Faculty Profiles - OZAKI Toshifumi

Papers - OZAKI Toshifumi

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Postoperative clinical outcomes of unicompartmental knee arthroplasty in patients with isolated medial compartmental osteoarthritis following medial meniscus posterior root tear. International journal

Takaaki Hiranaka, Takayuki Furumatsu, Yuki Okazaki, Takaaki Tanaka, Masatsugu Ozawa, Kenji Masuda, Noritaka Seno, Haowei Xue, Toshifumi Ozaki

Asia-Pacific journal of sports medicine, arthroscopy, rehabilitation and technology 26 15 - 20 2021.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Background: Cartilage degradation progresses rapidly following medial meniscus posterior root tear (MMPRT). Unicompartmental knee arthroplasty (UKA) has been performed for medial compartmental osteoarthritis following MMPRT. We evaluated the clinical and radiographic outcomes of UKA for medial compartmental osteoarthritis after an untreated MMPRT. Methods: Twenty-one patients who underwent UKA for isolated medial compartment osteoarthritis following MMPRT were retrospectively investigated. Clinical outcomes were assessed using the Knee Injury and Osteoarthritis Outcome Score and knee range of motion. The posterior tibial slope and tibial component inclination were evaluated using plain radiographs. Results: The mean follow-up periods were 25.5 ± 13.8 months. Clinical outcomes improved significantly postoperatively. The mean postoperative knee extension angle was -1.1° ± 2.1°, and the knee flexion angle was 134.3° ± 4.9°. The posterior tibial slope angle decreased from 9.0° ± 2.0° preoperatively to 5.4° ± 1.8° postoperatively, and postoperative tibial component inclination at the final follow-up was 2.9° ± 1.1° varus. No aseptic loosening or deep infections were observed. Conclusion: UKA significantly improved clinical outcomes and could be a viable surgical option for treating isolated medial compartmental osteoarthritis accompanied by untreated MMPRT.

DOI： 10.1016/j.asmart.2021.07.005

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変形性肩関節症モデルとしてのCCN3過剰発現マウス

廣瀬一樹, 服部高子, 中田英二, 鉄永智紀, 山田和希, 佐藤嘉洋, 桑原実穂, 尾崎敏文, 滝川正春, 久保田聡

日本骨代謝学会学術集会プログラム抄録集 39回 151 - 151 2021.10

脛骨プラトー・骨幹部合併骨折3例の治療経験

福岡史朗, 依光正則, 近藤宏也, 佐藤浩平, 畑利彰, 上原健敬, 尾崎敏文

中国・四国整形外科学会雑誌 33 ( 3 ) 330 - 330 2021.10

術前がん患者におけるがんロコモ・サルコペニアの有病率

堅山佳美, 中田英二, 濱田全紀, 国定俊之, 藤原智洋, 千田益生, 尾崎敏文

中国・四国整形外科学会雑誌 33 ( 3 ) 324 - 324 2021.10

リハビリテーション関連機器の現状と課題

千田益生, 濱田全紀, 堅山佳美, 伊勢真人, 本郷匡一, 尾崎敏文

The Japanese Journal of Rehabilitation Medicine 58 ( 秋季特別号 ) S185 - S185 2021.10

術前肺がん患者の筋肉量と術後合併症の関連性

堅山佳美, 千田益生, 濱田全紀, 濱崎比果瑠, 尾崎敏文

The Japanese Journal of Rehabilitation Medicine 58 ( 秋季特別号 ) S374 - S374 2021.10

内側半月板後根断裂患者における術前と術後1年の下肢機能の比較検討

濱崎比果瑠, 千田益生, 濱田全紀, 堅山佳美, 宮澤慎一, 尾崎敏文

The Japanese Journal of Rehabilitation Medicine 58 ( 秋季特別号 ) S372 - S372 2021.10

Mechanical stretching induces calcification and cartilage matrix metabolism, causing degeneration of the acetabular labrum International journal

Yoshi Kawamura, Tomonori Tetsunaga, Kazuki Yamada, Tomoaki Sanki, Yoshihiro Sato, Aki Yoshida, Takayuki Furumatsu, Toshifumi Ozaki

HIP International 112070002110446 - 112070002110446 2021.9

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：SAGE Publications

<sec><title>Purpose:</title> The acetabular labrum plays an important role in joint lubrication, and damage to this structure leads to osteoarthritis. This study aimed to histologically classify the degree of degeneration of the acetabular labrum and to investigate the changes in gene expression induced by mechanical stretching.

