Updated on 2024/04/15

写真a

 
Nakamichi Ryo
 
Organization
Okayama University Hospital Assistant Professor
Position
Assistant Professor
External link

Degree

  • 博士(医学) ( 岡山大学 )

Research Interests

  • 組織恒常性

  • 腱・靱帯組織

  • 運動機能

  • 整形外科学

  • 椎間板

Research Areas

  • Life Science / Orthopedics  / 腱・靭帯

  • Life Science / Developmental biology

  • Life Science / Molecular biology

  • Life Science / Biomaterials

Education

  • 岡山大学大学院医歯薬学総合研究科   整形外科   博士課程

    2011.4 - 2016.12

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  • 東京医科歯科大学大学院医歯学総合研究科   システム発生・再生医学分野   特別研究生

    2012.4 - 2016.3

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  • Okayama University   医学部医学科  

    2001.4 - 2007.3

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Research History

  • 岡山大学病院   助教、研究准教授

    2023.4

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  • 岡山大学病院   医員

    2022.4 - 2023.3

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  • Scripps Research   Postdoctoral fellow

    2018.2 - 2022.3

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  • 岡山大学病院   医員

    2017.3 - 2018.1

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  • 光生病院   医師

    2016.4 - 2017.3

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  • 赤穂中央病院   医師

    2015.4 - 2016.3

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  • 岡山大学病院   医員

    2011.4 - 2012.3

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  • 岡山済生会総合病院   初期、後期研修医

    2007.4 - 2011.3

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Professional Memberships

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Papers

  • Comparison of early clinical outcome in carpal tunnel release - mini-open technique with palmar incision vs. endoscopic technique with wrist crease incision. International journal

    Ryo Nakamichi, Taichi Saito, Yasunori Shimamura, Masanori Hamada, Keiichiro Nishida, Toshifumi Ozaki

    BMC musculoskeletal disorders   25 ( 1 )   251 - 251   2024.4

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    BACKGROUND: The purpose of this study was to examine two techniques for Carpal Tunnel Syndrome, mini-Open Carpal Tunnel Release (mini-OCTR) and Endoscopic Carpal Tunnel Release (ECTR), to compare their therapeutic efficacy. METHODS: Sixteen patients who underwent mini-OCTR in palmar incision and 17 patients who underwent ECTR in the wrist crease incision were included in the study. All patients presented preoperatively and at 1, 3, and 6 months postoperatively and were assessed with the Visual Analogue Scale (VAS) and the Disabilities of Arm, Shoulder and Hand Score (DASH). We also assessed the pain and cosmetic VAS of the entire affected hand or surgical wound, and the patient's satisfaction with the surgery. RESULTS: In the objective evaluation, both surgical techniques showed improvement at 6 months postoperatively. The DASH score was significantly lower in the ECTR group (average = 3 months: 13.6, 6 months: 11.9) than in the mini-OCTR group (average = 3 months: 27.3, 6 months: 20.6) at 3 and 6 months postoperatively. Also, the pain VAS score was significantly lower in the ECTR group (average = 17.1) than in the mini-OCTR group (average = 36.6) at 3 months postoperatively. The cosmetic VAS was significantly lower in the ECTR group (average = 1 month: 15.3, 3 months: 12.2, 6 months: 5.41) than in the mini-OCTR group (average = 1 month: 33.3, 3 months: 31.2, 6 months: 24.8) at all time points postoperatively. Patient satisfaction scores tended to be higher in the ECTR group (average = 3.3) compared to the mini-OCTR group (average = 2.7). CONCLUSIONS: ECTR in wrist increase incision resulted in better pain and cosmetic recovery in an early postoperative phase compared with mini-OCTR in palmar incision. Our findings suggest that ECTR is an effective technique for patient satisfaction.

    DOI: 10.1186/s12891-023-07151-w

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  • The Effectiveness of Rehabilitation after Open Surgical Release for Trigger Finger: A Prospective, Randomized, Controlled Study

    Taichi Saito, Ryo Nakamichi, Ryuichi Nakahara, Keiichiro Nishida, Toshifumi Ozaki

    Journal of Clinical Medicine   12 ( 22 )   7187 - 7187   2023.11

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

    Background: It is not clear whether rehabilitation after surgery for trigger finger is effective. The aim of this study was to reveal its effectiveness for trigger finger. Methods: This study was a randomized, controlled trial that included patients who underwent operations for trigger fingers. The patients in the rehabilitation group had postoperative occupational therapy (OT) for 3 months, while the patients in the control group were not referred for rehabilitation but received advice for a range of motion exercises. We evaluated the severity of trigger finger, Disability of Arm-Shoulder-Hand (DASH) score, pain-visual analogue scale (VAS), grip strength, whether they gained a full range of motion (ROM), and complications before and after surgery. Results: Finally, 29 and 28 patients were included in the control and rehabilitation groups, respectively. At final follow-up, the DASH score, grip strength, and ROM were significantly improved in the rehabilitation group compared to that preoperatively. At final follow-up, pain was significantly improved in both groups from that preoperatively. There were no significant differences in the results, including the DASH score, grip strength, ROM and pain-VAS between the control and rehabilitation groups at the final follow-up. Subgroup analysis showed that there is a significant difference in the DASH score of patients doing housework or light work and those with a duration of symptoms >12 months between the control and rehabilitation groups at the final follow-up.

    DOI: 10.3390/jcm12227187

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  • Fracture Line Distributions of Undisplaced Distal Radius Fractures in Relation to Rupture of the Extensor Pollicis Longus Tendon.

