An aptamer specifically targeting mCRP ameliorates experimental arthritis

Area of Science:

• Hepatology
• Immunology
• Rheumatology

Background:

• The liver-bone axis influences arthritis development, with C-reactive protein (CRP) elevated in rheumatoid arthritis (RA) and osteoarthritis (OA).
• CRP exists in two isoforms, native pentameric CRP (nCRP) and monomeric CRP (mCRP), with opposing functions, making its causal role in arthritis debated.
• Understanding CRP's isoforms is crucial for elucidating its role in arthritis pathogenesis.

Purpose of the Study:

• To investigate the causal role of hepatocyte-derived CRP in RA and OA using mouse models.
• To differentiate the effects of nCRP and mCRP on joint effector cells.
• To develop and evaluate aptamers targeting mCRP for potential arthritis therapy.

Main Methods:

• Generated hepatocyte-specific CRP knockout mice for RA and OA models.
• Performed in vitro studies on fibroblast-like synoviocytes, monocytes/macrophages, and chondrocytes exposed to mCRP and nCRP.
• Utilized SELEX to screen for aptamers against mCRP and tested their efficacy in vitro and in vivo.

Main Results:

• Hepatocyte-specific CRP knockout significantly reduced RA and OA severity in mice.
• mCRP promoted in vitro pathological changes in effector cells, while nCRP had minimal or protective effects.
• The aptamer ApmCRP3 effectively inhibited mCRP-induced pathology and demonstrated therapeutic effects and safety in arthritis models.

Conclusions:

• Hepatocyte-derived mCRP contributes to RA and OA pathogenesis.
• ApmCRP3 aptamer shows promise as a therapeutic agent for arthritis by targeting mCRP.
• This study validates mCRP as a therapeutic target for inflammatory joint diseases.