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Osteoblastic PLEKHO1 contributes to joint inflammation in rheumatoid arthritis

By Xiaojuan He, Kubilius Jonas, Chao Liang, Shaikh Atik Badshah, Kang Zheng, Lei Dang, Baosheng Guo, Defang Li, Cheng Lu, Qingqing Guo, Danping Fan, Yanqin Bian, Hui Feng, Lianbo Xiao, Xiaohua Pan, Cheng Xiao, BaoTing Zhang, Ge Zhang, Aiping Lu

Posted 30 Jul 2018
bioRxiv DOI: 10.1101/380303 (published DOI: 10.1016/j.ebiom.2019.02.009)

Osteoblasts participating in the inflammation regulation gradually obtain concerns. However, its role in joint inflammation of rheumatoid arthritis (RA) is largely unknown. Pleckstrin homology domain-containing family O member 1 (PLEKHO1) was previously identified as a negative regulator of osteogenic lineage activity. Here we demonstrated that PLEKHO1 was highly expressed in osteoblasts of articular specimens from RA patients and inflammatory arthritis mice. Genetic deletion of osteoblastic Plekho1 ameliorated joint inflammation in mice with collagen-induced arthritis (CIA) and K/BxN serum-transfer arthritis (STA), whereas overexpressing Plekho1 only within osteoblasts in CIA and STA mice demonstrated exacerbated local inflammation. Further in vitro studies indicated that PLEKHO1 was required for TRAF2-mediated RIP1 ubiquitination to activate NF-kB for inducing inflammatory cytokines production in osteoblasts. Moreover, osteoblastic PLEKHO1 inhibition improved joint inflammation and attenuated bone formation reduction in CIA mice and non-human primate arthritis model. These data strongly suggest that highly expressed PLEKHO1 in osteoblast mediates joint inflammation in RA. Targeting osteoblastic PLEKHO1 may exert dual therapeutic action of alleviating joint inflammation and promoting bone formation in RA.

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