscle-specific miRNA, is a key regulator of this process. miR-206 was expressed in osteoblasts, and its expression decreased over the course of osteoblast differentiation. Overexpression of miR-206 in osteoblasts inhibited their differentiation, and conversely, knockdown of miR-206 expression promoted osteoblast differentiation. In silico analysis and molecular experiments revealed connexin 43 (Cx43), a major gap junction protein in osteoblasts, as a target of miR-206, and restoration of Cx43 expression in miR-206-expressing osteoblasts rescued them from the inhibitory effect of miR-206 on osteoblast differentiation. Finally, transgenic mice expressing miR-206 in osteoblasts developed a low bone mass phenotype due to impaired osteoblast differentiation. Our data show that miRNA is a regulator of osteoblast differentiation.

Increase in paravertebral muscle activity in lumbar kyphosis patients by surface electromyography compared with lumbar spinal canal stenosis patients and healthy volunteers.

STUDY DESIGN: Paravertebral muscle activity measurement by surface electromyography (EMG) in lumbar degenerative patients and healthy volunteers. OBJECTIVE: Muscle activity was tested in the standing position, and the influence of low back pain and alignment of the lumbar spine was assessed in the patients with lumbar kyphosis (LDK) or canal stenosis. SUMMARY OF BACKGROUND DATA: The number of kyphosis patients has increased as the population has grown older. Advanced kyphosis can cause difficulties in maintaining a standing position and affect daily living activities. The most direct cause is the atrophy of erector spinae muscles. The activity of these muscles has not yet been sufficiently evaluated and needs to be assessed objectively for the purpose of diagnosis and treatment. METHODS: The subjects were kyphosis patients who were 60 years of age or older, age-matched lumbar spinal canal stenosis patients, and healthy volunteers. Muscular activity at the L1-L2 and the L4-L5 intervertebral areas was recorded by surface EMG in the resting standing position and also with a weight load held in the standing position. Muscle activity and muscle fatigue, and the association between the Visual Analogue Scale, the Japanese Orthopaedic Association score for low back pain, and muscle activity, were analyzed. RESULTS: Kyphosis patients had a greater muscle activity in the lower back in the resting standing position and more severe muscle fatigue at the upper lumbar spine in comparison with patients with lumbar spinal canal stenosis. There was no association between muscle activity and clinical findings in patients with LDK although. CONCLUSIONS: Our study revealed the constant activity of paravertebral muscles and the susceptibility to muscle fatigue in patients with LDK. The quantification of muscle activity by surface EMG may show the pathology of LDK, and the decrease in muscle activity in the standing position may be a potentially useful index for guiding treatment.

Long-term results from use of pasteurized bone.

BACKGROUND: Pasteurized bone (PB) is recycled bone. The pasteurization has a tumor cell-killing effect wit retention of initial strength. However, few reports have been published on its long-term course; thus, in this study, we evaluated the long-term course of use of PB and examined appropriate reconstruction methods. PATIENTS AND METHODS: We reviewed 27 cases in which reconstructive surgery using PB was performed between 1990 and 2002. Of these, we excluded 12 fatal cases and 1 case in which follow-up was discontinued. Therefore, our final analysis consisted of 14 cases with an average follow-up period of 165 months. The reconstruction methods used were: osteoarticular graft in 6 cases, composite graft with prosthesis in 3 cases, intercalary graft in 1 case, and reconstruction using PB from the pelvis in 4 cases. RESULTS: The PB survived in 7 of the 14 cases. Five and 10-year survival of the PB was 78.6 and 47.6%, respectively. Three of the 6 osteoarticular cases failed because of late-onset absorption or infection of the PB. For patients with composite graft or intercalary graft, long-term survival was achieved when small amounts of PB were used. For patients with pelvic grafts, long-term survival was achieved in a case of P1 pelvis, but large PB grafts on small bone-junction surfaces were not successful in the long term. On the basis of these results, we were able to achieve successful long-term results with small PB grafts on large bone-junction surfaces. CONCLUSIONS: To prevent bone absorption and achieve long-term survival of PB, it is important to use a small PB graft and create a large surface area of contact with normal bone. These factors are advantageous to PB survival and to gaining limb function.

Osteopontin deficiency impairs wear debris-induced osteolysis via regulation of cytokine secretion from murine macrophages.

