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1.  Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant 
The Journal of Clinical Investigation  2013;123(11):4909-4917.
Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family–based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.
PMCID: PMC3809787  PMID: 24216480
2.  Lumbar Spinal Stenosis Due to a Large Calcified Mass in the Ligamentum Flavum 
Asian Spine Journal  2013;7(3):236-241.
We describe a rare case of lumbar spinal stenosis due to a large calcified mass in the ligamentum flavum. This patient presented with a 12-month history of severe right leg pain and intermittent claudication. A computed tomography scan was performed, revealing a large calcified mass on the ligamentum flavum at the right-hand side of the lumbar spinal canal. We performed a laminotomy at the L4/5 level with resection of the calcified mass from the ligamentum flavum. The findings of various analyses suggested that the calcified mass consisted mostly of Ca3(PO4)2 and calcium phosphate intermixed with protein and water. The calcified mass in the ligamentum flavum was causing lumbar spinal stenosis. Surgical decompression by resection of the mass was effective in this patient. The calcified material was composed mainly of elements derived from calcium phosphate. Degenerative changes in the ligamentum flavum of the lumbar spine may have been involved in the production of this calcified mass.
PMCID: PMC3779778  PMID: 24066222
Spinal stenosis; Calcification; Ligamentum flavum; Calcium phosphate
3.  Minimum 10-Year Follow-up Study of Anterior Lumbar Interbody Fusion for Degenerative Spondylolisthesis: Progressive Pattern of the Adjacent Disc Degeneration 
Asian Spine Journal  2012;6(2):105-114.
Study Design
Retrospective study.
The aims of the current study are to evaluate the minimum 10-year follow-up clinical results of anterior lumbar interbody fusion (ALIF) for degenerative spondylolisthesis.
Overview of Literature
ALIF has been widely used as a treatment regimen in the management of lumbar spondylolisthesis. Still much controversy exists regarding the factors that affect the postoperative clinical outcomes.
The author performed a retrospective review of 20 patients with degenerative spondylolisthesis treated with ALIF (follow-up, 16.4 years). The clinical results were assessed by the Japanese Orthopaedic Association (JOA) score for low back pain, vertebral slip and disc height index on the radiographs.
The mean preoperative JOA score was 7.1 ± 1.8 points (15-point-method). At 1 year, 5 years, and 10 years or more after surgery, the JOA scores were assessed as 12.4 ± 2.2 points, 12.7 ± 2.6 points, 12.0 ± 2.5 points, respectively (excluding the data of reoperated cases). The adjacent disc degeneration developed in all cases during the long-term follow-up. The progressive pattern of disc degeneration was divided into three types. Initially, disc degeneration occurred due to disc space narrowing. After that, the intervertebral discs showed segmental instability with translation at the upper level. But the lower discs showed osteophyte formation, and occasionally lead to the collapse or spontaneous union.
The clinical results of the long-term follow-up data after ALIF became worse due to the adjacent disc degeneration. The progressive pattern of disc degeneration was different according to the adjacent levels.
PMCID: PMC3372545  PMID: 22708014
Spondylolisthesis; Lumbar regions; Intervertebral disc disease
4.  Myxoid Liposarcoma-Associated EWSR1-DDIT3 Selectively Represses Osteoblastic and Chondrocytic Transcription in Multipotent Mesenchymal Cells 
PLoS ONE  2012;7(5):e36682.
Liposarcomas are the most common class of soft tissue sarcomas, and myxoid liposarcoma is the second most common liposarcoma. EWSR1-DDIT3 is a chimeric fusion protein generated by the myxoid liposarcoma-specific chromosomal translocation t(12;22)(q13;q12). Current studies indicate that multipotent mesenchymal cells are the origin of sarcomas. The mechanism whereby EWSR1-DDIT3 contributes to the phenotypic selection of target cells during oncogenic transformation remains to be elucidated.
Methodology/Principal Findings
Reporter assays showed that the EWSR1-DDIT3 myxoid liposarcoma fusion protein, but not its wild-type counterparts EWSR1 and DDIT3, selectively repressed the transcriptional activity of cell lineage-specific marker genes in multipotent mesenchymal C3H10T1/2 cells. Specifically, the osteoblastic marker Opn promoter and chondrocytic marker Col11a2 promoter were repressed, while the adipocytic marker Ppar-γ2 promoter was not affected. Mutation analyses, transient ChIP assays, and treatment of cells with trichostatin A (a potent inhibitor of histone deacetylases) or 5-Aza-2′-deoxycytidine (a methylation-resistant cytosine homolog) revealed the possible molecular mechanisms underlying the above-mentioned selective transcriptional repression. The first is a genetic action of the EWSR1-DDIT3 fusion protein, which results in binding to the functional C/EBP site within Opn and Col11a2 promoters through interaction of its DNA-binding domain and subsequent interference with endogenous C/EBPβ function. Another possible mechanism is an epigenetic action of EWSR1-DDIT3, which enhances histone deacetylation, DNA methylation, and histone H3K9 trimethylation at the transcriptional repression site. We hypothesize that EWSR1-DDIT3-mediated transcriptional regulation may modulate the target cell lineage through target gene-specific genetic and epigenetic conversions.
