The long non-coding RNA HOTAIR contributes to joint-specific gene expression in rheumatoid arthritis

Area of Science:

• Molecular Biology
• Rheumatology
• Epigenetics

Background:

• Rheumatoid arthritis (RA) commonly presents with symmetrical joint involvement.
• However, varying disease patterns suggest joint-specific molecular mechanisms in RA progression.
• Synovial fibroblasts (SF) play a crucial role in joint inflammation.

Purpose of the Study:

• To identify joint-specific molecular differences in RA synovium and SF between knee and hand joints.
• To investigate the role of the long non-coding RNA HOTAIR in site-specific gene regulation in RA.

Main Methods:

• Analysis of RA synovium and SF from knee and hand joints.
• Quantification of HOTAIR expression in SF.
• Gene expression analysis in SF following HOTAIR knockdown.
• Assessment of signaling pathways (PI-Akt, IL-6, Wnt) and cellular functions (migration, osteoclastogenesis, B cell recruitment).

Main Results:

• The long non-coding RNA HOTAIR is exclusively expressed in knee SF and regulates over 50% of site-specific gene expression.
• HOTAIR expression is downregulated by pro-inflammatory cytokines and is lower in RA knee joints compared to osteoarthritis.
• HOTAIR knockdown in knee SF alters PI-Akt, IL-6, and Wnt signaling, inhibits SF migration and osteoclastogenesis, and increases B cell recruitment.

Conclusions:

• HOTAIR is a key epigenetic regulator of joint-specific gene expression in rheumatoid arthritis.
• HOTAIR influences critical cellular processes involved in RA pathogenesis, including inflammation, bone erosion, and immune cell recruitment.