研究者詳細 - 相馬　智也

論文 - 相馬　智也

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オスラー病を有する患者の上顎正中埋伏過剰歯の1例

木村大志, 相馬智也, 莇生田整治, 遠藤友樹, 中川種昭, 内田育宏

有病者歯科医療（(一社)日本有病者歯科医療学会） 32 （ 5 ） 291 - 303 2024年09月

査読有り, ISSN 0918-8150

オスラー病は皮膚や粘膜,全身臓器の血管異常をきたす常染色体優性遺伝疾患である.その診断にはCuracao criteriaと呼ばれる臨床診断が広く用いられている.今回われわれは,オスラー病を有する患者の上顎正中埋伏過剰歯の抜歯の1例を経験したためその概要を報告する.患者は8歳の男児,上顎正中埋伏過剰歯の精査・加療目的に当科を受診した.既往歴,家族歴から7歳時にオスラー病と診断されていた.上顎正中埋伏過剰歯は鼻腔底粘膜に接しており,反復性鼻出血の既往があることから入院・全身麻酔下に抜歯術を実施,術中・術後の異常出血は認められず経過は良好であった.本症例では術前からオスラー病と診断されていたが,既往歴や臨床所見,治療を契機として発見される可能性もあり,本疾患への理解を深める必要があると思われる.(著者抄録)

Factors affecting the quality of life of patients with medication-related osteonecrosis of the jaw during treatment: A quality-of-life survey and causal analysis

Kanako Munakata, Hidetaka Miyashita, Yuka Yamada, Tomoya Soma, Ryotaro Iwasaki, Taneaki Nakagawa, Seiji Asoda

Journal of Cranio-Maxillofacial Surgery （Journal of Cranio-Maxillofacial Surgery） 52 （ 6 ） 715 - 721 2024年03月

査読有り, ISSN 1010-5182

This prospective cohort study aimed to investigate the impact of medication-related osteonecrosis of the jaw (MRONJ) on health-related quality of life (HRQOL) and oral health-related QOL (OHRQOL) and the association between the downstaging of MRONJ and OHRQOL. The HRQOL and OHRQOL of 44 patients with MRONJ were assessed using the SF-36v2 and the General Oral Health Assessment Index (GOHAI), respectively. Treatment was performed in accordance with the AAOMS position paper (2014). The SF-36v2 and GOHAI scores at the beginning of the survey were used to evaluate the impact of MRONJ on QOL. Potential confounders affecting the association between downstaging and QOL improvement were selected using directed acyclic graphs. Multiple regression analysis was performed to evaluate causal inferences. HRQOL scale scores declined below the national average. The three-component summary score (3CS), comprising the physical component summary (PCS), mental component summary (MCS), and role/social component summary (RCS), revealed that performance status and primary disease significantly affected the PCS and RCS (P = 0.005 and P < 0.001, respectively) and PCS and MCS (P = 0.024 and P = 0.003, respectively). The MRONJ stage did not influence the 3CS; however, OHRQOL declined in a stage-dependent manner (P = 0.005). Downstaging of MRONJ was independently associated with the improvement rate of the total GOHAI scores after adjusting for variables (P = 0.045). The HRQOL of patients with MRONJ declined; however, this may depend on the underlying disease status rather than the MRONJ stage. Improvement of the disease status can potentially predict an improvement in OHRQOL, regardless of the treatment modality.

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Low energy availability reduces bone mass and gonadal function in male mice.

Ito E, Sato Y, Kobayashi T, Soma T, Matsumoto T, Kimura A, Miyamoto K, Matsumoto H, Matsumoto M, Nakamura M, Sato K, Miyamoto T

Journal of bone and mineral metabolism （Journal of Bone and Mineral Metabolism） 41 （ 2 ） 182 - 192 2023年03月