    Hidenori Kondo, Taichi Saito, Ryuichi Nakahara, Ryo Nakamichi, Yasunori Shimamura, Ryozo Harada, Junya Imatani, Toshifumi Ozaki

    Acta medica Okayama   77 ( 2 )   179 - 184   2023.4

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    Rupture of the extensor pollicis longus (EPL) tendon is a known complication after undisplaced distal radius fracture (DRF). However, no report has revealed the relationship between EPL tendon rupture and the fracture pattern. Thus, this study aimed to investigate the characteristics of fractures at risk of EPL tendon rupture using fracture line mapping of undisplaced DRFs. This study used computed tomography imaging data of undisplaced DRFs with (n=18) and without EPL tendon rupture (n=52). Fracture lines obtained from 3D reconstruction data were drawn manually after matching with a 2D template wrist model. Fracture maps represented the fracture line distribution by superimposing the fracture lines of all 70 patients. Heat maps showed the relative frequency of the fracture lines as a gradual color change. Fracture lines of cases with EPL tendon rupture were concentrated in the proximal border of Lister's tubercle. By contrast, fracture lines of cases without EPL tendon rupture were relatively dispersed.

    DOI: 10.18926/AMO/65147

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  • Motion-capture Analysis of Mice Using a Video Recorded on an iPhone Camera. International journal

    Ryo Nakamichi, Hiroshi Asahara

    Bio-protocol   12 ( 21 )   2022.11

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    When focusing on quick movements in the analysis of animal behavior, a high-speed camera can be used as a powerful tool. There are many options for high-speed cameras to record movement. In recent years, the quality and sophistication of videos captured on cell phones have evolved so much that the iPhone's slow-motion video system can function as a tool for behavior analysis. Here, we describe a method to analyze the movement of the ankle joint and jump speed during the jumping action of mice, using an iPhone.

    DOI: 10.21769/BioProtoc.4539

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  • The effect of mechanical stress on enthesis homeostasis in a rat Achilles enthesis organ culture model. International journal

    Taichi Saito, Ryo Nakamichi, Aki Yoshida, Takaaki Hiranaka, Yuki Okazaki, Satoshi Nezu, Minami Matsuhashi, Yasunori Shimamura, Takayuki Furumatsu, Keiichiro Nishida, Toshifumi Ozaki

    Journal of orthopaedic research : official publication of the Orthopaedic Research Society   40 ( 8 )   1872 - 1882   2022.8

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    Tendons and ligaments are jointed to bones via an enthesis that is essential to the proper function of the muscular and skeletal structures. The aim of the study is to investigate the effect of mechanical stress on the enthesis. We used ex vivo models in organ cultures of rat Achilles tendons with calcaneus including the enthesis. The organ was attached to a mechanical stretching apparatus that can conduct cyclic tensile strain. We made the models of 1-mm elongation (0.5 Hz, 3% elongation), 2-mm elongation (0.5 Hz, 5% elongation), and no stress. Histological evaluation by Safranin O staining and Toluidin Blue and Picro Sirius red staining was conducted. Expression of sex-determining region Y-box 9 (Sox9), scleraxis (Scx), Runt-related transcription factor 2 (Runx2), and matrix metalloproteinase 13 (Mmp13) were examined by real-time polymerase chain reaction and immunocytochemistry. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling and live/dead staining and was conducted for evaluation of the apoptosis and cell viability. The structure of the enthesis was most maintained in the model of 1-mm elongation. The electronic microscope showed that the enthesis of the no stress model had ill-defined borders between fibrocartilage and mineralized fibrocartilage, and that calcification of mineralized fibrocartilage occurred in the model of 2-mm elongation. Sox9 and Scx was upregulated by 1-mm elongation, whereas Runx2 and Mmp13 were upregulated by 2-mm elongation. Apoptosis was inhibited by low stress. The results of this study suggested that 1-mm elongation can maintain the structure of the enthesis, while 2-mm elongation promotes degenerative changes.

    DOI: 10.1002/jor.25210

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  • The mechanosensitive ion channel PIEZO1 is expressed in tendons and regulates physical performance. International journal

    Ryo Nakamichi, Shang Ma, Takayuki Nonoyama, Tomoki Chiba, Ryota Kurimoto, Hiroki Ohzono, Merissa Olmer, Chisa Shukunami, Noriyuki Fuku, Guan Wang, Errol Morrison, Yannis P Pitsiladis, Toshifumi Ozaki, Darryl D'Lima, Martin Lotz, Ardem Patapoutian, Hiroshi Asahara

    Science translational medicine   14 ( 647 )   eabj5557   2022.6

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    How mechanical stress affects physical performance via tendons is not fully understood. Piezo1 is a mechanosensitive ion channel, and E756del PIEZO1 was recently found as a gain-of-function variant that is common in individuals of African descent. We generated tendon-specific knock-in mice using R2482H Piezo1, a mouse gain-of-function variant, and found that they had higher jumping abilities and faster running speeds than wild-type or muscle-specific knock-in mice. These phenotypes were associated with enhanced tendon anabolism via an increase in tendon-specific transcription factors, Mohawk and Scleraxis, but there was no evidence of changes in muscle. Biomechanical analysis showed that the tendons of R2482H Piezo1 mice were more compliant and stored more elastic energy, consistent with the enhancement of jumping ability. These phenotypes were replicated in mice with tendon-specific R2482H Piezo1 replacement after tendon maturation, indicating that PIEZO1 could be a target for promoting physical performance by enhancing function in mature tendon. The frequency of E756del PIEZO1 was higher in sprinters than in population-matched nonathletic controls in a small Jamaican cohort, suggesting a similar function in humans. Together, this human and mouse genetic and physiological evidence revealed a critical function of tendons in physical performance, which is tightly and robustly regulated by PIEZO1 in tenocytes.

