Details of a Researcher - Matsumoto, Morio

Papers - Matsumoto, Morio

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Methotrexate inhibits osteoclastogenesis by decreasing RANKL-induced calcium influx into osteoclast progenitors

Kanagawa Hiroya, Masuyama Ritsuko, Morita Mayu, Sato Yuiko, Niki Yasuo, Kobayashi Tami, Katsuyama Eri, Fujie Atsuhiro, Hao Wu, Tando Toshimi, Watanabe Ryuichi, Miyamoto Kana, Morioka Hideo, Matsumoto Morio, Toyama Yoshiaki, Saya Hideyuki, Miyamoto Takeshi

Journal of Bone and Mineral Metabolism 2015.07

ISSN 0914-8779

The increasing number of osteoporosis patients is a pressing issue worldwide. Osteoporosis frequently causes fragility fractures, limiting activities of daily life and increasing mortality. Many osteoporosis patients take numerous medicines due to other health issues; thus, it would be preferable if a single medicine could ameliorate osteoporosis and other conditions. Here, we screened 96 randomly selected drugs targeting various diseases for their ability to inhibit differentiation of osteoclasts, which play a pivotal role in development of osteoporosis, and identified methotrexate (MTX), as a potential inhibitor. MTX is currently used to treat sarcomas or leukemic malignancies or auto-inflammatory diseases such as rheumatoid arthritis (RA) through its anti-proliferative and immunosuppressive activities; however, a direct effect on osteoclast differentiation has not been shown. Here, we report that osteoclast formation and expression of osteoclastic genes such as NFATc1 and DC-STAMP, which are induced by the cytokine RANKL, are significantly inhibited by MTX. We found that RANKL-dependent calcium (Ca) influx into osteoclast progenitors was significantly inhibited by MTX. RA patients often develop osteoporosis, and osteoclasts are reportedly required for joint destruction; thus, MTX treatment could have a beneficial effect on RA patients exhibiting high osteoclast activity by preventing both osteoporosis and joint destruction.

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Hyperglycemia promotes Schwann cell de-differentiation and de-myelination via sorbitol accumulation and Igf1 protein down-regulation

Hao Wu, Tashiro Syoichi, Hasegawa Tomoka, Sato Yuiko, Kobayashi Tami, Tando Toshimi, Katsuyama Eri, Fujie Atsuhiro, Watanabe Ryuichi, Morita Mayu, Miyamoto Kana, Morioka Hideo, Nakamura Masaya, Matsumoto Morio, Amizuka Norio, Toyama Yoshiaki, Miyamoto Takeshi

Journal of Biological Chemistry 290 ( 28 ) 17106 - 17115 2015.07

ISSN 0021-9258

Diabetes mellitus (DM) is frequently accompanied by complications, such as peripheral nerve neuropathy. Schwann cells play a pivotal role in regulating peripheral nerve function and conduction velocity; however, changes in Schwann cell differentiation status in DM are not fully understood. Here, we report that Schwann cells de-differentiate into immature cells under hyperglycemic conditions as a result of sorbitol accumulation and decreased Igf1 expression in those cells. We found that dedifferentiated Schwann cells could be re-differentiated in vitro into mature cells by treatment with an aldose reductase inhibitor, to reduce sorbitol levels, or with vitaminD<inf>3</inf>, to elevate Igf1 expression. In vivo DM models exhibited significantly reduced nerve function and conduction, Schwann cell de-differentiation, peripheral nerve de-myelination,andall conditionsweresignificantly rescued by aldose reductase inhibitor or vitamin D<inf>3</inf> administration. These findings reveal mechanisms underlying pathological changes in Schwann cells seen in DM and suggest ways to treat neurological conditions associated with this condition.

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Synergistic antiproliferative effect of imatinib and adriamycin in platelet-derived growth factor receptor-expressing osteosarcoma cells

Yamaguchi Sayaka I., Ueki Arisa, Sugihara Eiji, Onishi Nobuyuki, Yaguchi Tomonori, Kawakami Yutaka, Horiuchi Keisuke, Morioka Hideo, Matsumoto Morio, Nakamura Masaya, Muto Akihiro, Toyama Yoshiaki, Saya Hideyuki, Shimizu Takatsune

