講演情報
[I-02]Myeloid dendritic-cells (mDC), monocytes/macrophages (Mo/Mf), and osteoclasts (OC) axial progressions and inflammation-induced arthritic bone loss: The classical vs. alternative theme-pathways proposed
Liu Yen Chun G.1、○原田 和昭2,3、Teng Andy Yen-Tung 4,5 (1. Lab. of Adv. Dental Medicine & Hygiene vs. Overall Health; School of Dentistry, & Dept. of Dental Hygiene, School of Oral Health and Nursing, Kanagawa Dental University, Yokosuka, Kanagawa, Japan;、2. Harada Dental Clinic, Kitakyushu City、3. Kyushu Dental University, Kitakyushu City Fukuoka, Japan;、4. Center for Osteo-immunology and Biotechnology Research (COBR), College of Dental Medicine, Kaohsiung Medical University (KMU) & KMU-Hospital, Kaohsiung, Taiwan、5. The Eastman Institute for Oral Health (EIOH), School of Medicine & Dentistry, University of Rochester, Rochester, NY, USA.)
Background: Inflammation-induced arthritic bone loss in the elders involves the critical RANKL/RANK-OPG-triad via the TRAF6/ adaptor-complex leading to regulatory homeostasis vs. pathogenic sequelae at the osteo-immune interface, which remains unclear at present. And how and why do the multiple lineages (i.e., myeloid dendritic-cells-monocytes/ macrophages-osteoclasts: mDC-Mo/Mf-OC) develop and then interact during its pathogenesis awaits further study for an in-depth and better understanding.Methods: Our lab has employed various in-vitro and in-vivo approaches (e.g., gene knockout/siRNA-knockdown, Ab-neutralization, adoptive-transfer vs. reconstituted bone-marrow (BM) chimeras, etc.) to address and analyze: i) the classical Mo/Mf subset vs. myeloid-DCs/mDCs, as OC precursors/OCp, that develop osteoclastogenic activity; ii) the developmental potential and step-wise features of immature CD11c+mDCs, as compared to those of the classical Mo/Mf subsets, towards an alternative osteoclastogenesis for arthritic bone loss, iii) how signaling interactions of osteotropic cytokines (i.e., TGF-β, IL-17, etc.) with & without TRAF6/adaptor-complex in the local environmental-milieu may affect the osteoclastogenic progression under inflammation for analyses (by student-t-test & ANOVA).Results: The results have showed that: i) knock-out TGF-βRII-signaling robustly reduced mDDOCp/OCp-mediated osteoclastogenesis in-vitro & in-vivo (p<0.03); ii) though TRAF6-adaptor signaling was essential for RANKL/RANK-mediated osteoclastogenesis, adding exogenous TGF-β vs. IL-17 individually or synergistically rescued TRAF6-defect in the classical Mo-Mf/OCp-absentee/mediated bone resorption in-vitro (p=0.02); iii) such defective TRAF6-deficient phenotype without the endogenous Mo-Mf/OCp subsets analyzed, were more significantly rescued in the IL-17- treated chicken-type-II collagen immunized TRAF6(-/-)-BM chimeras, compared to those of TGF-β-treated alone (p<0.05), suggesting IL-17-signaling towards mDDOCp effector function required TGF-b in the local arthritic environment, regardless the presence or absence of TRAF6-signaling and endogenous Mo-Mf/OCpexisted in-situ.Conclusion: Collectively, it is suggested that immature-CD11c+DCs/mDDOCp are involved in inflammation-induced bone loss, independent of the classical Mo/Mf-derived-OCs in TRAF6-deficient hosts, and IL-17 can engage a distinct cross-talk with CD11c+mDDOCp before rendering CD11c+TRAF6(-/-)mDCs/OCp via TGF-b-mediated step-wise progression to alternative osteoclastogenic pathway. Such twist-in-turns osteoclastogenesis involving the classical-vs.-alternative pathways leading to arthritic bone loss and other osteoporotic conditions or disorders are to be theme-proposed-and-highlighted in this poster presentation as well. COI: The authors declare no conflict of interest (COI) regarding the contents of this abstract for scientific/poster presentation; where the present research project was conducted according to the guidelines of the Institution Animal Care & Use Committee (IACUC), approved via the IACUC-protocol #98017 & #98183. The project was supported in-parts by the National Health Research Institute of Taiwan, # NHRI-EX101-9946SI, and partly from the operating funds made available at COBR via AY TT and YCGL.