OBJECTIVE: To investigate the molecular mechanisms underlying particle-induced osteolysis, we focused on osteopontin (OPN), a cytokine and cell-attachment protein that is associated with macrophage chemoattractant and osteoclast activation. METHODS: We compared OPN protein levels in human periprosthetic osteolysis tissues with those in osteoarthritis (OA) synovial tissues. To investigate the functions of OPN during particle-induced osteolysis in vivo, titanium particles were implanted onto the calvaria of OPN-deficient mice and their wild-type (WT) littermates. Mice were killed on day 10 and evaluated immunohistologically. The effects of OPN deficiency on the secretion of inflammatory cytokines were examined using cultured bone marrow-derived macrophages (BMMs). BMMs from OPN-deficient and WT mice were cultured with titanium particles for 12 hours, and the concentrations of inflammatory cytokines in the conditioned media were measured by enzyme-linked immunosorbent assay. RESULTS: Expression of OPN protein was enhanced in human periprosthetic osteolysis tissues as compared with OA synovial tissues. In the particle-induced model of osteolysis of the calvaria, bone resorption was significantly suppressed by OPN deficiency via inhibition of osteoclastogenesis, whereas an inflammatory reaction was observed regardless of the genotype. Results of immunostaining indicated that OPN protein was highly expressed in the membrane and bone surface at the area of bone resorption in WT mice. When BMMs were exposed to titanium particles, the concentration of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin-1alpha (IL-1alpha), IL-1beta, and IL-6, as well as chemotactic factors, such as monocyte chemoattractant protein 1 and macrophage inflammatory protein 1alpha, in the conditioned medium were significantly reduced by OPN deficiency. Whereas phagocytic activity of BMMs was not attenuated by OPN deficiency, phagocytosis-mediated NF-kappaB activation was impaired in OPN-deficient BMMs. These data indicated that OPN was implicated in the development of particle-induced osteolysis via the orchestration of pro-/antiinflammatory cytokines secreted from macrophages. CONCLUSION: OPN plays critical roles in wear debris-induced osteolysis, suggesting that OPN is a candidate therapeutic target for periprosthetic osteolysis.

Transplanted neural progenitor cells expressing mutant NT3 promote myelination and partial hindlimb recovery in the chronic phase after spinal cord injury.

Neutrotrophin-3 (NT3) plays a protective role in injured central nervous system tissues through interaction with trk receptors. To enhance the regeneration of damaged tissue, a combination therapy with cell transplantation and neurotrophins has been under development. We examined whether the transplantation of neural progenitor cells (NPCs) secreting NT3/D15A, a multi-neurotrophin with the capacity to bind both trkB and trkC, would enhance the repair of damaged tissues and the functional recovery in a chronic phase of spinal cord injury. The cultured NPCs with lentiviral vector containing either GFP or NT3/D15A were transplanted into the contused spinal cord at 6 weeks after the initial thoracic injury. Eight weeks after the transplantation, the NT3/D15A transplants displayed better survival than the GFP transplants, and they exhibited enhanced myelin formation and partial improvement of hindlimb function. Our study revealed that NT3/D15A produced positive effects in injured spinal cords even in the chronic phase. These effects suggest an enhanced neurotrophin-trk signaling by NT3/D15A.

Diagnosis of incomplete conduction block of spinal cord from skin surface using spinal cord evoked magnetic fields.

BACKGROUND: We previously reported the usefulness of neuromagnetic recordings for the diagnosis of disorders in peripheral nerves or the spinal cord. However, there have been no reports on incomplete conduction block of the spinal cord, which is clinically common in conditions such as cervical myelopathy. Here, we estimated the usefulness of measuring spinal cord evoked magnetic fields for evaluating incomplete conduction block. METHODS: Incomplete conduction block models of the spinal cord of the rabbit were established using a Fogarty balloon catheter that was inserted into the epidural space of the cervical spine. Electrical stimuli were applied to the lower thoracic spinal cord with an epidural catheter electrode. Spinal cord evoked potentials were recorded using epidural electrodes. Spinal cord evoked magnetic fields were recorded over the skin surface of the neck using a biomagnetometer. RESULTS: The decrease in the conduction velocity and amplitude at the compression site could be detected by spinal cord evoked potentials from the epidural space, confirming the spinal cord lesion. The waveforms of the magnetic fields showed a biphasic configuration. The distribution of magnetic fields showed a characteristic quadrupolar pattern propagating from caudal to cranial. After compression, the amplitude and the conduction velocity of the magnetic fields decreased, and the distribution of magnetic fields were attenuated and decelerated near the compression site especially in the trailing magnetic fields. Diagnosis of the incomplete conduction block was thus possible. CONCLUSIONS: We report the first measurement of the spinal cord evoked magnetic field in the intact spinal cord from the skin surface and that it can be applied to incomplete conduction block of the injured spinal cord. The use of a biomagnetometer is promising as a less-invasive method for clinically evaluating spinal cord function.

