Osteoblastic PLEKHO1 contributes to joint inflammation in rheumatoid arthritis

Xiaojuan He, Jin LIU, 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, Bao Ting Zhang, Ge ZHANG*, Aiping LYU

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)538-555
Number of pages18
JournalEBioMedicine
Volume41
DOIs
Publication statusPublished - Mar 2019

Scopus Subject Areas

  • Biochemistry, Genetics and Molecular Biology(all)

User-Defined Keywords

  • Bone formation
  • Inflammation
  • Osteoblast
  • PLEKHO1
  • Rheumatoid arthritis

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