    DOI: 10.1126/scitranslmed.abj5557

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  • Generation of a tendon-like tissue from human iPS cells. International journal

    Hiroki Tsutsumi, Ryota Kurimoto, Ryo Nakamichi, Tomoki Chiba, Takahide Matsushima, Yuta Fujii, Risa Sanada, Tomomi Kato, Kana Shishido, Yuriko Sakamaki, Tsuyoshi Kimura, Akio Kishida, Hiroshi Asahara

    Journal of tissue engineering   13   20417314221074018 - 20417314221074018   2022

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    Tendons and ligaments are essential connective tissues that connect the muscle and bone. Their recovery from injuries is known to be poor, highlighting the crucial need for an effective therapy. A few reports have described the development of artificial ligaments with sufficient strength from human cells. In this study, we successfully generated a tendon-like tissue (bio-tendon) using human induced pluripotent stem cells (iPSCs). We first differentiated human iPSCs into mesenchymal stem cells (iPSC-MSCs) and transfected them with Mohawk (Mkx) to obtain Mkx-iPSC-MSCs, which were applied to a newly designed chamber with a mechanical stretch incubation system. The embedded Mkx-iPSC-MSCs created bio-tendons and exhibited an aligned extracellular matrix structure. Transplantation of the bio-tendons into a mouse Achilles tendon rupture model showed host-derived cell infiltration with improved histological score and biomechanical properties. Taken together, the bio-tendon generated in this study has potential clinical applications for tendon/ligament-related injuries and diseases.

    DOI: 10.1177/20417314221074018

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  • Single Cell RNA Sequencing Reveals Critical Functions of Mkx in Periodontal Ligament Homeostasis. International journal

    Kaho Takada, Tomoki Chiba, Takayuki Miyazaki, Lisa Yagasaki, Ryo Nakamichi, Takanori Iwata, Keiji Moriyama, Hiroyuki Harada, Hiroshi Asahara

    Frontiers in cell and developmental biology   10   795441 - 795441   2022

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    The periodontal ligament (PDL) comprises a fibrous tissue that connects teeth to alveolar bone and is essential for periodontal function. The transcription factor mohawk homeobox (Mkx) is expressed in the PDL where it plays an important role in the development and maintenance of the PDL. However, the precise and critical functions of Mkx in the cell populations comprising PDL have not yet been elucidated. The present study aimed to clarify the effects of a Mkx deficiency on PDL cellular heterogeneity and differences between gene expression in PDL tissues from wild-type (WT) (Mkx +/+ ) and Mkx knockout (Mkx -/- ) rats using single-cell RNA sequencing. We identified 12 cell clusters comprising mesenchymal cells and macrophages. The expression of Mkx and scleraxis (Scx; another key transcription factor of PDL), was mutually exclusive, and partitioned mesenchymal cell clusters into Mkx and Scx types that dominantly expressed proteoglycans and elastic fibers, and type 1 and 3 collagen, respectively. Ossification-related genes were upregulated in mesenchymal cell and osteoblast clusters with more Mkx -/- than Mkx +/+ PDLs. Increased number of cells and inflammatory mediators were observed in macrophage clusters of Mkx -/- PDL. These results suggested that Mkx plays an important role in maintaining PDL homeostasis by regulating specific cell populations and gene expression.

    DOI: 10.3389/fcell.2022.795441

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  • Mkx regulates the orthodontic tooth movement via osteoclast induction.

    Takayuki Miyazaki, Ryota Kurimoto, Tomoki Chiba, Takahide Matsushima, Ryo Nakamichi, Hiroki Tsutsumi, Kaho Takada, Lisa Yagasaki, Tomomi Kato, Kana Shishido, Yukiho Kobayashi, Tsutomu Matsumoto, Keiji Moriyama, Hiroshi Asahara

    Journal of bone and mineral metabolism   39 ( 5 )   780 - 786   2021.9

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    INTRODUCTION: The periodontal ligament (PDL) plays an important role in orthodontic tooth movement; however, the underlying molecular mechanism remains unclear. We have previously reported that the Mohawk homeobox (Mkx), a tendon-specific transcription factor, is expressed in the PDL and regulates its homeostasis. MATERIALS AND METHODS: In the present study, we examined the role of Mkx in orthodontic tooth movement via bone remodeling induced by mechanical stimulation in Mkx-deficient rats, which are widely used as experimental animals for orthodontic force application. Orthodontic tooth movement of the maxillary first molar was performed in 7-week-old male Mkx-deficient rats (n = 4) and wild-type Wistar rats (n = 4) using coil springs for 14 days. Hematoxylin and eosin (H&E) staining and tartrate-resistant acid phosphatase (TRAP) staining were performed to evaluate morphological changes and osteoclasts. Furthermore, changes in the expression of receptor activator nuclear factor-kappa B ligand (RANKL) were demonstrated using immunostaining. RESULTS: The amount of tooth movement was significantly lower in Mkx-deficient rats than in wild-type rats. The number of TRAP-positive cells was suppressed in Mkx-deficient rats on the compression side. CONCLUSION: Orthodontic tooth movement experiments in Mkx-deficient rats suggested that Mkx is involved in osteoclast induction at the alveolar bone surface on the compression side. This study reveals the possibility that Mkx plays a mechanosensory role in orthodontic tooth movement by inducing RANKL expression and osteoclastogenesis.