</sec><sec><title>Methods:</title> We obtained acetabular labrum cells from patients with hip osteoarthritis during total hip arthroplasty ( n = 25). The labrum was stained with safranin O, and images were histologically evaluated using a new parameter, the red/blue (R/B) value. The samples were divided into the degenerated group (D group: n = 18) and the healthy group (H group: n = 7) in accordance with the Kellgren-Lawrence (KL) grade. The cultured acetabular labral cells were subjected to loaded uniaxial cyclic tensile strain (CTS). After CTS, changes in gene expression were examined in both groups.

</sec><sec><title>Results:</title> Spearman’s correlation analysis revealed that the R/B value was significantly correlated with the KL grade and the Krenn score. The expression levels of genes related to cartilage metabolism, osteogenesis and angiogenesis significantly increased after CTS in the H group, while gene expression in the D group showed weaker changes after CTS than that in the H group compared to the nonstretched control group.

</sec><sec><title>Conclusions:</title> The degree of labral degeneration could be classified histologically using the R/B value and the KL grade. Mechanical stretching caused changes in gene expression that support the pathological features of labral degeneration.

</sec>

DOI： 10.1177/11207000211044675

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/11207000211044675

Adipose-Derived Extract Suppresses IL-1β-Induced Inflammatory Signaling Pathways in Human Chondrocytes and Ameliorates the Cartilage Destruction of Experimental Osteoarthritis in Rats

Hideki Ohashi, Keiichiro Nishida, Aki Yoshida, Yoshihisa Nasu, Ryuichi Nakahara, Yoshinori Matsumoto, Ayumu Takeshita, Daisuke Kaneda, Masanori Saeki, Toshifumi Ozaki

International Journal of Molecular Sciences 22 ( 18 ) 9781 - 9781 2021.9

Authorship：Last author Publishing type：Research paper (scientific journal) Publisher：MDPI AG

We investigated the effects of adipose-derived extract (AE) on cultured chondrocytes and in vivo cartilage destruction. AE was prepared from human adipose tissues using a nonenzymatic approach. Cultured human chondrocytes were stimulated with interleukin-1 beta (IL-1β) with or without different concentrations of AE. The effects of co-treatment with AE on intracellular signaling pathways and their downstream gene and protein expressions were examined using real-time PCR, Western blotting, and immunofluorescence staining. Rat AE prepared from inguinal adipose tissues was intra-articularly delivered to the knee joints of rats with experimental osteoarthritis (OA), and the effect of AE on cartilage destruction was evaluated histologically. In vitro, co-treatment with IL-1β combined with AE reduced activation of the p38 and ERK mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of the p65 subunit of nuclear factor-kappa B (NF-κB), and subsequently downregulated the expressions of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, IL-6, and IL-8, whereas it markedly upregulated the expression of IL-1 receptor type 2 (IL-1R2) in chondrocytes. Intra-articular injection of homologous AE significantly ameliorated cartilage destruction six weeks postoperatively in the rat OA model. These results suggested that AE may exert a chondroprotective effect, at least in part, through modulation of the IL-1β-induced inflammatory signaling pathway by upregulation of IL-1R2 expression.

DOI： 10.3390/ijms22189781

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Transtibial pullout repair of medial meniscus posterior root tears: effects on the meniscus healing score and ICRS grade among patients with mild osteoarthritis of the knee. International journal

Yuya Kodama, Takayuki Furumatsu, Yuki Okazaki, Shota Takihira, Takaaki Hiranaka, Shinichi Miyazawa, Yusuke Kamatsuki, Toshifumi Ozaki

Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA 29 ( 9 ) 3001 - 3009 2021.9