査読有り, ISSN 0914-8779

Introduction: In women, the female athlete triad, marked by low energy availability, functional hypothalamic amenorrhea and osteoporosis, is a recognized risk for stress fractures. Stress injuries also occur in men, but by contrast risks and mechanisms underlying them are less characterized. Materials and methods: 5 week-old wild-type male mice were fed ad libitum (ad) or subjected to 60% food restriction (FR) for five weeks. In both groups, some mice were allowed access to an exercise wheel in cages to allow voluntary wheel running (ex) and/or treated with active vitamin D analogues. Mice were sacrificed and analyzed at 10 weeks of age. Result: Male FR mice exhibited significantly reduced testicle weight, serum testosterone levels and bone mass. Such bone losses in FR male mice were enhanced by exercise. Histological analysis revealed that both bone-resorbing and -forming activities were significantly reduced in FR or FR plus exercise (FR + ex) mice, mimicking a state of low bone turnover. Significantly reduced bone mass in FR or FR + ex male mice was significantly rescued by treatment with active vitamin D analogues, with significant restoration of osteoblastic activities. Serum levels of insulin-like growth factor I (IGF-I), which is critical for bone remodeling, were significantly lower in FR versus control male mice. Conclusions: Low energy availability puts men at risk for stress injuries as well, and low energy availability is upstream of gonadal dysfunction and osteoporosis in males. Active vitamin D analogues could serve as therapeutic or preventive options for stress injuries in men.

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FOXA1 suppresses oral cancer progression through inhibiting p38 activation induced by lipid-derived aldehydes

Okazaki Shogo, Yoshikawa Momoko, Soma Tomoya, Asoda Seiji, Imai Kenichi, Goitsuka Ryo, Saya Hideyuki, Nagano Osamu

CANCER SCIENCE 114 1787 - 1787 2023年02月

ISSN 1347-9032

頰部の小唾液腺に発生した多形腺腫由来癌の1例

宮下英高, 相馬智也, 竹内照美, 宗像花楠子, 山田有佳, 中川種昭, 莇生田整治

日本口腔腫瘍学会誌（一般社団法人日本口腔腫瘍学会） 35 （ 3 ） 115 - 121 2023年

査読有り, ISSN 0915-5988

多形腺腫由来癌は主に耳下腺などの大唾液腺に生じ，その癌腫成分は腺癌（NOS）や唾液腺導管癌が多い。今回われわれは，頰部の小唾液腺由来の筋上皮癌を主体とする多形腺腫由来癌の1例を経験したので報告する。症例は74歳，女性で，左側頰部の腫脹を主訴に受診した。MRIでは左側咬筋前縁を取り囲む分葉状の腫瘤性病変を認めた。生検では，多形腺腫と癌腫成分が混在した所見を認め，多形腺腫由来癌の診断を得た。全身麻酔下に腫瘍切除術，肩甲舌骨筋上頸部郭清術，血管柄付き前外側大腿皮弁移植による再建術を実施した。術後経過は良好であったが，術後約5か月経過時に他病死の転帰となった。多形腺腫由来癌は小唾液腺ではまれな疾患であり，多施設からの症例の蓄積による術前診断法および治療法の確立が望まれる。

An ionic silver coating prevents implant-associated infection by anaerobic bacteria in vitro and in vivo in mice.

Soma T, Iwasaki R, Sato Y, Kobayashi T, Ito E, Matsumoto T, Kimura A, Homma F, Saiki K, Takahashi Y, Miyamoto K, Matsumoto M, Nakamura M, Morita M, Ishii K, Asoda S, Kawana H, Xingyu Z, Aizawa M, Nakagawa T, Miyamoto T

Scientific reports （Scientific Reports） 12 （ 1 ） 18387 - 18387 2022年11月

筆頭著者, 査読有り, ISSN 2045-2322

Currently, implants are utilized clinically for bone transplant procedures. However, if infectious osteomyelitis occurs at implant sites, removal of bacteria can be challenging. Moreover, altered blood flow at peri-implant infectious sites can create an anaerobic environment, making it more difficult to treat infection with antibiotics. Thus, it would be beneficial if implants could be modified to exhibit antibacterial activity, even in anaerobic conditions. Here, we show antibacterial activity of silver ions coated on titanium rods, even against the anaerobic bacteria Porphyromonas gingivalis (P. gingivalis), both in vitro and in vivo. Specifically, we implanted silver-coated or control uncoated titanium rods along with P. gingivalis in mouse femoral bone BM cavities and observed significantly inhibited P. gingivalis infection with silver-coated compared with non-coated rods, based on in vivo bio-imaging. Osteonecrosis by infectious osteomyelitis and elevation of the inflammatory factors C-reactive protein and IL-6 promoted by P. gingivalis s were also significantly reduced in the presence of silver-coated rods. Overall, our study indicates that silver ion coating of an implant represents a therapeutic option to prevent associated infection, even in anaerobic conditions or against anaerobic bacteria.

