An aptamer specifically targeting mCRP ameliorates experimental arthritis.

BACKGROUND: Recent evidence highlights the important role of the liver-bone axis in the development of arthritis, particularly rheumatoid arthritis (RA) and osteoarthritis (OA). The liver secretes various factors that impact joint health, one of which is C-reactive protein (CRP), elevated in RA and OA patients. Traditionally regarded as an inflammatory marker, the causal role of CRP in arthritis development remains a topic of debate due to the existence of its two isoforms with opposing functions: native pentameric CRP (nCRP) and monomeric CRP (mCRP). METHODS: We generated hepatocyte-specific CRP knockout mice to investigate the causal role of CRP in RA and OA mouse models. In vitro experiments were conducted to assess the effects of mCRP and nCRP on phenotypic changes in effector cells common to RA and OA, including fibroblast-like synoviocytes (FLSs), monocytes/macrophages, and chondrocytes. Using systematic evolution of ligands by exponential enrichment (SELEX), we screened nucleic acid aptamers targeting mCRP rather than nCRP. We determined the neutralizing effects of the selected aptamers on mCRP in vitro and explored their therapeutic potential and safety in RA and OA mouse models. RESULTS: Hepatocyte-specific knockout of CRP significantly reduced disease severity in RA and OA mouse models. mCRP promoted in vitro pathological changes in FLSs, monocytes/macrophages, and chondrocytes, while nCRP exhibited minimal or slightly protective effects. We identified an aptamer, ApmCRP3, which effectively inhibited mCRP-induced pathological changes of RA and OA effector cells in vitro. In mouse models of RA and OA, ApmCRP3 displayed strong therapeutic effects and a favorable safety profile. CONCLUSION: This study identifies hepatocyte-derived mCRP as a contributor to RA and OA pathogenesis and highlights ApmCRP3 aptamer as a promising therapeutic candidate. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study highlights the therapeutic potential of ApmCRP3 in attenuating mCRP-driven pathology and controlling arthritis progression.