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To assess the effects of transtibial pullout repair for medial meniscus posterior root tears (MMPRTs) among patients with early osteoarthritis of the knee as measured by the meniscus healing score and to determine whether the meniscus healing score correlates with the International Cartilage Repair Society (ICRS) grade progression. METHODS: Forty-seven patients with mild osteoarthritic knees (Kellgren-Lawrence grade ≤ 2 and varus alignment < 5°) who underwent transtibial pullout repair less than 3 months after MMPRT onset were assessed. The association between meniscus healing scores at 1 year postoperatively and cartilage damage of the medial compartment (medial femoral condyle [MFC] and medial tibial plateau [MTP]) were evaluated. The MFC was divided into six zones (A to F) and the MTP into two zones (G and H). The mean ICRS grade for each zone was compared between the primary surgery and second-look arthroscopy. The correlation between cartilage damage and meniscus healing status at the time of second-look arthroscopy in each zone was analysed. RESULTS: The mean time interval from injury to surgery was 63 days, and all clinical scores showed significant improvement. There were no significant differences in the extent of cartilage damage in areas B, C, E, or F (n.s.) for MFC or in areas G and H (n.s.) for MTP. The meniscus healing score and cartilage damage were correlated in the loading areas (B, C, E, and H; - 0.53, - 0.45, - 0.33, and - 0.38, respectively; p < 0.05). CONCLUSION: Transtibial pullout repair of MMPRTs among patients with mild osteoarthritic knees improved the clinical outcomes and showed a negative correlation between high meniscus healing scores and ICRS grades in the medial compartment loading area. This study suggests that early surgery should be undertaken for patients with mild osteoarthritic knee who develop MMPRTs. LEVEL OF EVIDENCE: Level IV.

DOI： 10.1007/s00167-020-06332-7

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Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression. International journal

Kazuhisa Sugiu, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Toshinori Omori, Tadashi Komatsubara, Yusuke Mochizuki, Hiroya Kondo, Shuhei Osaki, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Koji Ueda, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Cancer chemotherapy and pharmacology 88 ( 3 ) 513 - 524 2021.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Osteosarcoma (OS) is a malignant bone tumor primarily affecting children and adolescents. The prognosis of chemotherapy-refractory OS patients is poor. We developed a tumor suppressor p53-expressing oncolytic adenovirus (OBP-702) that exhibits antitumor effects against human OS cells. Here, we demonstrate the chemosensitizing effect of OBP-702 in human OS cells. MATERIALS AND METHODS: The in vitro and in vivo antitumor activities of doxorubicin (DOX) and OBP-702 were assessed using parental and DOX-resistant OS cells (U2OS, MNNG/HOS) and a DOX-resistant MNNG/HOS xenograft tumor model. RESULTS: DOX-resistant OS cells exhibited high multidrug resistant 1 (MDR1) expression, which was suppressed by OBP-702 or MDR1 siRNA, resulting in enhanced DOX-induced apoptosis. Compared to monotherapy, OBP-702 and DOX combination therapy significantly suppressed tumor growth in the DOX-resistant MNNG/HOS xenograft tumor model. CONCLUSION: Our results suggest that MDR1 is an attractive therapeutic target for chemoresistant OS. Tumor-specific virotherapy is thus a promising strategy for reversing chemoresistance in OS patients via suppression of MDR1 expression.

DOI： 10.1007/s00280-021-04310-5

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Semi-quantitative arthroscopic scoring system is related to clinical outcomes in patients after medial meniscus posterior root repair

Ximing Zhang, Takayuki Furumatsu, Yuki Okazaki, Takaaki Hiranaka, Keisuke Kintaka, Haowei Xue, Shinichi Miyazawa, Toshifumi Ozaki

Journal of Orthopaedic Science 2021.9

Comparison of two simple stitches and modified Mason-Allen suture for medial meniscus posterior root tear based on the progression of meniscal posterior extrusion: A retrospective cohort study

Keisuke Kintaka, Takayuki Furumatsu, Yuki Okazaki, Shin Masuda, Takaaki Hiranaka, Yuya Kodama, Yusuke Kamatsuki, Toshifumi Ozaki

Journal of Orthopaedic Surgery 29 ( 3 ) 230949902110495 - 230949902110495 2021.9

Authorship：Last author Publishing type：Research paper (scientific journal) Publisher：SAGE Publications