Cancer Science 106 ( 7 ) 875 - 882 2015.07

ISSN 1347-9032

Osteosarcoma (OS) is the most frequent primary solid malignant tumor of bone. Its prognosis remains poor in the substantial proportion of patients who do not respond to chemotherapy and novel therapeutic options are therefore needed. We previously established a mouse model that mimics the aggressive behavior of human OS. Enzyme-linked immunosorbent assay-based screening of such mouse tumor lysates identified platelet-derived growth factor-BB (PDGF-BB) as an abundant soluble factor, the gene for which was expressed dominantly in surrounding non-malignant cells of the tumor, whereas that for the cognate receptor (PDGF receptor β) was highly expressed in OS cells. Platelet-derived growth factor-BB induced activation of both MEK-ERK and phosphatidylinositol 3-kinase-protein kinase B signaling pathways and promoted survival in OS cells deprived of serum, and these effects were blocked by the PDGF receptor inhibitor imatinib. However, these actions of PDGF-BB and imatinib were mostly masked in the presence of serum. Whereas imatinib alone did not manifest an antitumor effect in mice harboring OS tumors, combined treatment with imatinib and adriamycin exerted a synergistic antiproliferative effect on OS cells in vivo. These results suggest that treatment of OS with imatinib is effective only when cell survival is dependent on PDGF signaling or when imatinib is combined with another therapeutic intervention that renders the tumor cells susceptible to imatinib action, such as by inducing cellular stress.

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Breast carcinoma metastasis to meningioma in the thoracic spine

Okada Eijiro, Nakamura Masaya, Koshida Yoshitomo, Mukai Kiyoshi, Toyama Yoshiaki, Matsumoto Morio

Journal of Spinal Cord Medicine 38 ( 2 ) 231 - 235 2015.03

ISSN 1079-0268

Context: Systemic metastasis to a primary tumor of the central nervous system is uncommon. Breast carcinomas metastasizing to a possibly preexisting meningioma in the spine are reported very rarely. Study design: Case report. Findings: A 69-year-old female was referred to us with progressive gait disturbance. She had undergone a total mastectomy for carcinoma of the right breast 11 years previously. A magnetic resonance imaging of the thoracic spine showed an intra- and extradural spinal cord tumor. The patient underwent resection of the tumor via laminectomy from T2 to T4. After the operation, the patient's neurological status improved significantly, and she was able to walk without assistance. Histological examination showed the tumor to be a fibrous-type meningioma within a metastatic breast cancer tumor. The patient underwent 40 Gy radiation treatment for local control of the tumor. However, the tumor recurred locally 7 months after the surgery. The patient died of carcinomatous pleurisy 13 months after the surgery. Conclusion: This case illustrates that a primary meningioma in the thoracic spine can be a recipient of breast cancer metastasis, which may alter the treatment strategy.

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Bcl6 promotes osteoblastogenesis through stat1 inhibition

Fujie Atsuhiro, Funayama Atsushi, Miyauchi Yoshiteru, Sato Yuiko, Kobayashi Tami, Kanagawa Hiroya, Katsuyama Eri, Hao Wu, Tando Toshimi, Watanabe Ryuichi, Morita Mayu, Miyamoto Kana, Kanaji Arihiko, Morioka Hideo, Matsumoto Morio, Toyama Yoshiaki, Miyamoto Takeshi

Biochemical and Biophysical Research Communications 457 ( 3 ) 451 - 456 2015.02

ISSN 0006-291X

Bone mass is tightly controlled by a balance between osteoclast and osteoblast activities. Although these cell types mature via different pathways, some factors reportedly regulate differentiation of both. Here, in a search for factors governing osteoblastogenesis but also expressed in osteoclasts to control both cell types by one molecule, we identified B cell lymphoma 6 (Bcl6) as one of those factors and show that it promotes osteoblast differentiation. Bcl6 was previously shown to negatively regulate osteoclastogenesis. We report that lack of Bcl6 results in significant inhibition of osteoblastogensis in vivo and in vitro and in defects in secondary ossification center formation in vivo. Signal transducer and activator of transcription 1 (Stat1) reportedly attenuates osteoblast differentiation by inhibiting nuclear translocation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation. We found that lack of Bcl6 resulted in signifi cant elevation of Stat1 mRNA and protein expression in osteoblasts and showed that Stat1 is a direct target of Bcl6 using a chromatin immune-precipitation assay. Mice lacking both Bcl6 and Stat1 (DKO) exhibited significant rescue of bone mass and osteoblastic parameters as well as partial rescue of secondary ossification center formation compared with Bcl6-de ficient mice in vivo. Altered osteoblastogenesis in Bcl6-defi cient cells was also restored in DKO in vitro. Thus, Bcl6 plays crucial roles in regulating both osteoblast activation and osteoclast inhibition.