    DOI: 10.1007/s00774-021-01233-2

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  • Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis. International journal

    Yoshiaki Ito, Tokio Matsuzaki, Fumiaki Ayabe, Sho Mokuda, Ryota Kurimoto, Takahide Matsushima, Yusuke Tabata, Maiko Inotsume, Hiroki Tsutsumi, Lin Liu, Masahiro Shinohara, Yoko Tanaka, Ryo Nakamichi, Keiichiro Nishida, Martin K Lotz, Hiroshi Asahara

    Nature communications   12 ( 1 )   4148 - 4148   2021.7

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    Osteoarthritis (OA), the most common aging-related joint disease, is caused by an imbalance between extracellular matrix synthesis and degradation. Here, we discover that both strands of microRNA-455 (miR-455), -5p and -3p, are up-regulated by Sox9, an essential transcription factor for cartilage differentiation and function. Both miR-455-5p and -3p are highly expressed in human chondrocytes from normal articular cartilage and in mouse primary chondrocytes. We generate miR-455 knockout mice, and find that cartilage degeneration mimicking OA and elevated expression of cartilage degeneration-related genes are observed at 6-months-old. Using a cell-based miRNA target screening system, we identify hypoxia-inducible factor-2α (HIF-2α), a catabolic factor for cartilage homeostasis, as a direct target of both miR-455-5p and -3p. In addition, overexpression of both miR-455-5p and -3p protect cartilage degeneration in a mouse OA model, demonstrating their potential therapeutic value. Furthermore, knockdown of HIF-2α in 6-month-old miR-455 knockout cartilage rescues the elevated expression of cartilage degeneration-related genes. These data demonstrate that both strands of a miRNA target the same gene to regulate articular cartilage homeostasis.

    DOI: 10.1038/s41467-021-24460-7

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  • Regulation of tendon and ligament differentiation. International journal

    Ryo Nakamichi, Hiroshi Asahara

    Bone   143   115609 - 115609   2021.2

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    Tendons transmit power from muscles to bones, and ligaments maintain the stability of joints, thus producing smooth and flexible movements of articular joints. However, tendons have poor self-healing ability upon damage due to injuries, diseases, or aging. To maintain homeostasis or promote regeneration of the tendon/ligament, it is critical to understand the mechanism responsible for the coordination of tendon/ligament-specific gene expression and subsequent cell differentiation. In this review, we have discussed the core molecular mechanisms involved in the development and homeostasis of tendons and ligaments, with particular focus on transcription factors, signaling, and mechanical stress.

    DOI: 10.1016/j.bone.2020.115609

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  • MicroRNA Expression Profiling, Target Identification, and Validation in Chondrocytes. International journal

    Tomoki Chiba, Ryota Kurimoto, Takahide Matsushima, Yoshiaki Ito, Ryo Nakamichi, Martin Lotz, Hiroshi Asahara

    Methods in molecular biology (Clifton, N.J.)   2245   151 - 166   2021

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    MicroRNAs (miRNAs) are a class of noncoding small RNAs, which play a critical role in various biological processes including musculoskeletal formation and arthritis pathogenesis via regulating target gene expressions, raising the potentially substantial effects on gene expression networks. Over 2000 miRNAs are encoded in the human genome and a single miRNA potentially targets hundreds of genes. To examine the expression and function of miRNAs in chondrocytes and arthritis pathogenesis, we describe the protocols for the current miRNA related experiments including miRNA expression profiling by (1) Next Generation Sequencing and by TaqMan Array system, (2) miRNA target prediction by TargetScan, (3) miRNA target screening by cell-based reporter library assay, and (4) miRNA and its target interaction by HITS-CLIP (high-throughput sequencing of RNAs isolated by cross-linking immunoprecipitation) in cartilage and chondrocyte research.

    DOI: 10.1007/978-1-0716-1119-7_11

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  • Transcriptional, epigenetic and microRNA regulation of growth plate. International journal

    Ryo Nakamichi, Ryota Kurimoto, Yusuke Tabata, Hirosi Asahara

    Bone   137   115434 - 115434   2020.8

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    Endochondral ossification is a critical event in bone formation, particularly in long shaft bones. Many cellular differentiation processes work in concert to facilitate the generation of cartilage primordium to formation of trabecular structures, all of which occur within the growth plate. Previous studies have revealed that the growth plate is tightly regulated by various transcription factors, epigenetic systems, and microRNAs. Hence, understanding these mechanisms that regulate the growth plate is crucial to furthering the current understanding on skeletal diseases, and in formulating effective treatment strategies. In this review, we focus on describing the function and mechanisms of the transcription factors, epigenetic systems, and microRNAs known to regulate the growth plate.

    DOI: 10.1016/j.bone.2020.115434

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  • The transcription factors regulating intervertebral disc development. International journal

    Ryo Nakamichi, Hiroshi Asahara

    JOR spine   3 ( 1 )   e1081   2020.3

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    Damage to the intervertebral discs (IVDs) occurs due to aging or excessive mechanical stress, causing a series of IVD-related degenerative diseases, such as spinal disc herniation and spondylosis. These IVD-related diseases are difficult to cure, partially because the regeneration ability of IVDs is not sufficient. As a novel strategy for treatment of IVD-related diseases, mesenchymal stem cell transplantation to the damaged discs has been reported in animal studies. To further develop and improve this approach, it is necessary to gain a better understanding of the molecular network regulating IVD development by critical transcription factors. Recent findings reveal that during IVD development, nucleus pulposus and annuls fibrosus differentiation is coordinated by a series of transcription factors, such as Mkx, Pax1, 9, Shh, Foxa1, 2, T-Brachyury, and Sox5, 6, 9. The combination of mesenchymal stem cell transplantation with the regulation of these molecules may provide a novel strategy for treatment of degenerative disc diseases.