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Evaluation of the surgical approach based on impacted position and direction of mesiodens

Kimura M., Yasui T., Asoda S., Nagamine H., Soma T., Karube T., Kodaka R., Muraoka W., Nakagawa T., Onizawa K.

Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology （Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology） 35 （ 1 ） 23 - 29 2022年08月

査読有り, ISSN 2212-5558

Objective: This study aimed to reveal the relationship between the approach of extraction and the position of the mesiodens by systematic classification. Methods: This retrospective study included patients with impacted mesiodens that required computed tomography for extraction. The direction, sagittal and axial position, eruption from the nasal floor, surrounding bone thickness, surgical approach, and anesthesia type for the impacted mesiodens were analyzed. Mesiodens were classified into three groups (V: vertical position, H: horizontal position, and D: direction), and each group was classified into three subgroups (V1, 2, 3; H1, 2, 3; D1, 2, 3). Results: A total of 169 impacted mesiodens were included in this study. The palatal approach was the most common (151 teeth, 89.3%), followed by the labial approach (11 teeth, 6.5%) and nasal floor approach (6 teeth, 3.6%). The bone thickness from the mesiodens to the palatal surface were significantly shorter in palatal far region of nasopalatine duct (H3) than in palatal near region (H2) (P < 0.05). In vertical high position (V3), the percentage of the palatal approach in H3 (87.5%) was higher than that in H2 (71.4%). Additionally, 15 teeth erupting from the nasal floor wherein four were extracted by the nasal floor approach in H2 but only one tooth in H3. Conclusions: Even at higher positions, mesiodens located in the palatal far region tended to be extracted by the palatal approach because of the thin bone thickness.

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Transcription factor FOXA1 is a negative regulator for xCT-dependent tumor formation in oral cancer

Okazaki Shogo, Nakano Yuki, Yoshikawa Momoko, Soma Tomoya, Asoda Seiji, Goitsuka Ryo, Saya Hideyuki, Nagano Osamu

CANCER SCIENCE 113 1324 - 1324 2022年02月

ISSN 1347-9032

Hao1 Is Not a Pathogenic Factor for Ectopic Ossifications but Functions to Regulate the TCA Cycle In Vivo

Atsushi Kimura, Akiyoshi Hirayama, Tatsuaki Matsumoto, Yuiko Sato, Tami Kobayashi, Satsuki Ikeda, Midori Maruyama, Mari Kaneko, Mayo Shigeta, Eri Ito, Tomoya Soma, Kana Miyamoto, Tomoyoshi Soga, Masaru Tomita, Akihito Oya, Morio Matsumoto, Masaya Nakamura, Arihiko Kanaji, Takeshi Miyamoto

Metabolites （MDPI AG） 12 （ 1 ） 82 - 82 2022年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2218-1989

Ossification of the posterior longitudinal ligament (OPLL), a disease characterized by the ectopic ossification of a spinal ligament, promotes neurological disorders associated with spinal canal stenosis. While blocking ectopic ossification is mandatory to prevent OPLL development and progression, the mechanisms underlying the condition remain unknown. Here we show that expression of hydroxyacid oxidase 1 (Hao1), a gene identified in a previous genome-wide association study (GWAS) as an OPLL-associated candidate gene, specifically and significantly decreased in fibroblasts during osteoblast differentiation. We then newly established Hao1-deficient mice by generating Hao1-flox mice and crossing them with CAG-Cre mice to yield global Hao1-knockout (CAG-Cre/Hao1flox/flox; Hao1 KO) animals. Hao1 KO mice were born normally and exhibited no obvious phenotypes, including growth retardation. Moreover, Hao1 KO mice did not exhibit ectopic ossification or calcification. However, urinary levels of some metabolites of the tricarboxylic acid (TCA) cycle were significantly lower in Hao1 KO compared to control mice based on comprehensive metabolomic analysis. Our data indicate that Hao1 loss does not promote ectopic ossification, but rather that Hao1 functions to regulate the TCA cycle in vivo.