This study elucidates the molecular mechanisms underlying EWSR1-DDIT3 fusion protein-mediated phenotypic selection of putative target multipotent mesenchymal cells during myxoid liposarcoma development. A better understanding of this process is fundamental to the elucidation of possible direct lineage reprogramming in oncogenic sarcoma transformation mediated by fusion proteins.
PMCID: PMC3343026  PMID: 22570737
5.  Vertebroplasty Using Calcium Phosphate Cement for Osteoporotic Vertebral Fractures: Study of Outcomes at a Minimum Follow-up of Two Years 
Asian Spine Journal  2012;6(1):34-42.
Study Design
A case-series study.
To assess the long-term clinical and radiographic outcomes after vertebroplasty using calcium phosphate cement (CPC) for treatment of osteoporotic vertebral fractures (OVF).
Overview of Literature
Vertebroplasty has become common for the treatment of OVF. However, few studies have reported the clinical application of CPC to vertebroplasty.
We reviewed 86 consecutive patients undergoing 99 vertebroplasties using CPC. Following repositioning and curettage of the pathological soft tissue of the vertebral body (VB), vertebroplasty using CPC was performed in patients with osteoporotic burst fracture and pseudoarthrosis (procedure A). Vertebroplasty was also performed in patients with osteoporotic compression fractures (procedure B). Back pain and lower back pain were evaluated using the visual analogue scale (VAS). The VB deformity index was measured in a lateral radiograph as the ratio of the VB's height to its longitudinal diameter.
The mean age at time of surgery was 77 years old. The mean duration of follow-up was forty-four months. All patients reported decreased pain according to the VAS immediately after vertebroplasty, and pain relief was maintained at the last follow-up in all patients without new OVFs. Complete bone union was observed in all cases by six months after surgery. The mean recovery rate of deformity index was 5.9% in procedure A and 0.02% in procedure B at the final follow-up visit.
Vertebroplasty using CPC gave a satisfactory outcome and no delayed complications in elderly patients with osteoporotic vertebral fractures at follow-up times of at least two years.
PMCID: PMC3302913  PMID: 22439086
Osteoporosis; Vertebral fracture; Biodegradable bone cement substitutes; Calcium phosphate cement; Vertebroplasty
6.  Loss of Deacetylation Activity of Hdac6 Affects Emotional Behavior in Mice 
PLoS ONE  2012;7(2):e30924.
Acetylation is mediated by acetyltransferases and deacetylases, and occurs not only on histones but also on diverse proteins. Although histone acetylation in chromatin structure and transcription has been well studied, the biological roles of non-histone acetylation remain elusive. Histone deacetylase 6 (Hdac6), a member of the histone deacetylase (HDAC) family, is a unique deacetylase that localizes to cytoplasm and functions in many cellular events by deacetylating non-histone proteins including α-tubulin, Hsp90, and cortactin. Since robust expression of Hdac6 is observed in brain, it would be expected that Hdac6-mediated reversible acetylation plays essential roles in CNS. Here we demonstrate the crucial roles of Hdac6 deacetylase activity in the expression of emotional behavior in mice. We found that Hdac6-deficient mice exhibit hyperactivity, less anxiety, and antidepressant-like behavior in behavioral tests. Moreover, administration of Hdac6-specific inhibitor replicated antidepressant-like behavior in mice. In good agreement with behavioral phenotypes of Hdac6-deficient mice, Hdac6 dominantly localizes to the dorsal and median raphe nuclei, which are involved in emotional behaviors. These findings suggest that HDAC6-mediated reversible acetylation might contribute to maintain proper neuronal activity in serotonergic neurons, and also provide a new therapeutic target for depression.
PMCID: PMC3273475  PMID: 22328923
7.  Multi-focal Myxopapillary Ependymoma in the Lumbar and Sacral Regions Requiring Cranio-spinal Radiation Therapy: A Case Report 
Asian Spine Journal  2011;5(1):68-72.
Ependymomas are uncommon tumors that arise in the brain, spinal cord or cauda equina. Myxopapillary ependymomas is located exclusively in the conus medullaris or cauda equina, or film terminale region. In most myxopapillary ependymomas, the histological examination reveals low mitotic activity that is associated with a low MIB-1 labeling index (LI). The prognosis is generally favorable, when the appropriate treatment, including a total resection, is performed. The authors encountered a 39-year-old man with multifocal type of myxopapillary ependymomas compressing the cauda equina from the L2 to L3 level and L5-S1 level. A subtotal resection of the tumor was carried out. The histological examination revealed extremely high mitotic activity with a MIB-1 LI of 9.1%. Therefore, cranio-spinal radiation was added after surgery. The postoperative course was uneventful over the 3.5 year follow-up period.