    DOI: 10.1002/jsp2.1081

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  • In vitro Neo-Genesis of Tendon/Ligament-Like Tissue by Combination of Mohawk and a Three-Dimensional Cyclic Mechanical Stretch Culture System. International journal

    Kensuke Kataoka, Ryota Kurimoto, Hiroki Tsutsumi, Tomoki Chiba, Tomomi Kato, Kana Shishido, Mariko Kato, Yoshiaki Ito, Yuichiro Cho, Osamu Hoshi, Ayako Mimata, Yuriko Sakamaki, Ryo Nakamichi, Martin K Lotz, Keiji Naruse, Hiroshi Asahara

    Frontiers in cell and developmental biology   8   307 - 307   2020

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    Tendons and ligaments are pivotal connective tissues that tightly connect muscle and bone. In this study, we developed a novel approach to generate tendon/ligament-like tissues with a hierarchical structure, by introducing the tendon/ligament-specific transcription factor Mohawk (MKX) into the mesenchymal stem cell (MSC) line C3H10T1/2 cells, and by applying an improved three-dimensional (3D) cyclic mechanical stretch culture system. In our developed protocol, a combination of stable Mkx expression and cyclic mechanical stretch synergistically affects the structural tendon/ligament-like tissue generation and tendon related gene expression. In a histological analysis of these tendon/ligament-like tissues, an organized extracellular matrix (ECM), containing collagen type III and elastin, was observed. Moreover, we confirmed that Mkx expression and cyclic mechanical stretch, induced the alignment of structural collagen fibril bundles that were deposited in a fibripositor-like manner during the generation of our tendon/ligament-like tissues. Our findings provide new insights for the tendon/ligament biomaterial fields.

    DOI: 10.3389/fcell.2020.00307

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  • Wwp2 maintains cartilage homeostasis through regulation of Adamts5. International journal

    Sho Mokuda, Ryo Nakamichi, Tokio Matsuzaki, Yoshiaki Ito, Tempei Sato, Kohei Miyata, Masafumi Inui, Merissa Olmer, Eiji Sugiyama, Martin Lotz, Hiroshi Asahara

    Nature communications   10 ( 1 )   2429 - 2429   2019.6

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    The WW domain-containing protein 2 (Wwp2) gene, the host gene of miR-140, codes for the Wwp2 protein, which is an HECT-type E3 ubiquitin ligases abundantly expressed in articular cartilage. However, its function remains unclear. Here, we show that mice lacking Wwp2 and mice in which the Wwp2 E3 enzyme is inactivated (Wwp2-C838A) exhibit aggravated spontaneous and surgically induced osteoarthritis (OA). Consistent with this phenotype, WWP2 expression level is downregulated in human OA cartilage. We also identify Runx2 as a Wwp2 substrate and Adamts5 as a target gene, as similar as miR-140. Analysis of Wwp2-C838A mice shows that loss of Wwp2 E3 ligase activity results in upregulation of Runx2-Adamts5 signaling in articular cartilage. Furthermore, in vitro transcribed Wwp2 mRNA injection into mouse joints reduces the severity of experimental OA. We propose that Wwp2 has a role in protecting cartilage from OA by suppressing Runx2-induced Adamts5 via Runx2 poly-ubiquitination and degradation.

    DOI: 10.1038/s41467-019-10177-1

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  • Essential role of Mohawk for tenogenic tissue homeostasis including spinal disc and periodontal ligament. International journal

    Ryo Nakamichi, Kensuke Kataoka, Hiroshi Asahara

    Modern rheumatology   28 ( 6 )   933 - 940   2018.11

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    Tendons and ligaments play essential roles in connecting muscle and bone and stabilizing the connections between bones. The damage to tendons and ligaments caused by aging, injury, and arthritis induces the dysfunction of the musculoskeletal system and reduces the quality of life. Current therapy for damaged tendons and ligaments depends on self-repair; however, it is difficult to reconstruct normal tissue. Regeneration therapy for tendons and ligaments has not been achieved, partly because the mechanism, cell biology, and pathophysiology of tendon and ligament development remain unclear. This review summarizes the role of the transcription factor, Mohawk, which controls tendon and ligament cell differentiation, in the maintenance of cell homeostasis, as well as its function in disease and the possibility of new therapeutic approaches.

    DOI: 10.1080/14397595.2018.1466644

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  • [Cartilage/chondrocyte research and osteoarthritis. Current topics and future of ligament regeneration therapy.].

    Ryo Nakamichi, Kensuke Kataoka, Hiroshi Asahara

    Clinical calcium   28 ( 6 )   809 - 816   2018

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

    Ligaments of joint have an essential role of proper mobilization and stabilization between bone and bone. Damage to ligaments caused by ageing, injury, and arthritis induce a disability of musculoskeletal system and has a problem to reduce our quality of life. To aim for the regeneration of ligaments, we have researched from the point of view of the developmet, found out that the transcription factor Mohawk has been important for the development and homeostasis of tendons and ligaments, and analyzed its function. Furthermore, we have also attempted to induce stem cells to tendon and ligament cells to produce type Ⅰ collagen fibers. In this article, we outline the mechanism of the development that has been reported including our approaches.

