Department of Clinical Immunology, Sun Yat-sen University Third Affiliated Hospital, Guangzhou 510000, PR China; Division of Rheumatology, Department of Medicine at Penn State College of Medicine and Milton S. Hershey Medical Center, Hershey 17033, USA; Department of Neurology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, PR China.
Department of Clinical Immunology, Sun Yat-sen University Third Affiliated Hospital, Guangzhou 510000, PR China.
EBioMedicine. 2019 May;43:620-631. doi: 10.1016/j.ebiom.2019.04.058. Epub 2019 May 7.
Bone destruction is one of many severe complications that occurs in patients with rheumatoid arthritis (RA) and current therapies are unable to cure this manifestation. This study here aims to determine whether GMSC can directly inhibit osteoclast formation and eventually attenuate osteoclastogenesis and bone erosion in an inflammatory milieu.
GMSC were co-cultured with osteoclast precursors with or without CD39 inhibitor, CD73 inhibitor or adenosine receptors inhibitors pretreatment and osteoclast formation were evaluated in vitro. 2×10^6 GMSC per mouse were transferred to CIA mice and pathology scores, the frequency of osteoclasts, bone erosion in joints were assessed in vivo.
GMSC but not control cells, markedly suppressed human or mice osteoclastogenesis in vitro. GMSC treatment also resulted in a dramatically decreased level of NF-κB p65/p50 in osteoclasts in vitro. Infusion of GMSC to CIA significantly attenuated the severity of arthritis, pathology scores, frequency of osteoclasts, particularly bone erosion, as well as a decreased expression of RANKL in synovial tissues in vivo. Blockade of CD39/CD73 or adenosine receptors has significantly abrogated the suppressive ability of GMSC in vitro and therapeutic effect of GMSC on bone erosion during CIA in vivo.
GMSC inhibit osteoclast formation in vitro and in vivo partially via CD39-CD73-adenosine signals. Manipulation of GMSC may have a therapeutic implication on rheumatoid arthritis and other bone erosion related diseases. FUND: This study was supported by grants from the National Key R&D Program of China (2017YFA0105801 to F.H); the Zhujiang Innovative and Entrepreneurial Talent Team Award of Guangdong Province (2016 ZT 06S 252 to F·H) and National Institutes of Health (R01 AR059103, R61 AR073409 and NIH Star Award to S.G.Z).
骨破坏是类风湿关节炎（RA）患者发生的许多严重并发症之一，目前的治疗方法无法治愈这种表现。本研究旨在确定 GMSC 是否可以直接抑制破骨细胞的形成，从而最终减轻炎症环境中的破骨细胞生成和骨侵蚀。
将 GMSC 与破骨细胞前体共培养，或用 CD39 抑制剂、CD73 抑制剂或腺苷受体抑制剂预处理，然后在体外评估破骨细胞的形成。将 2×10^6 个 GMSC 转移到 CIA 小鼠体内，评估体内病理学评分、破骨细胞频率、关节骨侵蚀情况。
GMSC 而非对照细胞，明显抑制人或鼠破骨细胞体外生成。GMSC 治疗还导致体外破骨细胞中 NF-κB p65/p50 水平显著降低。GMSC 输注到 CIA 显著减轻关节炎严重程度、病理学评分、破骨细胞频率，特别是骨侵蚀，以及滑膜组织中 RANKL 的表达降低。阻断 CD39/CD73 或腺苷受体显著消除了 GMSC 在体外的抑制能力和 GMSC 在 CIA 体内对骨侵蚀的治疗效果。
GMSC 通过 CD39-CD73-腺苷信号部分抑制体外和体内的破骨细胞形成。对 GMSC 的操作可能对类风湿关节炎和其他骨侵蚀相关疾病具有治疗意义。资助：本研究得到中国国家重点研发计划（2017YFA0105801 至 F·H）、广东省珠江创新和创业人才团队奖（2016 ZT 06S 252 至 F·H）和美国国立卫生研究院（R01 AR059103、R61 AR073409 和 NIH Star Award 至 S·G·Z）的资助。