Incidence of complications associated with spinal endoscopic surgery: nationwide survey in 2007 by the Committee on Spinal Endoscopic Surgical Skill Qualification of Japanese Orthopaedic Association.

BACKGROUND: This report was conducted to elucidate the current status of spinal endoscopic surgery and relevant incidents through analysis of the results of a questionnaire survey conducted in 2007 by the Committee on Spinal Endoscopic Surgical Skill Qualification of the Japanese Orthopaedic Association (JOA). METHODS: Questionnaire forms were sent to 2011 training facilities nationwide certified by the JOA, and 1082 of these facilities returned the filled questionnaires (response rate 53.8%). Of these facilities, 257 (23.8% of the responding facilities) undertook spinal endoscopic surgery in 2007. These institutions were asked to fill in the survey form with the details of the operations and relevant incidents as well as the incident levels. RESULTS: In total, the 257 facilities performed 6239 spinal endoscopic surgeries during 2007. Posterior spinal endoscopic surgery constituted most of the operations (6217 cases, 98.2%) including 4336 cases of microendoscopic discectomy (MED), 1273 cases of microendoscopic laminectomy or fenestration, and 379 cases of transforaminal or posterior lumbar interbody fusion. The total number of incidents was 133 (2.13%). The numbers of incidents by operative method were 75 (56.4%) during MED, 57 (42.9%) during microendoscopic laminectomy or fenestration, and 1 (0.8%) during interbody fusion. Of 133 incidents, dural tear occurred in 99 (74.4%), injury of the cauda equina or a nerve root in 7 (5.3%), facet fracture in 7 (5.3%), hematoma and wrong level in 6 each (4.5%), and wrong side and bedsore in 1 each (0.8%). The incident level was level 1 in 6, level 2 in 24, level 3a in 82, level 3b in 16, level 4 in 5, and level 5 (fatal) in 0. CONCLUSIONS: The results of this survey revealed an increasing trend of spinal endoscopic surgery and a decreasing trend of the complication rates. The complication rates of spinal endoscopic surgery were not higher than those of conventional surgery, indicating the safety of this surgical method.

CCAAT/enhancer-binding protein homologous protein (CHOP) regulates osteoblast differentiation.

Differentiation of committed osteoblasts is controlled by complex activities involving signal transduction and gene expression, and Runx2 and Osterix function as master regulators for this process. Recently, CCAAT/enhancer-binding proteins (C/EBPs) have been reported to regulate osteogenesis in addition to adipogenesis. However, the roles of C/EBP transcription factors in the control of osteoblast differentiation have yet to be fully elucidated. Here we show that C/EBP homologous protein (CHOP; also known as C/EBPzeta) is expressed in bone as well as in mesenchymal progenitors and primary osteoblasts. Overexpression of CHOP reduces alkaline phosphatase activity in primary osteoblasts and suppresses the formation of calcified bone nodules. CHOP-deficient osteoblasts differentiate more strongly than their wild-type counterparts, suggesting that endogenous CHOP plays an important role in the inhibition of osteoblast differentiation. Furthermore, endogenous CHOP induces differentiation of calvarial osteoblasts upon bone morphogenetic protein (BMP) treatment. CHOP forms heterodimers with C/EBPbeta and inhibits the DNA-binding activity as well as Runx2-binding activity of C/EBPbeta, leading to inhibition of osteocalcin gene transcription. These findings indicate that CHOP acts as a dominant-negative inhibitor of C/EBPbeta and prevents osteoblast differentiation but promotes BMP signaling in a cell-type-dependent manner. Thus, endogenous CHOP may have dual roles in regulating osteoblast differentiation and bone formation.

The distinct role of the Runx proteins in chondrocyte differentiation and intervertebral disc degeneration: findings in murine models and in human disease.