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  • The transcription factor mohawk homeobox regulates homeostasis of the periodontal ligament. International journal

    Naoki Koda, Tempei Sato, Masahiro Shinohara, Shizuko Ichinose, Yoshiaki Ito, Ryo Nakamichi, Tomohiro Kayama, Kensuke Kataoka, Hidetsugu Suzuki, Keiji Moriyama, Hiroshi Asahara

    Development (Cambridge, England)   144 ( 2 )   313 - 320   2017.1

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    The periodontal ligament (PDL), which connects the teeth to the alveolar bone, is essential for periodontal tissue homeostasis. Although the significance of the PDL is recognized, molecular mechanisms underlying PDL function are not well known. We report that mohawk homeobox (Mkx), a tendon-specific transcription factor, regulates PDL homeostasis by preventing its degeneration. Mkx is expressed in the mouse PDL at the age of 10 weeks and expression remained at similar levels at 12 months. In Mkx-/- mice, age-dependent expansion of the PDL at the maxillary first molar (M1) furcation area was observed. Transmission electron microscopy (TEM) revealed that Mkx-/- mice presented collagen fibril degeneration in PDL with age, while the collagen fibril diameter gradually increased in Mkx+/+ mice. PDL cells lost their shape in Mkx-/- mice, suggesting changes in PDL properties. Microarray and quantitative polymerase chain reaction (qPCR) analyses of Mkx-/- PDL revealed an increase in osteogenic gene expression and no change in PDL- and inflammatory-related gene expression. Additionally, COL1A1 and COL1A2 were upregulated in Mkx-overexpressing human PDL fibroblasts, whereas osteogenic genes were downregulated. Our results indicate that Mkx prevents PDL degeneration by regulating osteogenesis.

    DOI: 10.1242/dev.135798

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  • Mohawk promotes the maintenance and regeneration of the outer annulus fibrosus of intervertebral discs. International journal

    Ryo Nakamichi, Yoshiaki Ito, Masafumi Inui, Naoko Onizuka, Tomohiro Kayama, Kensuke Kataoka, Hidetsugu Suzuki, Masaki Mori, Masayo Inagawa, Shizuko Ichinose, Martin K Lotz, Daisuke Sakai, Koichi Masuda, Toshifumi Ozaki, Hiroshi Asahara

    Nature communications   7   12503 - 12503   2016.8

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

    The main pathogenesis of intervertebral disc (IVD) herniation involves disruption of the annulus fibrosus (AF) caused by ageing or excessive mechanical stress and the resulting prolapse of the nucleus pulposus. Owing to the avascular nature of the IVD and lack of understanding the mechanisms that maintain the IVD, current therapies do not lead to tissue regeneration. Here we show that homeobox protein Mohawk (Mkx) is a key transcription factor that regulates AF development, maintenance and regeneration. Mkx is mainly expressed in the outer AF (OAF) of humans and mice. In Mkx(-/-) mice, the OAF displays a deficiency of multiple tendon/ligament-related genes, a smaller OAF collagen fibril diameter and a more rapid progression of IVD degeneration compared with the wild type. Mesenchymal stem cells overexpressing Mkx promote functional AF regeneration in a mouse AF defect model, with abundant collagen fibril formation. Our results indicate a therapeutic strategy for AF regeneration.

    DOI: 10.1038/ncomms12503

    PubMed

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  • Gene targeting of the transcription factor Mohawk in rats causes heterotopic ossification of Achilles tendon via failed tenogenesis. International journal

    Hidetsugu Suzuki, Yoshiaki Ito, Masahiro Shinohara, Satoshi Yamashita, Shizuko Ichinose, Akio Kishida, Takuya Oyaizu, Tomohiro Kayama, Ryo Nakamichi, Naoki Koda, Kazuyoshi Yagishita, Martin K Lotz, Atsushi Okawa, Hiroshi Asahara

    Proceedings of the National Academy of Sciences of the United States of America   113 ( 28 )   7840 - 5   2016.7

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    Cell-based or pharmacological approaches for promoting tendon repair are currently not available because the molecular mechanisms of tendon development and healing are not well understood. Although analysis of knockout mice provides many critical insights, small animals such as mice have some limitations. In particular, precise physiological examination for mechanical load and the ability to obtain a sufficient number of primary tendon cells for molecular biology studies are challenging using mice. Here, we generated Mohawk (Mkx)(-/-) rats by using CRISPR/Cas9, which showed not only systemic hypoplasia of tendons similar to Mkx(-/-) mice, but also earlier heterotopic ossification of the Achilles tendon compared with Mkx(-/-) mice. Analysis of tendon-derived cells (TDCs) revealed that Mkx deficiency accelerated chondrogenic and osteogenic differentiation, whereas Mkx overexpression suppressed chondrogenic, osteogenic, and adipogenic differentiation. Furthermore, mechanical stretch stimulation of Mkx(-/-) TDCs led to chondrogenic differentiation, whereas the same stimulation in Mkx(+/+) TDCs led to formation of tenocytes. ChIP-seq of Mkx overexpressing TDCs revealed significant peaks in tenogenic-related genes, such as collagen type (Col)1a1 and Col3a1, and chondrogenic differentiation-related genes, such as SRY-box (Sox)5, Sox6, and Sox9 Our results demonstrate that Mkx has a dual role, including accelerating tendon differentiation and preventing chondrogenic/osteogenic differentiation. This molecular network of Mkx provides a basis for tendon physiology and tissue engineering.