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Osteonecrosis development by tooth extraction in zoledronate treated mice is inhibited by active vitamin D analogues, anti-inflammatory agents or antibiotics

Tomoya Soma, Ryotaro Iwasaki, Yuiko Sato, Tami Kobayashi, Eri Ito, Tatsuaki Matsumoto, Atsushi Kimura, Kana Miyamoto, Morio Matsumoto, Masaya Nakamura, Mayu Morita, Seiji Asoda, Hiromasa Kawana, Taneaki Nakagawa, Takeshi Miyamoto

Scientific Reports （Springer Science and Business Media LLC） 12 （ 1 ） 19 - 19 2022年01月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 2045-2322

<title>Abstract</title>Invasive dental treatment such as tooth extraction following treatment with strong anti-bone resorptive agents, including bisphosphonates and denosumab, reportedly promotes osteonecrosis of the jaw (ONJ) at the extraction site, but strategies to prevent ONJ remain unclear. Here we show that in mice, administration of either active vitamin D analogues, antibiotics or anti-inflammatory agents can prevent ONJ development induced by tooth extraction during treatment with the bisphosphonate zoledronate. Specifically, tooth extraction during treatment with zoledronate induced osteonecrosis in mice, but administration of either 1,25(OH)₂D₃ or ED71, both active vitamin D analogues, significantly antagonized osteonecrosis development, even under continuous zoledronate treatment. 1,25(OH)₂D₃ or ED71 administration also significantly inhibited osteocyte apoptosis induced by tooth extraction and bisphosphonate treatment. Administration of either active vitamin D analogue significantly inhibited elevation of serum inflammatory cytokine levels in mice in response to injection of lipopolysaccharide, an infection mimetic. Furthermore, administration of either anti-inflammatory or antibiotic reagents significantly blocked ONJ development following tooth extraction and zoledronate treatment. These findings suggest that administration of active vitamin D, anti-inflammatory agents or antibiotics could prevent ONJ development induced by tooth extraction in patients treated with zoledronate.

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Remarkable response of diffuse sclerosing osteomyelitis of the mandible to zoledronate by single infusion without prior treatment of other bisphosphonates

Yamada M., Iwata S., Nishi K., Ochiai S., Araki D., Soma T., Yamada Y., Miyashita H., Suga K., Asoda S.

Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology （Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology） 34 （ 6 ） 777 - 783 2022年

査読有り, ISSN 22125558

Diffuse sclerosing osteomyelitis of the mandible (DSOM) is a nonsuppurative osteomyelitis mainly characterized by recurrent local mandibular swelling and pain. Because of the unknown pathophysiological mechanism underlying DSOM, treatment can be challenging. Reported treatment options include long-term analgesic medication, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, corticosteroids, hyperbaric oxygen, and surgical treatment. However, these treatments cannot reliably lead to a long-lasting reduction of complaints. Recently, bisphosphonates has been reported effective in managing DSOM. We herein report a case of DSOM with a favorable response to a single infusion of zoledronate without prior treatment of other bisphosphonates. The patient was a 19-year-old woman who visited our hospital complaining of swelling and remarkable spontaneous pain in the right mandibular angle region. Under the diagnosis of osteomyelitis of the mandible, the clinical symptoms were improved by administering an antimicrobial agent and anti-inflammatory analgesic, but computed tomography (CT) showed exacerbation of bone resorption. A biopsy showed fibrosis between the bone tissue and trabeculae, a finding consistent with post-inflammatory changes. 99mTc scintigraphy showed an abnormal accumulation in the right mandibular ramus. Based on these results, she was diagnosed with DSOM. As a result of discussing with the physician in charge of internal medicine, it became the policy of the bisphosphonates and the intravenous administration of zoledronate 4 mg was enforced. Her bone sclerosis and bone resorption showed an improving trend on CT three months after the zoledronate administration, and there have been no symptoms or exacerbation of findings in three years since the administration.

