TNF계 CD137L 및 RANKL의 파골세포와 T 세포에 대한 활성조절 = STUDY ON THE REGULATION OF OSTEOCLAST AND T CELL ACTIVATION VIA CELL MEMBRANE PROTEINS OF TNF FAMILY, CD137 LIGAND AND RANK LIGAND

국문 초록 (Abstract)

본 연구는 TNFR family인 CD137 및 RANK. 파골세포의 CD137L와 T 세포의 RANKL 간의 역신호에 의한 이들 세포의 역할을 알아보고자 하였다. 이에 RANKL 및 CD137L 자극으로 유도되는 역신호 전달에 의한 T 세포 활성과 파골세포분화에 미치는 영향을 규명하고자 웅성 생쥐의 골수세포와 T 세포를 공동배양하여 다음과 같은 결과를 얻었다.
1. 생쥐 단핵세포주 및 골수유도 단핵전구세포에서 CD137L이 발현되며, CD137L 단클론 항체로 자극을 주었을 경우 파 골세포 표지단백절인 TRAP 양성 파골세포의 형성이 억제되었다.
2. 활성화된 CD4^(+) 및 CD8^(+) T 세포에서 RANKL을 발현하였으며 RANKL의 유사 수용체인 OPG 재조합 단백질을 처리하여 CD4^(+) 및 CD8^(+) T 세포의 세포증식이 억제되었다.
이 연구의 결과는 CD137자극에 의한T세포활성 및 RANK 자극에 의한파골세포분화및 활성이 각각수용체에 결합하는 라이겐드의 역신호에 의해 억제되었는데, 이는 파골세포와 T 세포의 과도한 활성을 제어하는 생체의 항상성조절에 관여하는 기전으로 생각된다.

다국어 초록 (Multilingual Abstract)

Resorption of alveolar bone in periodontitis is due to excessive differentiation and activation of osteoclasts. Bacterial antigens causing periodontitis activates CD4 T cells, which leads to expressing RANK ligand (RANKL) on CD4 T cells. RANKL binds RANK on preosteoclasts or osteoclasts, and enhances the differentiation preosteoclasts into osteoclasts and the activation of mature osteoclasts. CD137, one of TNF receptor (TNFR) family, expressed on activated T cells binds with CD137 ligand (CD137L) on antigen presenting cells. Cross-linking of CD137 by CD137L acts as T cell co-stimulatory signals and, therefore, enhances the activation of T cell. In this study, I elucidated the biological responses of CD137L on (pre)osteoclasts and RANKL on T cells in the context of in vivo interaction between T cells and osteoclasts. RAW264.7. murine monocytic cells, constitutively express CD137L. Ligation of CD137L with anti-CD137L mAb inhibited RANKL-induced osteoclast formation in a dose-dependent manner. Bone marrow cells are expressed CD137L by the treatment with M-CSF. Cross-linking of CD137L abolished M-CSF/RANKL-evoked the formation of multi-nucleated osteoclasts. Both mouse CD4 and CD8 T cells are expressed RANKL following their activation. Ligation of RANKL with OPG, the decoy receptor for RANKL, inhibited both CD4 and CD8 T cell proliferation. These effects were attributed to RANKL-induced apoptosis. These data indicate that CD137L and RANKL on osteoclasts and T cells, respectively provide them with inhibitory signal.

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