PT  - JOURNAL ARTICLE
AU  - Xiaojuan He
AU  - Jin Liu
AU  - Chao Liang
AU  - Shaikh Atik Badshah
AU  - Kang Zheng
AU  - Lei Dang
AU  - Baosheng Guo
AU  - Defang Li
AU  - Cheng Lu
AU  - Qingqing Guo
AU  - Danping Fan
AU  - Yanqin Bian
AU  - Hui Feng
AU  - Lianbo Xiao
AU  - Xiaohua Pan
AU  - Cheng Xiao
AU  - BaoTing Zhang
AU  - Ge Zhang
AU  - Aiping Lu
TI  - Osteoblastic PLEKHO1 contributes to joint inflammation in rheumatoid arthritis
AID  - 10.1101/380303
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 380303
4099  - http://biorxiv.org/content/early/2018/07/30/380303.short
4100  - http://biorxiv.org/content/early/2018/07/30/380303.full
AB  - 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.