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Transient alendronate administration to pregnant or lactating mothers prevents bone loss in mice without adverse effects on offspring

Eri Ito, Yuiko Sato, Tami Kobayashi, Tomoya Soma, Tatsuaki Matsumoto, Atsushi Kimura, Kana Miyamoto, Hideo Matsumoto, Morio Matsumoto, Masaya Nakamura, Kazuki Sato, Takeshi Miyamoto

Bone （Elsevier BV） 153 116133 - 116133 2021年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 8756-3282

Changes in bone metabolism occur in mothers during pregnancy or lactation that may decrease bone mass and result in fragility fractures after partum. However, use of drugs during pregnancy or lactation to counteract these effects is often prohibited or strongly discouraged. Therefore, approaches to protect mothers from fragility fractures have not been established. Here we show that bone mineral density was significantly lower in female mice after partum than in age-matched female mice without partum. We also show that temporary administration of the bisphosphonate alendronate, either just before or just after pregnancy, to female mice was protective against bone loss due to pregnancy or lactation and had no adverse effects on offspring, such as growth retardation. Furthermore, we show that alendronate administration to female mice during lactation was effective in increasing bone mass in mothers without promoting bone abnormalities or growth retardation in offspring. Calcium levels in milk from female mice administered alendronate during lactation were equivalent to those in milk from mothers not treated with alendronate. Overall, we propose that alendronate administration to mothers could prevent bone loss and fragility fractures during pregnancy and lactation.

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Clinical value of entire-circumferential intraoperative frozen section analysis for the complete resection of superficial squamous cell carcinoma of the tongue.

Asoda S, Miyashita H, Soma T, Munakata K, Yamada Y, Yasui Y, Kudo Y, Usuda S, Hasegawa T, Nakagawa T, Kawana H

Oral oncology （Elsevier BV） 123 105629 - 105629 2021年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1368-8375

Objectives: We aimed to evaluate the clinical value of an entire-circumferential intraoperative frozen section analysis (e-IFSA) for the complete resection of superficial squamous cell carcinoma (SCC) of the tongue. Materials and Methods: A total 276 specimens from 51 patients with pT1-2, N0, mucosal or submucosal invasion SCC were analyzed to evaluate the diagnostic accuracy of the e-IFSA and the added value of the e-IFSA to iodine staining. The e-IFSA results were compared with the final histologic results obtained using permanent sections. All specimens for the e-IFSA were taken over the entire circumference 5 mm outside from the iodine unstained areas. The outline of the main resected specimen after taking these outer mucosal specimens were defined as the surgical margins determined by iodine staining alone. Results: The e-IFSA results were in excellent agreement with final histological results (Cohen's kappa value: 0.85) and the e-IFSA showed high sensitivity (100%) and high negative predictive value (100%). The actual complete resection rate with an e-IFSA was 100% (51/51), and no patient required additional resection after surgery. In contrast, 10/51 patients (20%) patients showed residual atypical mucosal epithelium at or beyond the margin determined by iodine staining alone; this difference was statistically significant (P = 0.002). The 5-year local control rate and 5-year overall survival rate after this procedure were both 100%. Conclusion: An e-IFSA has additional value when performed in conjunction with iodine staining. An e-IFSA would be useful for achieving complete resection of superficial SCC of the tongue.

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Adipose-Derived Stem Cell Sheets Improve Early Biomechanical Graft Strength in Rabbits After Anterior Cruciate Ligament Reconstruction.

Matsumoto T, Sato Y, Kobayashi T, Suzuki K, Kimura A, Soma T, Ito E, Kikuchi T, Kobayashi S, Harato K, Niki Y, Matsumoto M, Nakamura M, Miyamoto T

The American journal of sports medicine （American Journal of Sports Medicine） 49 （ 13 ） 3635465211041582 - 3635465211041582 2021年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0363-5465