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ADAM17 regulates IL-1 signaling by selectively releasing IL-1 receptor type 2 from the cell surface

Uchikawa Shinichi, Yoda Masaki, Tohmonda Takahide, Kanaji Arihiko, Matsumoto Morio, Toyama Yoshiaki, Horiuchi Keisuke

Cytokine 71 ( 2 ) 238 - 245 2015.02

ISSN 1043-4666

Interleukin (IL)-1 is one of the most evolutionarily conserved cytokines and plays an essential role in the regulation of innate immunity. IL-1 binds to two different receptors, IL-1R1 and IL-1R2, which share approximately 28% amino acid homology. IL-1R1 contains a cytoplasmic domain and is capable of transducing cellular signals; by contrast, IL-1R2 lacks a functional cytoplasmic domain and serves as a decoy receptor for IL-1. Interestingly, IL-1R2 is proteolytically cleaved and also functions as a soluble receptor that blocks IL-1 activity. In the present study, we examined the shedding properties of IL-1R2 and demonstrate that ADAM17 is de facto the major sheddase for IL-1R2 and that introducing a mutation into the juxta-membrane domain of IL-1R2 significantly desensitizes IL-1R2 to proteolytic cleavage. IL-1R1 was almost insensitive to ADAM17-dependent cleavage; however, the replacement of the juxta-membrane domain of IL-R1 with that of IL-1R2 significantly increased the sensitivity of IL-1R1 to shedding. Furthermore, we demonstrate that ADAM17 indirectly enhances IL-1 signaling in a cell-autonomous manner by selectively cleaving IL-1R2. Taken together, the data collected in the present study indicate that ADAM17 affects sensitivity to IL-1 by changing the balance between IL-1R1 and the decoy receptor IL-1R2.

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Effects of Reduction Osteotomy on Gap Balancing During Total Knee Arthroplasty for Severe Varus Deformity

Niki Yasuo, Harato Kengo, Nagai Katsuya, Suda Yasunori, Nakamura Masaya, Matsumoto Morio

Journal of Arthroplasty 2015.01

ISSN 0883-5403

This study aimed to assess the effects of down-sizing and lateralizing of the tibial component (reduction osteotomy) on gap balancing in TKA, and the clinical feasibility of an uncemented modular trabecular metal tibial tray in this technique. Reduction osteotomy was performed for 39 knees of 36 patients with knee OA with a mean tibiofemoral angle of 21° varus. In 20 knees, appropriate gap balance was achieved by release of the deep medial collateral ligament alone. Flexion gap imbalance could be reduced by approximately 1.7° and 2.8° for 4-mm osteotomy and 8-mm osteotomy, respectively. Within the first postoperative year, clinically-stable tibial component subsidence was observed in 9 knees, but it was not progressive, and the clinical results were excellent at a mean follow-up of 3.3years.

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The paravertebral muscle and psoas for the maintenance of global spinal alignment in patient with degenerative lumbar scoliosis

Yagi Mitsuru, Hosogane Naobumi, Watanabe Kota, Asazuma Takashi, Matsumoto Morio

Spine Journal 2015.01

ISSN 1529-9430

Background context: Various factors are reported to affect the spinal alignment in degenerative lumbar scoliosis (DLS). Although trunk muscles also appear to affect spinal alignment, the role of the trunk muscles is not yet clear. Purpose: The aim was to elucidate the role of the multifidus (MF) and psoas (PS) in maintaining global spinal alignment in patients with DLS. Study design: This was a multicenter retrospective matched cohort study. Patient sample: Surgically treated 60 paired DLS and lumbar spinal stenosis (LSS) female (120 patients), matched for age and body mass index (BMI; DLS age 68.0±6.8 vs. LSS 67.1±8.9 years; BMI 21.6±3.3 vs. 23.2±3.8 kg/m2), were included and were followed for at least 2 years. Outcome measures: Spinal alignment, muscle area, and volume were measured from radiographs, magnetic resonance images (MRIs), and whole-body dual-energy X-ray absorptiometry (DXA) scans. Muscle strength was measured by grip power and peak expiratory flow (PEF). Methods: As a surrogate of muscle area, we obtained the cross-sectional area (CSA) at the L5-S level from preoperative MRIs. Results: The MF and PS CSAs were significantly smaller in the DLS group than in the LSS group (MF 477.7±192.5 vs. 779.8±248.6 mm2, p<.01; PS 692.3±201.2 vs. 943.4±272.4 mm2, p=.002), whereas percentage of difference between the right and left sides was significantly larger in the DLS group (MF 18.4±30.6 vs. 2.4±3.3%, p<.01; PS 14.4±15.8 vs. 2.1±2.2%, p<.01). In the extremities, there were no significant differences in the left- or right-side lean composition and grip strength or PEF tests between the groups. Correlation coefficient tests showed moderate correlations between the MF average CSA (avCSA) and global spinal alignment and spinopelvic alignment (pelvic incidence-lumbar lordosis; R=-0.37, -0.38) in the DLS group. The MF avCSA was correlated with the postoperative progression of kyphosis at the unfused thoracic vertebrae in the DLS group (R=0.34). Conclusions: The CSAs of the MF and PS were significantly smaller in the DLS group. Whole-body DXA showed no significant difference in the lean composition between the groups. There were significant correlations in the DLS patients between the MF CSA and sagittal spinal alignment. These findings suggest the causal relationship between muscles and global spine alignment.

