The acute phase reactant orosomucoid-2 directly promotes rheumatoid inflammation

Area of Science:

• Immunology
• Proteomics
• Rheumatology

Background:

• Systematic analysis of acute phase proteins in chronic inflammatory diseases is lacking.
• Orosomucoid-2 (ORM2) was identified as a highly differentially expressed protein in rheumatoid arthritis (RA) patients through global proteome profiling.

Purpose of the Study:

• To investigate the role of ORM2 in rheumatoid arthritis pathogenesis.
• To determine if ORM2 actively participates in rheumatoid inflammation.

Main Methods:

• Global proteome profiling of serum and urine from RA patients.
• Analysis of ORM2 expression in synovial fluids and membranes.
• In vitro studies using recombinant ORM2 on RA macrophages and fibroblast-like synoviocytes (FLSs).
• In vivo studies involving intra-articular injection of ORM2 in mice.

Main Results:

• ORM2 expression was significantly upregulated in RA synovial fluids and membranes, primarily produced by synovial macrophages and FLSs.
• Recombinant ORM2 stimulated the production of key inflammatory cytokines (IL-6, TNF-α, CXCL8, CCL2) via NF-κB and p38 MAPK pathways.
• Glycophorin C was identified as the receptor for ORM2.
• Intra-articular ORM2 injection exacerbated arthritis severity and macrophage infiltration in mice.
• Circulating ORM2 levels correlated with RA disease activity and radiographic progression.

Conclusions:

• The acute phase protein ORM2 directly promotes inflammation and exacerbates arthritis.
• ORM2 plays an active role in rheumatoid inflammation.
• ORM2 represents a potential novel therapeutic target for rheumatoid arthritis.