@article{b682d3ad29e449cc8c007d99c4716f13,
title = "Osteoblastic PLEKHO1 contributes to joint inflammation in rheumatoid arthritis",
abstract = "Background: Osteoblasts participating in the inflammation regulation gradually obtain concerns. However, its role in joint inflammation of rheumatoid arthritis (RA) is largely unknown. Here, we investigated the role of osteoblastic pleckstrin homology domain-containing family O member 1 (PLEKHO1), a negative regulator of osteogenic lineage activity, in regulating joint inflammation in RA. Methods: The level of osteoblastic PLEKHO1 in RA patients and collagen-induced arthritis (CIA) mice was examined. The role of osteoblastic PLEKHO1 in joint inflammation was evaluated by a CIA model and a K/BxN serum-transfer arthritis (STA) model which were induced in osteoblast-specific Plekho1 conditional knockout mice and mice expressing high Plekho1 exclusively in osteoblasts, respectively. The effect of osteoblastic PLEKHO1 inhibition was explored in a CIA mice model and a non-human primate arthritis model. The mechanism of osteoblastic PLEKHO1 in regulating joint inflammation were performed by a series of in vitro studies. Results: PLEKHO1 was highly expressed in osteoblasts from RA patients and CIA mice. Osteoblastic Plekho1 deletion ameliorated joint inflammation, whereas overexpressing Plekho1 only within osteoblasts exacerbated local inflammation in CIA mice and STA mice. PLEKHO1 was required for TRAF2-mediated RIP1 ubiquitination to activate NF-κB for inducing inflammatory cytokines production in osteoblasts. Moreover, osteoblastic PLEKHO1 inhibition diminished joint inflammation and promoted bone formation in CIA mice and non-human primate arthritis model. Conclusions: These data strongly suggest that the highly expressed PLEKHO1 in osteoblasts contributes to joint inflammation in RA. Targeting osteoblastic PLEKHO1 may exert dual therapeutic action of alleviating joint inflammation and promoting bone formation in RA.",
keywords = "Bone formation, Inflammation, Osteoblast, PLEKHO1, Rheumatoid arthritis",
author = "Xiaojuan He and Jin Liu and Chao Liang and Shaikh, {Atik Badshah} and Kang Zheng and Lei Dang and Baosheng Guo and Defang Li and Cheng Lu and Qingqing Guo and Danping Fan and Yanqin Bian and Hui Feng and Lianbo Xiao and Xiaohua Pan and Cheng Xiao and Zhang, {Bao Ting} and Ge Zhang and Aiping Lu",
note = "Funding Information: We thank the technical staff from Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University and Institute of Basic Theory, China Academy of Chinese Medical Sciences for providing critical comments and technical support. This study was supported by the Hong Kong General Research Fund ( HKBU479111 , HKBU478312 , HKBU 12114416 , HKBU262913 , HKBU261113 , HKBU12122516 ), the Natural Science Foundation Council of China ( 81272045 , 81470072 , 81700780 ), the Research Grants Council & Natural Science Foundation Council of China ( N_HKBU435/12 ), the Hong Kong Baptist University Strategic Development Fund ( SDF15-0324-P02 ), and the National Key R&D Program of China ( 2018YFC1705205 ). The funding institutions had not any role in study design, data collection, data analysis, interpretation or writing of the report in this study. Funding Information: We thank the technical staff from Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University and Institute of Basic Theory, China Academy of Chinese Medical Sciences for providing critical comments and technical support. This study was supported by the Hong Kong General Research Fund (HKBU479111, HKBU478312, HKBU 12114416, HKBU262913, HKBU261113, HKBU12122516), the Natural Science Foundation Council of China (81272045, 81470072, 81700780), the Research Grants Council & Natural Science Foundation Council of China (N_HKBU435/12), the Hong Kong Baptist University Strategic Development Fund (SDF15-0324-P02), and the National Key R&D Program of China (2018YFC1705205). The funding institutions had not any role in study design, data collection, data analysis, interpretation or writing of the report in this study. Publisher copyright: {\textcopyright} The Author(s) 2020 ",
year = "2019",
month = mar,
doi = "10.1016/j.ebiom.2019.02.009",
language = "English",
volume = "41",
pages = "538--555",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}