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Interleukin-1 receptor-associated kinase-4 (IRAK4) promotes inflammatory osteolysis by activating osteoclasts and inhibiting formation of foreign body giant cells

Katsuyama Eri, Miyamoto Hiroya, Kobayashi Tami, Sato Yuiko, Hao Wu, Kanagawa Hiroya, Fujie Atsuhiro, Tando Toshimi, Watanabe Ryuichi, Morita Mayu, Miyamoto Kana, Niki Yasuo, Morioka Hideo, Matsumoto Morio, Toyama Yoshiaki, Miyamoto Takeshi

Journal of Biological Chemistry 290 ( 2 ) 716 - 726 2015.01

ISSN 0021-9258

Formation of foreign body giant cells (FBGCs) occurs following implantation of medical devices such as artificial joints and is implicated in implant failure associated with inflammation or microbial infection. Two major macrophage subpopulations, M1 and M2, play different roles in inflammation and wound healing, respectively. Therefore, M1/M2 polarization is crucial for the development of various inflammation-related diseases. Here, we show that FBGCs do not resorb bone but rather express M2 macrophage-like wound healing and inflammation-terminating molecules in vitro. We also found that FBGC formation was significantly inhibited by inflammatory cytokines or infection mimetics in vitro . Interleukin-1 receptor-associated kinase-4 (IRAK4) deficiency did not alter osteoclast formation in vitro, and IRAK4-deficient mice showed normal bone mineral density in vivo. However, IRAK4-deficient mice were protected from excessive osteoclastogenesis induced by IL-1β in vitro or by LPS, an infection mimetic of Gram-negative bacteria, in vivo. Furthermore, IRAK4 deficiency restored FBGC formation and expression of M2 macrophage markers inhibited by inflammatory cytokines in vitro or by LPS in vivo. Our results demonstrate that osteoclasts and FBGCs are reciprocally regulated and identify IRAK4 as a potential therapeutic target to inhibit stimulated osteoclastogenesis and rescue inhibited FBGC formation under inflammatory and infectious conditions without altering physiological bone resorption.

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Coronal plane spinal malalignment and Parkinson's disease

Choi Hong June, Smith Justin S., Shaffrey Christopher I., Lafage Virginie C., Schwab Frank J., Ames Christopher P., Matsumoto Morio, Baik Jong Sam, Ha Yoon

Spine Journal 15 ( 1 ) 115 - 121 2015.01

ISSN 1529-9430

Background context Parkinson's disease (PD) is a progressive degenerative disorder of the central nervous system. Patients with PD often present with abnormal posturing.Purpose To investigate coronal plane deformities in patients with PD, and to evaluate the correlation between clinical features, coronal parameters related to spine alignment, and disease severity.Study design A cross-sectional study.Patient sample Eighty-nine patients with PD and 89 controls were included.Outcome measures A medical history was collected from the medical records.Methods This study was a prospective assessment of consecutive patients with PD. Clinical and demographic parameters were collected from medical records and outpatient interviews. Full-length standing anteroposterior and lateral spine radiographs were used to assess the spinal parameters. The threshold for scoliosis was set at a 10° Cobb angle, and the curve type was classified using Schwab classification.Results A total of 178 patients (89 in PD and 89 in control groups) were included. Scoliosis was identified in 27 patients (30%) and 22 controls (p=.502). However, coronal imbalance was more common in patients with PD than in controls (11 vs. 0 patients, p=.001). Scoliosis was more common in women than in men (male:female=8:19, p=.04). Back pain was more common in patients with scoliosis than in those without scoliosis (14 of 27 vs. 17 of 62, p=.036). Schwab Type IV (thoracolumbar major) was the most common type of scoliosis in patients with PD and Type V (lumbar major) was the most common type in controls. With adjustment for patient age and gender, multiple linear regression analysis revealed that severity of PD (Unified Parkinson's Disease Rating Scale, p=.037) and magnitude of global coronal malalignment (p=.003) were associated with the scoliosis Cobb angle (p=.037, B=0.139). Direction of scoliosis and side of global coronal malalignment were not significantly correlated with the laterality of predominant PD symptoms (p>.05).Conclusions Global coronal malalignment is more prevalent in patients with PD than in controls. Greater severity of PD was significantly associated with greater magnitude of scoliosis Cobb angle, even after adjusting for the effects of patient age and gender. However, direction of scoliosis and side of global coronal malalignment were not significantly associated with the dominant laterality of PD symptoms.

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Antibacterial polyetheretherketone implants immobilized with silver ions based on chelate-bonding ability of inositol phosphate

Kakinuma H., Ishii K., Ishihama H., Honda M., Toyama Y., Matsumoto M., Aizawa M.