BACKGROUND: Although various reconstruction techniques are available for anterior cruciate ligament (ACL) injuries, a long recovery time is required before patients return to sports activities, as the reconstructed ACL requires time to regain strength. To date, several studies have reported use of mesenchymal stem cells in orthopaedic surgery; however, no studies have used adipose-derived stem cell (ADSC) sheets in ACL reconstruction (ACLR). HYPOTHESIS: ADSC sheet transplantation can improve biomechanical strength of the autograft used in ACLR. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 68 healthy Japanese white rabbits underwent unilateral ACLR with a semitendinosus tendon autograft after random enrollment into a control group (no sheet; n = 34) and a sheet group (ADSC sheet; n = 34). At 2, 4, 8, 16, and 24 weeks after surgery, rabbits in each group were sacrificed to evaluate tendon-bone healing using histological staining, micro-computed tomography, and biomechanical testing. At 24 weeks, scanning transmission electron microscopy of the graft midsubstance was performed. RESULTS: The ultimate failure load for the control and sheet groups, respectively, was as follows: 17.2 ± 5.5 versus 37.3 ± 10.3 (P = .01) at 2 weeks, 28.6 ± 1.9 versus 47.4 ± 10.4 (P = .003) at 4 weeks, 53.0 ± 14.3 versus 48.1 ± 9.3 (P = .59) at 8 weeks, 66.2 ± 9.3 versus 95.2 ± 43.1 (P = .24) at 16 weeks, and 66.7 ± 27.3 versus 85.3 ± 29.5 (P = .39) at 24 weeks. The histological score was also significantly higher in the sheet group compared with the control group at early stages up to 8 weeks. On micro-computed tomography, relative to the control group, the bone tunnel area was significantly narrower in the sheet group at 4 weeks, and the bone volume/tissue volume of the tendon-bone interface was significantly greater at 24 weeks. Scanning transmission electron microscopy at 24 weeks indicated that the mean collagen fiber diameter in the midsubstance was significantly greater, as was the occupation ratio of collagen fibers per field of view, in the sheet group. CONCLUSION: ADSC sheets improved biomechanical strength, prevented bone tunnel enlargement, and promoted tendon-bone interface healing and graft midsubstance healing in an in vivo rabbit model. CLINICAL RELEVANCE: ADSC sheets may be useful for early tendon-bone healing and graft maturation in ACLR.

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口腔扁平上皮癌においてFOXA1発現はxCT依存的腫瘍成長を抑制する

岡崎章悟, 中野友暉, 吉川桃子, 相馬智也, 莇生田整治, 後飯塚僚, 佐谷秀行, 永野修

日本癌学会総会記事（(一社)日本癌学会） 80回 [E11 - 3] 2021年09月

ISSN 0546-0476

Undifferentiated carcinoma of the mandible detected simultaneously with the liver: A case report

Seiji Asoda, Mayu Morita, Tomoya Soma, Hitoshi Sato, Toshihiro Hasegawa, Taneaki Nakagawa, Akinori Hashiguchi, Hiromasa Kawana

Oral and Maxillofacial Surgery Cases （Elsevier BV） 7 （ 3 ） 100228 - 100228 2021年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2214-5419

We herein report a rare case of undifferentiated carcinoma that originated in the mandible with the same pathological findings as seen in the liver. A 64-year-old man underwent surgery for a hepatic tumor in October 2006, and the pathological diagnosis was undifferentiated carcinoma. The patient was referred to our department in January 2007, when whole-body positron emission tomography/computed tomography showed the uptake of fluorodeoxyglucose in the right mandibular ramus. The patient underwent right hemimandibulectomy in April 2007. The resected tumor was also undifferentiated carcinoma. In May 2014, seven years after the lower mandibular operation, the tumor recurred at the site corresponding to the right mandibular ramus after resection, and tumor resection and right neck dissection were performed. As a result of the histopathological examination, the undifferentiated carcinoma findings were the same as before. There have been no signs of local recurrence or metastases for over six years since the second mandibular surgery.

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Synoviolin is not a pathogenic factor for auto-inflammatory diseases.

Matsumoto T, Sato Y, Kobayashi T, Ito E, Soma T, Kimura A, Miyamoto K, Kobayashi S, Harato K, Matsumoto M, Nakamura M, Niki Y, Miyamoto T

Biochemical and biophysical research communications （Elsevier BV） 558 183 - 188 2021年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-291X

Auto-inflammatory syndromes are rare diseases characterized by arthritis and joint destruction, symptoms similar to but distinct from rheumatoid arthritis (RA). Therapeutic targets have not been well characterized for auto-inflammatory syndromes, although the E3 ligase Synoviolin was previously shown to be a novel therapeutic target for RA. Here, we show that Synoviolin loss has little impact on a model of auto-inflammatory diseases. We previously established such a model, the hIL-1 cTg mouse, in which IL-1 signaling was constitutively activated, and animals exhibit symptoms recapitulating auto-inflammatory syndromes such as major joint dominant arthritis. Here, we crossed hIL-1 cTg with Synoviolin flox'd mice to yield hIL-1 cTg/Synoviolin cKO mice. Synoviolin gene expression was ablated in adult hIL-1 cTg/Synoviolin cKO mice by injection of pIpC to activate Mx1 promoter-driven Cre recombinase. However, symptoms seen in hIL-1 cTg mice such as arthritis and joint destruction were not alleviated by targeting Synoviolin, ruling out Synoviolin as a therapeutic target for auto-inflammatory disease. Our results indicate that although similar, RA and auto-inflammatory diseases are different diseases, and treatment strategies should differ accordingly.

