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  • [Radiother Oncol.] Low-dose irradiation could mitigate osteoarthritis progression via anti-inflammatory action that modulates mitochondrial function

    [Radiother Oncol.] Low-dose irradiation could mitigate osteoarthritis progression via anti-inflammatory action that modulates mitochondrial function

    서울의대 / 김병혁*, 한혁수*

  • 출처
    Radiother Oncol.
  • 등재일
    2022 May
  • 저널이슈번호
    170:231-241. doi: 10.1016/j.radonc.2022.02.039. Epub 2022 Mar 5.
  • 내용

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    Abstract
    Purpose: The use of low-dose radiation therapy (LDRT) for osteoarthritis (OA) are rarely implemented, except in some European regions. Its clinical effects are controversial but little is known about how LDRT affects actual disease progression. We conducted a preclinical study to reveal the potential underlying mechanisms related to its disease modifying abilities.

    Methods and materials: Using primary cultured human chondrocytes and synovium-derived cells obtained from OA patients, the effects of LDRT were measured by quantitative real-time PCR, western blotting, and mRNA sequencing. For in vivo validation, a surgically-induced isolated OA model was used after anterior cruciate ligament transection or surgical destabilization of the medial meniscus.

    Results: LDRT decreased the expression of pro-inflammatory factor matrix metalloproteinase 13 (MMP13) in chondrocytes. By contrast, collagen type 2 (COL2) protein expression was increased. LDRT induced large transcriptomic changes in both chondrocytes/synoviocytes, especially in mitochondrial activities. Gene set variation analysis demonstrated inverted U-shaped response in several categories, such as mitochondrial unfolded protein responses and extracellular matrix interactions. Growth differentiation factor 15 (GDF15), which is a mitohormetic signaling factor, was increased after LDRT and mediated the anti-inflammatory effects. Aggrecan was increased in synoviocyte's medium and TNF-α was decreased in chondrocyte's medium after LDRT. Conversely, knockdown of GDF15 did not result in decreased MMP13 expression by LDRT. Next, OA rats treated with LDRT exhibited a decreased OA severity when compared with the no-irradiation group at 10 weeks post-surgery (mean OARSI score 3.7 in 0 Gy, 2.8 in 0.5 Gy, and 1.8 in 1 Gy; p = 0.003). Osteoclast activity was significantly reduced in the LDRT group.

    Conclusions: Taken together, these data show that LDRT could mitigate osteoarthritis progression by exerting its anti-inflammatory effects via mitochondrial function modulation.

     

     

    Affiliations

    Byoung Hyuck Kim  1 , Hyun Cheol Bae  2 , Sun Young Wang  2 , Bum-Sup Jang  3 , Ji Hyun Chang  4 , Eui Kyu Chie  4 , Hyon-Seung Yi  5 , Jeanny Kwon  6 , Hyuk-Soo Han  7 , Hak Jae Kim  8
    1 Department of Radiation Oncology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Republic of Korea. Electronic address: karlly71@snu.ac.kr.
    2 Department of Orthopaedic Surgery, Seoul National University College of Medicine, Republic of Korea.
    3 Department of Radiation Oncology, Seoul National University Bundang Hospital, Republic of Korea.
    4 Department of Radiation Oncology, Seoul National University College of Medicine, Republic of Korea.
    5 Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
    6 Department of Radiation Oncology, Chungnam National University College of Medicine, Daejeon, Republic of Korea.
    7 Department of Orthopaedic Surgery, Seoul National University College of Medicine, Republic of Korea. Electronic address: oshawks7@snu.ac.kr.
    8 Department of Radiation Oncology, Seoul National University College of Medicine, Republic of Korea; Cancer Research Institute, Seoul National University, Republic of Korea.

  • 키워드
    Chondrocyte; Gdf15; Low-dose radiotherapy; Mmp13; Osteoarthritis.
  • 연구소개
    저선량방사선은 비침습적으로 통증을 줄이고 약물 부작용을 피할 수 있다는 장점이 있어, 유럽 등지에서는 임상적으로 치료에 사용되기도 하나 아직 국내에는 도입된적이 없었습니다. 작용기전을 보다 상세히 관찰하고자 무릎관절치환술을 받는 환자의 연골세포 및 활막세포를 분리하여, 다양한 저선량방사선 조사 후 염증 인자 변화 및 유전자 발현 변화 분석 등을 시행하였습니다. 이에 mitochondrial function modulation을 통한 anti-inflammatory mechanism이 저선량방사선치료 효과를 설명할 수 있는 새로운 기전일 수 있음을 제시하였습니다. 또한, 기존 선행문헌들의 관절염 모델의 한계점을 극복하고자 surgically induced osteoarthritis model을 활용하여, in vivo 에서도 long-term arthritis progression을 완화할 수 있는 가능성을 관찰하였습니다.
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