Journal of Biomedical Materials Research - Part A 103 ( 1 ) 57 - 64 2015.01

ISSN 1549-3296

We developed a novel antibacterial implant by forming a hydroxyapatite (HAp) film on polyetheretherketone (PEEK) substrate, and then immobilizing silver ions (Ag⁺) on the HAp film based on the chelate-bonding ability of inositol phosphate (IP6). First, the PEEK surface was modified by immersion into concentrated sulfuric acid for 10 min. HAp film was formed on the acid-treated PEEK via the soft-solution process using simulated body fluid (SBF), urea, and urease. After HAp coating, specimens were immersed into IP6 solution, and followed by immersion into silver nitrite solution at concentrations of 0, 0.5, 1, 5 or 10 mM. Ag⁺ ions were immobilized on the resulting HAp film due to the chelate-bonding ability of IP6. On cell-culture tests under indirect conditions by Transwell®, MC3T3-E1 cells on the specimens derived from the 0.5 and 1 mM Ag⁺ solutions showed high relative growth when compared with controls. Furthermore, on evaluation of antibacterial activity in halo test, elution of Ag⁺ ions from Ag⁺-immobilized HAp film inhibited bacterial growth. Therefore, the above-mentioned results demonstrated that specimens had both biocompatibility and strong antibacterial activity. The present coating therefore provides bone bonding ability to the implant surface and prevents the formation of biofilms in the early postoperative period.

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Posterior correction and fusion surgery using pedicle-screw constructs for Lenke type 5c adolescent idiopathic scoliosis

Okada Eijiro, Watanabe Kota, Pang Long, Ogura Yoji, Takahashi Yohei, Hosogane Naobumi, Toyama Yoshiaki, Matsumoto Morio

Spine 40 ( 1 ) 25 - 30 2015.01

ISSN 0362-2436

STUDY DESIGN.: A retrospective case series.OBJECTIVE.: To assess whether a short fusion strategy is applicable when treating adolescent idiopathic scoliosis with Lenke type 5C curve by posterior correction and fusion surgery using pedicle-screw constructs.SUMMARY OF BACKGROUND DATA.: Previous studies have discussed the selection of the lower instrumented vertebra to best preserve motion segments and obtain coronal balance. However, reports evaluating the selection of the upper instrumented vertebra when treating Lenke type 5C curves are not available.METHODS.: We evaluated 29 patients who were treated surgically for adolescent idiopathic scoliosis with Lenke type 5C curve (mean age, 16.8 ± 4.7 yr; range, 10-29 yr). The mean follow-up period was 28.0 ± 6.3 months (range, 24-48 mo). We compared radiographical parameters and clinical outcomes between patients with an upper instrumented vertebra at the end vertebra (EV) (n = 10) and those treated by short fusion (S group), with a upper instrumented vertebra 1-level caudal to the EV (n = 19 patients).RESULTS.: In the EV group, a preoperative mean Cobb angle of 50°± 15° was corrected to 8°± 7°, which was maintained at the final follow-up (7°± 1°). In the S group, a mean preoperative Cobb angle of 47°± 4° was corrected to 8°± 5°, but this increased significantly to 12°± 7° at final follow-up (P = 0.033). The mean correction rate at final follow-up was significantly lower in the S group (72%) than in the EV group (86%) (P = 0.027). Coronal and sagittal balance, thoracic kyphosis, lumbar lordosis, L4 tilt, and clinical outcomes evaluated by Scoliosis Research Society patient questionnaire-22 were equivalent between the 2 groups.CONCLUSION.: Scoliosis Research Society patient questionnaire-22 scores and radiographical parameters other than the correction rate were equivalent between the 2 groups. A short fusion strategy, in which the upper instrumented vertebra is 1-level caudal to the upper EV, is applicable to posterior correction and fusion surgery with pedicle-screw constructs for Lenke type 5C curves.

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In vivo evaluation of chelate-Setting cement fabricated from hydroxyapatite including bone minerals using a rabbit's tibia model

Aizawa Mamoru, Chibu Yuki, Nagata Kohei, Konishi Toshiisa, Ishii Ken, Funao Haruki, Toyama Yoshiaki, Matsumoto Morio, Honda Michiyo

402 - 407 2015

Hydroxyapatite (HAp) is one of components of bone and teeth, and has an osteoconductivity. Thus, the HAp has been used as biomaterials for bone graftings. We have succeeded in development of the novel chelate-setting calcium-phosphate cement (CPC) using pure HAp particles surface-modified with inositol phosphate (IP6). While, biological apatite presented in bone and teeth of mammals contains various ions: Na<inf>+</inf>, K<inf>+</inf>, Mg<inf>2+</inf>, C1<inf>-</inf>", F" and C0<inf>3</inf><inf>2-</inf>", in addition to Ca<inf>2+</inf> and P0<inf>4</inf> ions. In this work, in order to create the chelate-setting CPC with enhanced osteoconductivity, the above-mentioned biological apatite powder (hereafter, bone HAp), instead of pure HAp, was used as a starting powder for fabrication of the chelate-setting cement. The biocompatibility of the resulting chelate-setting bone HAp cement (hereafter, IP6-bone HAp cement) was examined using a rabbit's tibia model. When the living reaction to hard tissue was histologically examined after 4 weeks implantation, we could observe that newly-formed bone directly bonded to the surface of the specimen. The newly-formed bone was also present around the cement specimen. The amounts of newly-formed bone around IP6-bone HAp cement was about 1.5 times those around IP6-pure HAp cement without bone minerals. The above findings demonstrate that the present IP6-bone HAp cements are one of the promising candidates as novel CPC with enhanced osteoconductivity.