    DOI: 10.1073/pnas.1522054113

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  • Gtf2ird1-Dependent Mohawk Expression Regulates Mechanosensing Properties of the Tendon. International journal

    Tomohiro Kayama, Masaki Mori, Yoshiaki Ito, Takahide Matsushima, Ryo Nakamichi, Hidetsugu Suzuki, Shizuko Ichinose, Mitsuru Saito, Keishi Marumo, Hiroshi Asahara

    Molecular and cellular biology   36 ( 8 )   1297 - 309   2016.4

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

    Mechanoforces experienced by an organ are translated into biological information for cellular sensing and response. In mammals, the tendon connective tissue experiences and resists physical forces, with tendon-specific mesenchymal cells called tenocytes orchestrating extracellular matrix (ECM) turnover. We show that Mohawk (Mkx), a tendon-specific transcription factor, is essential in mechanoresponsive tenogenesis through regulation of its downstream ECM genes such as type I collagens and proteoglycans such as fibromodulin both in vivo and in vitro Wild-type (WT) mice demonstrated an increase in collagen fiber diameter and density in response to physical treadmill exercise, whereas in Mkx(-/-) mice, tendons failed to respond to the same mechanical stimulation. Furthermore, functional screening of the Mkx promoter region identified several upstream transcription factors that regulate Mkx In particular, general transcription factor II-I repeat domain-containing protein 1 (Gtf2ird1) that is expressed in the cytoplasm of unstressed tenocytes translocated into the nucleus upon mechanical stretching to activate the Mkx promoter through chromatin regulation. Here, we demonstrate that Gtf2ird1 is essential for Mkx transcription, while also linking mechanical forces to Mkx-mediated tendon homeostasis and regeneration.

    DOI: 10.1128/MCB.00950-15

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Books

  • Cartilage: From Biology to Biofabrication

    ( Role: Contributor ,  Role and Application of Biomolecules for Regeneration of Cartilage Tissue)

    2023 

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  • レジデントのための整形外科診療

    ( Role: Contributor ,  鎖骨骨幹部骨折、鎖骨遠位端骨折、肩鎖関節脱臼骨折)

    2023 

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  • 疾患バイオマーカーとしてのマイクロRNAと診断応用

    ( Role: Contributor)

    2022 

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  • Methods Mol Biol.

    ( Role: Contributor ,  MicroRNA Expression Profiling, Target Identification, and Validation in Chondrocytes.)

    2021 

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  • Encyclopedia of bone biology

    ( Role: Contributor ,  Genetic, Epigenetic, and MicroRNA Regulation of Osteoarthritis.)

    2020 

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MISC

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Presentations

  • Comprehension of Tendon Homeostasis Mechanism and Application for Therapy Invited

    2024.2.16 

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  • Tendons affect physical performance via mechano-transduction Invited

    Ryo Nakamichi

    2023.7.27 

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  • 米国における基礎留学 Invited

    中道亮

    第96回 日本整形外科学会学術総会  2023.5.13 

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  • 鏡視下手根管開放術と小切開手根管開放術 の短期成績の比較検討

    中道 亮, 齋藤 太一, 島村 安則, 古谷 友希, 堅山 佳美, 濱田 全一, 那須 義久, 西田圭一, 尾﨑 敏文

    第66回日本手外科学会学術集会  2023.4.21 

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  • PIEZO1 promotes tendon growth in adults via mechanical stress

    Ryo Nakamichi, Toshifumi Ozaki, Hiroshi Asahara

    2023.2.13 

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  • 機械刺激応答チャネルPIEZO1 は運動刺激を感知し腱成長を促進する

    中道 亮, 尾﨑 敏文, 浅原

    第55回 中国・四国整形外科学会  2022.11.19 

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  • 械感受性イオンチャネルPIEZO1は腱を通じて身体能力を制御する

    中道 亮, 栗本遼太, 千葉朋希, 尾﨑 敏文, 浅原 弘嗣

    第9回JCRベーシックリサーチカンファレンス  2022.11.18 

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  • 腱特異的なPIEZO1-MKXによる個体瞬発力の増進

    中道 亮, 尾﨑, 敏文, 浅原 弘嗣

    第21回運動器科学研究会  2022.9.16 

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  • 米国留学帰郷報告

    第18回笠岡セミナー  2022.7.30 

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  • 骨を繋ぎ、稼働させる筋と腱を俯瞰する Invited

    中道 亮, 栗本遼太, 千葉朋希, 尾﨑 敏文, 浅原 弘嗣

    第40回 日本骨代謝学会学術集会  2022.7.23 

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  • microRNA-455-5pおよび3pは協調してHIF-2αを抑制し軟骨の恒常性を維持する

    中道 亮, 伊藤 義晃, 浅原

    第39回日本運動器再生移植研究会  2020.11.7 

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  • 椎間板組織の転写因子制御 -線維輪に注目して- Invited

    中道 亮

    基礎研究セミナー (東京医科歯科大学)  2020.2.26 

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  • Mohawk promotes the maintenance and regeneration of the outer annulus fibrosus of intervertebral discs.