Purpose: Medial meniscus (MM) posterior root (PR) tear leads to severe MM posterior extrusion (PE), resulting in rapid knee cartilage degeneration. MMPR repairs are recommended to reduce MMPE, especially during knee flexion. However, the difference in MMPE between different repair techniques remains unknown. This study aimed to investigate preoperative and postoperative MMPE following several pullout repair techniques. We hypothesized that a technique using two simple stitches (TSS) would be more useful than FasT-Fix-dependent modified Mason-Allen suture (F-MMA) to prevent the progression of MMPE in knee extension. Methods: This retrospective study included 35 patients who underwent MMPR repair. To compare MMPE, patients were divided into two groups according to the use of F-MMA while grasping the posterior capsule and TSS without grasping it. Open magnetic resonance imaging was performed at 10° and 90° knee flexion preoperatively, and at 3 and 12 months postoperatively, and the MMPE of both groups was evaluated. Results: A significant difference was observed between preoperative and 3-month postoperative MMPE at 90° knee flexion in both groups ( p < .01). A significant difference was observed in 3- and 12-month postoperative MMPE at 10° knee flexion between both groups ( p = .04/.02), whereas no significant difference in the preoperative MMPE at 10° knee flexion was observed between them ( p = .45). Conclusions: Both repairs were found to be useful to reduce MMPE in knee flexion. Further, F-MMA repair increased MMPE in knee extension, unlike TSS repair. These findings suggest that TSS might have more advantages for load distribution when standing or walking.

DOI： 10.1177/23094990211049569

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/23094990211049569

尺骨非定型骨折の2例

望月雄介, 齋藤太一, 尾崎敏文

中国・四国整形外科学会雑誌 33 ( 2 ) 216 - 216 2021.9

肉腫におけるがん遺伝子パネルによる融合遺伝子の検出

中田英二, 国定俊之, 藤原智洋, 遠西大輔, 冨田秀太, 尾崎敏文

中部日本整形外科災害外科学会雑誌 64 ( 秋季学会 ) 107 - 107 2021.9

肺転移能を有する骨肉腫細胞はM2様マクロファージへの分化を強力に誘導する

近藤宏也, 田澤大, 久禮美穂, 藤原智洋, 国定俊之, 尾崎敏文, 藤原俊義

日本癌学会総会記事 80回 [J14 - 4] 2021.9

尺骨非定型骨折の2例

望月雄介, 齋藤太一, 尾崎敏文

中国・四国整形外科学会雑誌 33 ( 2 ) 216 - 216 2021.9

Effect of Patient Clinical Variables in Osteoporosis Classification Using Hip X-rays in Deep Learning Analysis. International journal

Norio Yamamoto, Shintaro Sukegawa, Kazutaka Yamashita, Masaki Manabe, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Toshifumi Ozaki, Keisuke Kawasaki, Hitoshi Nagatsuka, Yoshihiko Furuki, Takashi Yorifuji

Medicina (Kaunas, Lithuania) 57 ( 8 ) 2021.8

Language：English Publishing type：Research paper (scientific journal)

Background and Objectives: A few deep learning studies have reported that combining image features with patient variables enhanced identification accuracy compared with image-only models. However, previous studies have not statistically reported the additional effect of patient variables on the image-only models. This study aimed to statistically evaluate the osteoporosis identification ability of deep learning by combining hip radiographs with patient variables. Materials andMethods: We collected a dataset containing 1699 images from patients who underwent skeletal-bone-mineral density measurements and hip radiography at a general hospital from 2014 to 2021. Osteoporosis was assessed from hip radiographs using convolutional neural network (CNN) models (ResNet18, 34, 50, 101, and 152). We also investigated ensemble models with patient clinical variables added to each CNN. Accuracy, precision, recall, specificity, F1 score, and area under the curve (AUC) were calculated as performance metrics. Furthermore, we statistically compared the accuracy of the image-only model with that of an ensemble model that included images plus patient factors, including effect size for each performance metric. Results: All metrics were improved in the ResNet34 ensemble model compared with the image-only model. The AUC score in the ensemble model was significantly improved compared with the image-only model (difference 0.004; 95% CI 0.002-0.0007; p = 0.0004, effect size: 0.871). Conclusions: This study revealed the additional effect of patient variables in identification of osteoporosis using deep CNNs with hip radiographs. Our results provided evidence that the patient variables had additive synergistic effects on the image in osteoporosis identification.