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Japanese orthopaedic association back pain evaluation questionnaire (JOABPEQ) as an outcome measure for patients with low back pain

Hashizume Hiroshi, Konno Shin Ichi, Takeshita Katsushi, Fukui Mitsuru, Takahashi Kazuhisa, Chiba Kazuhiro, Miyamoto Masabumi, Matsumoto Morio, Kasai Yuichi, Kanamori Masahiko, Matsunaga Shunji, Hosono Noboru, Kanchiku Tsukasa, Taneichi Hiroshi, Tanaka Nobuhiro, Kanayama Masahiro, Shimizu Takachika, Kawakami Mamoru

Journal of Orthopaedic Science 20 ( 2 ) 264 - 280 2015

ISSN 0949-2658

Background: In 2007, the Japanese orthopaedic association back pain evaluation questionnaire (JOABPEQ) was established to overcome the limitations of the original JOA scoring system developed in 1986. Although this new self-administered questionnaire is a more accurate outcome measure for evaluating patients with low back pain, physicians were unable to as certain the exact status of a patient at a single time point because of a lack of reference values. This study aimed to establish the reference values of JOABPEQ in different age and gender groups using data obtained from healthy volunteers. Methods: This study was conducted in 21 university hospitals and affiliated hospitals from October 2012 to July 2013. The JOABPEQ includes 25 questions that yield five domains to evaluate individuals with low back pain from five different perspectives. A total of 1,456 healthy volunteers (719 men, 737 women; age range, 20–89 years) answered the questionnaire. The differences in scores according to age and gender were examined by non-parametric tests. Results: The JOABPEQ scores significantly decreased with age in the domains of lumbar spine dysfunction, gait disturbance, and social life dysfunction. In these three domains, the median scores approached the 100 possible points in individuals aged 20–70 for both genders. However, the median scores for lumbar spine dysfunction and social life dysfunction decreased to 83.0 and 65.0–78.0 points, respectively, in individuals in their 80 s and 70–80 s, respectively; and the scores for gait disturbance decreased to 93.0 and 71.0 points for males and females in their 80 s. Overall, the median scores for pain-related and psychological disorders were 100 and 60.0–72.0 points, respectively. Conclusion: The reference values for JOABPEQ according to age and gender were established herein. Patients with low back pain should be evaluated with this new self-administered questionnaire taking these reference values into account.

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A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females

Sharma Swarkar, Londono Douglas, Eckalbar Walter L., Gao Xiaochong, Zhang Dongping, Mauldin Kristen, Kou Ikuyo, Takahashi Atsushi, Matsumoto Morio, Kamiya Nobuhiro, Murphy Karl K., Cornelia Reuel, Herring John A., Burns Dennis, Ahituv Nadav, Ikegawa Shiro, Gordon Derek, Wise Carol A., Karol L., Rathjen K., Sucato D., Birch J., Johnston C., Richards B. S., Mildrant T., Talwakar V., Iwinski H., Muchow R., Tassone J. C., Liu X. C., Shindell R., Schrader W., Eberson C., Lapinsky A., Loder R., Davey J., Hosogane Naobumi, Ogura Yoji, Takahashi Yohei, Miyake Atushi, Watanabe Kota, Chiba Kazuhiro, Toyama Yoshiaki, Kono Katsuki, Kawakami Noriaki, Tsuji Taichi, Uno Koki, Suzuki Teppei, Ito Manabu, Sudo Hideki, Minami Shohei, Kotani Toshiaki, Yanagida Haruhisa, Taneichi Hiroshi, Yonezawa Ikuho, Kaneko Kazuo

Nature Communications 6 2015

Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10 ^-9) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10 -10, OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells.