    Ryo Nakamichi, Martin Lotz, Hiroshi Asahara

    Gordon Research Conference 2019  2019.3 

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  • 転写因子Mohawkは椎間板線維輪の維持・再生に重要である Invited

    中道 亮, 浅原 弘嗣, 尾﨑 敏文

    第 91 回日本整形外科学会学術総会  2018.5.25 

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  • 転写因子Mokawkの椎間板線維輪における機能解析 Invited

    中道 亮, 尾﨑 敏文, 浅原

    第4回 JCRベーシックリサーチカンファレンス  2017.10.13 

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  • 転写因子Mokawkは椎間板線維輪の維持・再生に重要である

    中道 亮, 尾﨑 敏文

    第129回中部整形外科災害外科学術集会  2017.10.7 

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  • 椎間板線維輪の転写因子制御 Invited

    中道 亮, 尾﨑 敏文, 浅原 弘嗣

    第35回日本骨代謝学会学術集会  2017.7.29 

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  • 転写因子Mohawkは椎間板線維輪の維持・再生に重要である Invited

    中道 亮, 浅原 弘嗣, 尾﨑 敏文

    第21回リウマチフォーラム  2017.1.28 

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  • Mohawk promotes the maintenance and regeneration of the outer annulus fibrosus of intervertebral discs. Invited

    中道 亮, 浅原 弘嗣

    第 19 回骨代謝研究会  2016.11.26 

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  • 転写因子Mohawkは椎間板線維輪の発生に重要である

    中道 亮, 浅原 弘嗣, 尾﨑 敏文

    第36回日本運動器移植・再生医学研究会  2016.9.24 

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  • 転写因子Mohawkは椎間板線維輪の発生・再生に重要である

    中道 亮, 浅原 弘嗣, 尾﨑 敏文

    第30回日本整形外科基礎学会  2015.10.23 

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  • 転写因子Mohawkは椎間板線維輪の再生に重要である

    中道 亮, 浅原 弘嗣, 尾﨑 敏文

    第35回日本運動器移植・再生医学研究会  2015.9.25 

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  • 筋・腱・靭帯シンポジウム骨のダイナミズムを司る筋・腱・靭帯のフロンティア Invited

    中道 亮, 浅原 弘嗣

    第33回 日本骨代謝学会学術集会  2015.7.23 

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  • 転写因子 Mohawk の椎間板における機能解析

    中道 亮, 浅原 弘嗣

    第 15 回運動器科学研究会  2014.9.5 

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  • Transcription factor Mohawk is essential in Intervertebral Disc Maintenance

    Ryo Nakamichi, Naoko Onizuka, Yoshiaki Ito, Tomohiro Kayama, Naoki Kouda, Toshifumi Ozaki, Hiroshi Asahara

    2014.3 

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Awards

  • 令和5年度岡山大学若手トップリサーチャー研究奨励賞

    2024.4  

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  • ポスター賞

    2022   JCRベーシックリサーチカンファレンス  

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  • 海外特別研究員

    2021   日本学術振興会  

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  • 日本整形外科学会 奨励賞 (基礎研究)

    2018.5  

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  • 学術奨励賞

    2017.12   岡山大学桃整会  

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Research Projects

  • メカノシグナルで靭帯骨化を制御する

    2024.04 - 2026.03

    第8回内藤記念次世代育成支援研究助成金 

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  • 種々の組織由来幹/前駆細胞のメカノシグナルによる固有分化制御機構の理解と腱損傷治療への応用

    2024.04

    一般社団法人 日本手外科学会  2023年度 学術研究プロジェクト 

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  • Development of a New Tendon Repair Approach by Regulating Mechanical Stress Response

    Grant number:23K08631  2023.04 - 2026.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    中道 亮

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    Authorship:Principal investigator 

    Grant amount:\4680000 ( Direct expense: \3600000 、 Indirect expense:\1080000 )

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  • バイオ腱骨組織創出のための細胞周囲環境の役割の解明

    2023.04 - 2026.03

    JST  創発的研究支援事業 

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  • メカニカルストレス応答制御による新規椎間板繊維輪治療法の開発

    2023.04

    中冨健康科学振興財団 

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  • 機械刺激応答シグナル調整を利用した肩腱板損傷に対する新治療法の開発

    2023.04

    第40回 公益財団法人 整形災害外科学研究助成財団 研究助成 

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  • メカニカルストレス応答調整を介した効率的な腱細胞誘導法の確立

    Grant number:22K20940  2022.08 - 2024.03

    日本学術振興会  科学研究費助成事業  研究活動スタート支援

    中道 亮

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    Grant amount:\2860000 ( Direct expense: \2200000 、 Indirect expense:\660000 )

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  • 機械刺激応答制御による靭帯恒常性制御機構の解明

    2022.04

    2021年度JCR次世代基礎研究推進プログラム研究助成 

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  • 腱・靭帯細胞の分化機構の解明と誘導システムの構築

    2016.04

    岡山大学振興会  第17回 医学研究助成 

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Media Coverage

  • 運動能力向上させる遺伝子特定 岡山大病院医師ら、腱成長に関与 Newspaper, magazine

    山陽新聞  2022.11.28

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  • Your mighty tendons help you sprint, jump and move – a genetic mutation in one key protein may increase athletic performance Internet

    The Conversation  2022.9.28

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  • Tokyo Medical and Dental University, The Scripps Research Institute research group clarifies role of mechanosensitive ion channel PIEZO1 in individuals Internet

    Science Japan by JST  2022.7.19

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  • 瞬発力の鍵は筋より腱? Newspaper, magazine

    朝日新聞  2022.6.6

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  • 瞬発力高める遺伝子変異、東京医歯大チーム特定…ジャマイカ短距離選手に特に多く Newspaper, magazine

    読売新聞  2022.6.5

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  • ジャンプ力の大幅向上に特殊なタンパク質関係か 治療法開発に TV or radio program

    NHKニュースおはよう日本  2022.6.2

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