PMCID: PMC3047901  PMID: 21386949
Myxopapillary ependymoma; Lumbar and sacral regions; Cranio-spinal radiation therapy; MIB-1 index; Tumor recurrence
9.  Postoperative Meningitis in Patients with Cervical Cord Tumor: A Case Report 
Asian Spine Journal  2010;4(2):136-140.
Postoperative meningitis after spinal surgery is a rare complication that can result in a life-threatening condition. Linezolid (LZD) is an oxazolidinone which has been approved in Japan for infections caused by methicillin-resistant Staphylococcus aureus. The authors encountered a case of postoperative meningitis with cerebrospinal fluid leakage (liquorrhoea) that occurred after resection of a cervical cord tumor. The infection was caused by methicillin-resistant Staphylococcus epidermidis(MRSE). Debridement and suture of the dura matter was carried out. LZD was given intravenously. The infection was cured without any sequelae. Based on this result, we concluded that LZD might be considered as one of the first choices for the treatment of postsurgical meningitis caused by MRSE.
PMCID: PMC2996627  PMID: 21165319
CSF leakage; Postoperative meningitis; Surgical site infection; Methicillin-resistant Staphylococcus epidermidis; Linezolid
10.  The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis 
Cancer research  2008;68(18):7561-7569.
Histone deacetylase inhibitors (HDACI) are promising anti-tumor agents. Although transcriptional deregulation is thought to be the main mechanism underlying their therapeutic effects, the exact mechanism and targets by which HDAC inhibitors achieve their anti-tumor effects remains poorly understood. It is not known whether any of the HDAC members support robust tumor growth. In this report we show that HDAC6, a cytoplasmic localized and cytoskeleton-associated deacetylase, is required for efficient oncogenic transformation and tumor formation. We found that HDAC6 expression is induced upon oncogenic Ras transformation. Fibroblasts deficient in HDAC6 are more resistant to both oncogenic Ras and ErbB2-dependent transformation, indicating a critical role for HDAC6 in oncogene-induced transformation. Supporting this hypothesis, inactivation of HDAC6 in several cancer cell lines reduces anchorage-independent growth and the ability to form tumors in mice. The loss of anchorage-independent growth is associated with increased anoikis and defects in AKT and ERK kinase activation upon loss of adhesion. Lastly, HDAC6 null mice are more resistant to chemical carcinogen-induced skin tumors. Our results provide the first experimental evidence that a specific HDAC member is required for efficient oncogenic transformation and indicate that HDAC6 is an important component underlying the anti-tumor effects of HDAC inhibitors.
PMCID: PMC2978070  PMID: 18794144
HDAC6; deacetylation; anoikis; transformation; HDAC inhibitor
11.  Effect of small interference RNA (siRNA) for ADAMTS5 on intervertebral disc degeneration in the rabbit anular needle-puncture model 
Arthritis Research & Therapy  2009;11(6):R166.
The etiology of degenerative disc disease is unknown. Several investigators have reported the presence of proteolytic enzymes, such as the matrix metalloproteinase (MMP) and ADAMTS (a disintegrin and metalloprotease with thrombospondin-like repeats) families, in degenerated human discs. Glasson and colleagues recently reported that a significant reduction occurs in the severity of cartilage destruction in ADAMTS5 knockout mice compared with wild-type mice. The purpose of this study was to evaluate the suppressive effects of injections of ADAMTS5 small interference RNA (siRNA) oligonucleotide on intervertebral disc degeneration in the rabbit anular needle-puncture model.
Rabbit nucleus pulposus (NP) cells were transfected with siRNA oligonucleotides specific for ADAMTS5 or the control. The suppression of the ADAMTS5 gene by siRNA transfection was assessed by using real-time polymerase chain reaction (PCR), both in monolayer and alginate bead cultures with or without interleukin-1β (IL-1β) stimulation. The effect of siRNA was determined in vivo by using the rabbit anular needle-puncture model (control group: n = 8; ADAMTS5 group: n = 8). One week after the initial anular puncture, the animals received an injection of the control or anti-ADAMTS5 oligonucleotide (100 μg each at the L2/3 and L4/5 level; 16 discs/group). Disc height, magnetic resonance imaging (MRI) (Thompson classification and signal intensity), and safranin-O staining (histologic grade) were assessed.
IL-1β treatment significantly increased the ADAMTS5 mRNA level in NP cells (P < 0.01). ADAMTS5 gene suppression was 70% compared with the control oligonucleotide in both monolayer and alginate bead culture with or without stimulation with IL-1β. The injection of anti-ADAMTS5 oligonucleotide in vivo resulted in improved MRI scores with increased signal intensity and improved histologic grade scores with statistical significance (P < 0.05). No significant change in disc height was observed.
A single injection of ADAMTS5 siRNA induced the suppression of degradation in NP tissues, as shown by significantly improved MRI and histologic grades. The mechanism of response to siRNA may be worthy of exploration for possible therapeutic purposes.
PMCID: PMC3003501  PMID: 19889209

Results 1-11 (11)