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Treatment with an active vitamin D analogue blocks hypothalamic dysfunction-induced bone loss in mice.

Eri Ito, Yuiko Sato, Tami Kobayashi, Satoshi Nakamura, Yosuke Kaneko, Tomoya Soma, Tatsuaki Matsumoto, Atushi Kimura, Kana Miyamoto, Hideo Matsumoto, Morio Matsumoto, Masaya Nakamura, Kazuki Sato, Takeshi Miyamoto

Biochemical and biophysical research communications （Elsevier BV） 542 48 - 53 2021年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-291X

Estrogen deficiency can be caused by ovarian dysfunction in females. Mechanisms underlying osteoporosis in this condition have been characterized in animal models, such as ovariectomized mice and rats, although it remains unclear how hypothalamic dysfunction promotes osteoporosis. Here, we show that administration of a gonadotropin-releasing hormone antagonist (GnRHa) significantly decreases uterine weight, a manifestation of hypothalamic dysfunction, and promotes both cortical and trabecular bone loss in female mice in vivo. We also report that osteoclast number significantly increased in mice administered GnRHa, and that the transcription factor hypoxia inducible factor 1 alpha (HIF1α) accumulated in those osteoclasts. We previously reported that treatment of mice with the active vitamin D analogue ED71, also known as eldecalcitol, inhibited HIF1α accumulation in osteoclasts. We show here that in mice, co-administration of ED71 with GnRHa significantly rescued the reduced cortical and trabecular bone mass promoted by GnRHa administration alone. GnRHa-dependent HIF1α accumulation in osteoclasts was also blocked by co-administration of ED71. We conclude that hypothalamic dysfunction promotes HIF1α accumulation in osteoclasts and likely results in reduced bone mass. We conclude that treatment with ED71 could serve as a therapeutic option to counter osteoporotic conditions in humans.

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Food restriction reduces cortical bone mass and serum insulin-like growth factor-1 levels and promotes uterine atrophy in mice.

Biochemical and biophysical research communications （Elsevier BV） 534 165 - 171 2021年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-291X

Low energy availability in female athletes often causes hypothalamic amenorrhea and osteoporosis, in turn promoting stress fractures. Mechanisms underlying these conditions remain unclear. Here we show that model mice subjected to food restriction (FR) or FR-plus-voluntary running exercise exhibit significantly reduced bone mineral density, cortical bone parameters and uterine weight than do control mice, and that these parameters worsen in the FR-plus-exercise group. Relative to controls, FR and FR-plus-exercise groups showed significantly lower mineral apposition rate and osteoclast number and significantly reduced serum insulin-like growth factor-1 (IGF1) levels. Outcomes were rescued by ED71 or 1.25(OH)2D3 treatment. Thus, we conclude that administration of active vitamin D analogues represents a possible treatment to prevent these conditions.

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Development of a microsurgery‐assisted robot for high‐precision thread traction and tension control, and confirmation of its applicability

Satoshi Hangai, Takahiro Nozaki, Tomoya Soma, Hidetaka Miyashita, Seiji Asoda, Masaki Yazawa, Kazuki Sato, Hiromasa Kawana, Kouhei Ohnishi, Eiji Kobayashi

The International Journal of Medical Robotics and Computer Assisted Surgery （Wiley） 17 （ 2 ） e2205 2020年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-5951

Background: Microsurgery requires high skills for suturing using fragile threads, often within narrow surgical fields. Precise tension is required for good healing and to avoid the risk of thread breakage. Methods: To meet the demands, we developed a novel assist robot utilizing high-precision sensorless haptic technology. The robot adopts a cable-driven mechanism to maintain a distance from the surgical area and enhances compatibility with surgical equipment such as microscopes. The robot performance was verified through in vitro and in vivo experiments using a rat model. Results: The realization of precise tension control was confirmed in both experiments. In particular, in the in vivo experiments, the developed robot succeeded to produce a knot with an accurate tension of 0.66% error. Conclusions: The developed robot can realize to control traction force precisely. This technology might open up the window for a full assist robot for microsurgery with haptic feeling.

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