OBJECTIVE: Runx2 is a transcription factor that regulates chondrocyte differentiation. This study was undertaken to address the role of the different Runx proteins (Runx1, Runx2, or Runx3) in chondrocyte differentiation using chondrocyte-specific Runx-transgenic mice, and to study the importance of the QA domain of Runx2, which is involved in its transcriptional activation. METHODS: Runx expression was analyzed in the mouse embryo by in situ hybridization. Overexpression of Runx1, Runx2 (lacking the QA domain [DeltaQA]), or Runx3 was induced in chondrocytes in vivo, to produce alpha(1)II-Runx1, alpha(1)II-Runx2DeltaQA, and alpha(1)II-Runx3 mice, respectively, for histologic and molecular analyses. Runx expression was also examined in an experimental mouse model of mechanical stress-induced intervertebral disc (IVD) degeneration and in human patients with IVD degeneration. RESULTS: Runx1 expression was transiently observed in condensations of mesenchymal cells, whereas Runx2 and Runx3 were robustly expressed in prehypertrophic chondrocytes. Similar to alpha(1)II-Runx2 mice, alpha(1)II-Runx2DeltaQA and alpha(1)II-Runx3 mice developed ectopic mineralization of cartilage, but this was less severe in the alpha(1)II-Runx2DeltaQA mice. In contrast, alpha(1)II-Runx1 mice displayed no signs of ectopic mineralization. Surprisingly, alpha(1)II-Runx1 and alpha(1)II-Runx2 mice developed scoliosis due to IVD degeneration, characterized by an accumulation of extracellular matrix and ectopic chondrocyte hypertrophy. During mouse embryogenesis, Runx2, but not Runx1 or Runx3, was expressed in the IVDs. Moreover, both in the mouse model of IVD degeneration and in human patients with IVD degeneration, there was significant up-regulation of Runx2 expression. CONCLUSION: Each Runx protein has a distinct, yet overlapping, role during chondrocyte differentiation. Runx2 contributes to the pathogenesis of IVD degeneration.

Postoperative hip motion and functional recovery after simultaneous bilateral total hip arthroplasty for bilateral osteoarthritis.

BACKGROUND: Simultaneous bilateral total hip arthroplasty (THA) can offer a potential benefit of greater postoperative hip motion without the negative influence of contralateral hip disabilities, compared to two-stage THA. However, postoperative changes in hip motion after simultaneous bilateral THA have rarely been reported. The purpose of this study was to clarify the efficacy of simultaneous procedures on postoperative hip motion and functional recovery. METHODS: We retrospectively compared hip motion in 27 patients treated with simultaneous bilateral THA to those in 11 patients with two-stage bilateral THA, 35 patients with unilateral THA for unilateral disease, and 15 patients with unilateral THA for bilateral disease. We also evaluated the clinical manifestations according to the Japanese Orthopaedic Association (JOA) hip scores and compared the outcomes among the groups. All of the THA surgeries were primarily performed through a posterolateral approach using cement-less prostheses. The diagnosis at surgery was dysplastic osteoarthritis in all patients, and the patients were followed up for at least 4 years. RESULTS: The postoperative improvement of motion in hip flexion was significantly greater in patients treated with simultaneous procedures compared to patients with two-stage THA and unilateral THA for bilateral disease. The differences in improvement of motion in hip abduction were less marked than the improvement in hip flexion among the groups. Although there were no significant differences in pain scores among the groups, the values for activity of daily living were significantly greater in patients treated with simultaneous bilateral THA and patients with unilateral THA for unilateral disease than in patients with unilateral and two-stage bilateral THA for bilateral disease. CONCLUSIONS: The simultaneous procedure was considered to be more effective in patients with bilateral hip osteoarthritis and demonstrated a substantial improvement in hip motion and functional recovery after THA.

The effect of preoperative lateral flexibility of the lumbar spine on perceived leg length discrepancy after total hip arthroplasty.

BACKGROUND: Leg length discrepancy (LLD) after total hip arthroplasty (THA) is a significant factor of patient dissatisfaction. Patients with dissociation between preoperative radiographic LLD and perceived LLD sometimes feel LLD postoperatively even if bilateral leg lengths are equal. There is no publication describing how to decide the amount of leg lengthening in such cases. PURPOSE: By examining the influence of preoperative lumbar lateral flexibility on postoperative perceived LLD, this study aims at creating a guideline for the optimal planning of leg lengthening in THA. METHODS: In 59 cases undergoing primary unilateral THA, radiographic LLD, perceived LLD, pelvic tilting and lumbar lateral flexibility were measured preoperatively. The amount of leg lengthening and the sequential change of the perceived LLD were measured postoperatively. RESULTS: Twelve cases (20%) felt the perceived LLD at two years after surgery. All these cases felt the operative side longer than the non-operative side. In 32 cases with preoperative pelvic inclination to the affected side, postoperative perceived LLD was significantly greater if lumbar spine was rigid. In eight cases with pelvic tilting and rigid lumber spine, the amount of leg lengthening that exceeded preoperative perceived LLD affected the postoperative perceived LLD. CONCLUSIONS: In cases with preoperative pelvic inclination downward to the affected side and with rigid lumbar spine, amount of leg lengthening should not be excessively greater than preoperative perceived LLD. In other cases, lengthening the leg to the same length as the contralateral side rarely results in postoperative perceived LLD.