DOI： 10.3390/medicina57080846

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CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment. International journal

Tomohiro Fujiwara, Mohamed A Yakoub, Andrew Chandler, Alexander B Christ, Guangli Yang, Ouathek Ouerfelli, Vinagolu K Rajasekhar, Aki Yoshida, Hiroya Kondo, Toshiaki Hata, Hiroshi Tazawa, Yildirim Dogan, Malcolm A S Moore, Toshiyoshi Fujiwara, Toshifumi Ozaki, Ed Purdue, John H Healey

Molecular cancer therapeutics 20 ( 8 ) 1388 - 1399 2021.8

Language：English Publishing type：Research paper (scientific journal)

Colony-stimulating factor 1 (CSF1) is a primary regulator of the survival, proliferation, and differentiation of monocyte/macrophage that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). Considering current advances in understanding the role of the inflammatory tumor microenvironment, targeting the components of the sarcoma microenvironment, such as TAMs, is a viable strategy. Here, we investigated the effect of PLX3397 (pexidartinib) as a potent inhibitor of the CSF1 receptor (CSF1R). PLX3397 was recently approved by the Food and Drug Administration (FDA) to treat tenosynovial giant cell tumor and reprogram TAMs whose infiltration correlates with unfavorable prognosis of sarcomas. First, we confirmed by cytokine arrays of tumor-conditioned media (TCM) that cytokines including CSF1 are secreted from LM8 osteosarcoma cells and NFSa fibrosarcoma cells. The TCM, like CSF1, stimulated ERK1/2 phosphorylation in bone marrow-derived macrophages (BMDMs), polarized BMDMs toward an M2 (TAM-like) phenotype, and strikingly promoted BMDM chemotaxis. In vitro administration of PLX3397 suppressed pERK1/2 stimulation by CSF1 or TCM, and reduced M2 polarization, survival, and chemotaxis in BMDMs. Systemic administration of PLX3397 to the osteosarcoma orthotopic xenograft model significantly suppressed the primary tumor growth and lung metastasis, and thus improved metastasis-free survival. PLX3397 treatment concurrently depleted TAMs and FOXP3+ regulatory T cells and, surprisingly, enhanced infiltration of CD8+ T cells into the microenvironments of both primary and metastatic osteosarcoma sites. Our preclinical results show that PLX3397 has strong macrophage- and T-cell-modulating effects that may translate into cancer immunotherapy for bone and soft-tissue sarcomas.

DOI： 10.1158/1535-7163.MCT-20-0591

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Induction and expansion of human PRRX1+ limb-bud-like mesenchymal cells from pluripotent stem cells. International journal

Daisuke Yamada, Masahiro Nakamura, Tomoka Takao, Shota Takihira, Aki Yoshida, Shunsuke Kawai, Akihiro Miura, Lu Ming, Hiroyuki Yoshitomi, Mai Gozu, Kumi Okamoto, Hironori Hojo, Naoyuki Kusaka, Ryosuke Iwai, Eiji Nakata, Toshifumi Ozaki, Junya Toguchida, Takeshi Takarada

Nature biomedical engineering 5 ( 8 ) 926 - 940 2021.8

Language：English Publishing type：Research paper (scientific journal)

Current protocols for the differentiation of human pluripotent stem cells (hPSCs) into chondrocytes do not allow for the expansion of intermediate progenitors so as to prospectively assess their chondrogenic potential. Here we report a protocol that leverages PRRX1-tdTomato reporter hPSCs for the selective induction of expandable and ontogenetically defined PRRX1+ limb-bud-like mesenchymal cells under defined xeno-free conditions, and the prospective assessment of the cells' chondrogenic potential via the cell-surface markers CD90, CD140B and CD82. The cells, which proliferated stably and exhibited the potential to undergo chondrogenic differentiation, formed hyaline cartilaginous-like tissue commensurate to their PRRX1-expression levels. Moreover, we show that limb-bud-like mesenchymal cells derived from patient-derived induced hPSCs can be used to identify therapeutic candidates for type II collagenopathy and we developed a method to generate uniformly sized hyaline cartilaginous-like particles by plating the cells on culture dishes coated with spots of a zwitterionic polymer. PRRX1+ limb-bud-like mesenchymal cells could facilitate the mass production of chondrocytes and cartilaginous tissues for applications in drug screening and tissue engineering.

DOI： 10.1038/s41551-021-00778-x

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Papers - OZAKI Toshifumi