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Neural stem/progenitor cell-laden microfibers promote transplant survival in a mouse transected spinal cord injury model

Sugai Keiko, Nishimura Soraya, Kato-Negishi Midori, Onoe Hiroaki, Iwanaga Shintaroh, Toyama Yoshiaki, Matsumoto Morio, Takeuchi Shoji, Okano Hideyuki, Nakamura Masaya

Journal of Neuroscience Research 2015

ISSN 0360-4012

Previous studies have demonstrated that transplantation of neural stem/progenitor cells (NS/PCs) into the lesioned spinal cord can promote functional recovery following incomplete spinal cord injury (SCI) in animal models. However, this strategy is insufficient following complete SCI because of the gap at the lesion epicenter. To obtain functional recovery in a mouse model of complete SCI, this study uses a novel collagen-based microfiber as a scaffold for engrafted NS/PCs. We hypothesized that the NS/PC-microfiber combination would facilitate lesion closure as well as transplant survival in the transected spinal cord. NS/PCs were seeded inside the novel microfibers, where they maintained their capacity to differentiate and proliferate. After transplantation, the stumps of the transected spinal cord were successfully bridged by the NS/PC-laden microfibers. Moreover, the transplanted cells migrated into the host spinal cord and differentiated into three neural lineages (astrocytes, neurons, and oligodendrocytes). However, the NS/PC-laden scaffold could not achieve a neural connection between the rostral end of the injury and the intact caudal area of the spinal cord, nor could it achieve recovery of motor function. To obtain optimal functional recovery, a microfiber design with a modified composition may be useful. Furthermore, combinatorial therapy with rehabilitation and/or medications should also be considered for practical success of biomaterial/cell transplantation-based approaches to regenerative medicine.

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The vitamin D analogue ED71 but not 1,25(OH)₂D₃ targets HIF1α protein in osteoclasts

Sato Yuiko, Miyauchi Yoshiteru, Yoshida Shigeyuki, Morita Mayu, Kobayashi Tami, Kanagawa Hiroya, Katsuyama Eri, Fujie Atsuhiro, Hao Wu, Tando Toshimi, Watanabe Ryuichi, Miyamoto Kana, Morioka Hideo, Matsumoto Morio, Toyama Yoshiaki, Miyamoto Takeshi

PLoS ONE 9 ( 11 ) 2014.11

Although both an active form of the vitamin D metabolite, 1,25(OH)₂D₃, and the vitamin D analogue, ED71 have been used to treat osteoporosis, anti-bone resorbing activity is reportedly seen only in ED71-but not in 1,25(OH)₂D₃ -treated patients. In addition, how ED71 inhibits osteoclast activity in patients has not been fully characterized. Recently, HIF1α expression in osteoclasts was demonstrated to be required for development of post-menopausal osteoporosis. Here we show that ED71 but not 1,25(OH)₂D₃, suppress HIF1α protein expression in osteoclasts in vitro. We found that 1,25(OH)₂D₃ or ED71 function in osteoclasts requires the vitamin D receptor (VDR). ED71 was significantly less effective in inhibiting M-CSF and RANKL-stimulated osteoclastogenesis than was 1,25(OH)₂D₃ in vitro. Downregulation of c-Fos protein and induction of Ifnβ mRNA in osteoclasts, both of which reportedly block osteoclastogenesis induced by 1,25(OH)₂D₃ in vitro, were both significantly higher following treatment with 1,25(OH)₂D₃ than with ED71. Thus, suppression of HIF1α protein activity in osteoclasts in vitro, which is more efficiently achieved by ED71 rather than by 1,25(OH)₂D₃, could be a reliable read-out in either developing or screening reagents targeting osteoporosis.

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Postoperative shoulder imbalance in Lenke Type 1A adolescent idiopathic scoliosis and related factors

Matsumoto Morio, Watanabe Kota, Kawakami Noriaki, Tsuji Taichi, Uno Koki, Suzuki Teppei, Ito Manabu, Yanagida Haruhisa, Minami Shohei, Akazawa Tsutomu

BMC Musculoskeletal Disorders 366 2014.11

Backgrounds: The purpose of this study was to investigate the occurrence and factors associated with postoperative shoulder imbalance (PSI) in Lenke type 1A curve. Methods: This study included 106 patients with Lenke Type 1A curve who were followed up more than two years after posterior correction surgery. Pedicle screw (PS) constructs were used in 84 patients, and hybrid constructs in 22. The upper instrumented vertebra was rostral to the upper-end vertebra (UEV) in 70 patients, at UEV in 26, and below UEV in 10. The clavicle angle and T1 tilt angle were measured as PSI indicators, and correlations between radiographic parameters of shoulder balance and other radiographic parameters and associations between PSI and clinical parameters were investigated. For statistical analyses, paired and unpaired t-tests were used. Results: The mean Cobb angles of the main and proximal thoracic curves were 54.6 ± 9.5 and 26.7 ± 7.9 degrees before surgery, 14.5 ± 7.5, and 14.9 ± 7.1 at follow-up. Clavicle angle and T1 tilt angle were -2.9 ± 2.8 and -2.6 ± 6.3 before surgery, 2.4 ± 2.8 and 4.4 ± 4.3 immediately after surgery, and 1.8 ± 2.1 and 3.4 ± 5.5 at follow-up. Twenty patients developed distal adding-on. Clavicle angle at follow-up correlated weakly but significantly with preoperative clavicle angle (r = 0.34, p = 0.001) and with the correction rates of the main thoracic curve (r = 0.34, p = 0.001); it correlated negatively with the proximal curve spontaneous correction rate (r = -0.21, p = 0.034). The clavicle angle at follow-up was significantly larger in patients with PS-only constructs (PS 2.1 degrees vs. hybrid 0.9, p = 0.02), and tended to be smaller in patients with distal adding-on (adding-on 1.1 vs. non adding-on 2.0, p = 0.09). Conclusions: PSI was more common with better correction of the main curve (using PS constructs), in patients with a larger preoperative clavicle angle, and with a larger and more rigid proximal curve. Distal adding-on may compensate for PSI.

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Massive hemothorax caused by Gelpi retractor during posterior correction surgery for adolescent idiopathic scoliosis

Pang Long, Watanabe Kota, Toyama Yoshiaki, Matsumoto Morio

Scoliosis 9 ( 1 ) 2014.10

Background context: Gelpi retractors are used in surgery because they can reduce paravertebral muscle damage during retraction. No pleural injuries associated with their use in posterior spine surgery have been reported. Purpose: To describe a patient who suffered a massive postoperative hemothorax caused by a Gelpi retractor used during posterior correction surgery for adolescent idiopathic scoliosis (AIS). Study design: Case report. Methods: A case report of a rare hemothorax complication due to a Gelpi retractor is reported. The relevant literature was reviewed. Results: A 12-year-old girl with Lenke type 2 AIS, with curves of 60° at T2-7 and 75° at T7-L1, underwent posterior correction and fusion surgery using a segmental pedicle screw construct placed between T2 and L2. Although the patient's vital signs were stable during and soon after the surgery, a chest x-ray taken one day later revealed a massive left hemothorax. Her hemoglobin concentration was decreased to 5.5g/dl, and SpO<inf>2</inf> remained as low as 92% even with oxygen administration. Thoracoscopy revealed subpleural hemorrhaging at several points in the left upper intercostal area (T3-6), and a penetration of the pleura between the left 4th and 5th ribs. Active bleeding had already stopped. The tip of the Gelpi retractor appeared to have penetrated the pleura. A chest tube was placed in the patient to treat the hemothorax. Conclusions: A pleural injury by the Gelpi retractor was determined to be the cause of the hemothorax in this case. The patient's prominent thoracic hump may have increased the risk of such an injury because the tip of a Gelpi retractor might easily have become stuck in the intercostal space rather than the paravertebral muscles.

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Pulmonary function recovery demonstrated by ventilation-perfusion scan after posterior vertebral column resection for severe adolescent idiopathic scoliosis

Fujii Takeshi, Watanabe Kota, Toyama Yoshiaki, Matsumoto Morio

Spine 39 ( 19 ) 2014.09

ISSN 0362-2436

Study Design. Case report. Objective. To describe a case in which a patient regained pulmonary function, assessed by ventilation-perfusion scans, after undergoing posterior vertebral column resection (VCR) to correct severe adolescent idiopathic scoliosis (AIS) with associated pulmonary dysfunction. Summary of Background Data. Pulmonary improvement after corrective surgery for AIS has been reported. Ventilation-perfusion scans are useful for assessing pulmonary function. However, these scans have not been used to examine the recovery of pulmonary function after VCR for severe AIS with pulmonary dysfunction. Methods. A patient was described in whom ventilation-perfusion scans were used to examine improvements in impaired air ventilation and blood perfusion after VCR surgery for severe AIS. The relevant literature was reviewed. Results. An 18-year-old male came to Keio University Hospital with exertional dyspnea associated with severe AIS. Radiographs showed severe scoliosis of 91° at T6-T12, and hypokyphosis of 6° at T5-T12. Computed tomographic scans showed narrowing of the thoracic cage on the convex side of the main thoracic curve, with the vertebral bodies at the apex of the curve obstructing the right main bronchus. Pulmonary function tests revealed a percent vital capacity of 44% and percent forced expiratory volume in 1 second of 76%. A ventilation-perfusion scan showed decreased air ventilation and blood perfusion in the right lung. The patient underwent posterior correction surgery, which used segmental pedicle screws with a VCR at T9. The scoliosis was corrected to 28°, and the kyphosis to 14°. Postoperative computed tomographic scans showed expansion of the right main bronchus. A ventilation-perfusion scan conducted 1 year after surgery showed clear improvement in both ventilation and blood perfusion in the right lung. The patient's forced expiratory volume in 1 second had increased to 91%. Conclusion. This is the first report in which ventilation-perfusion scans were used to examine improvements in impaired air ventilation and blood perfusion after VCR surgery in a patient with severe AIS. © 2014, Lippincott Williams & Wilkins.

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