Antibodies to Citrullinated Proteins (ACPA) Associate with Markers of Osteoclast Activation and Bone Destruction in the Bone Marrow of Patients with Rheumatoid Arthritis

Abstract

Normalizing bone metabolism is a challenge in rheumatoid arthritis (RA). Studies in mice suggest that anti-citrullinated protein antibodies (ACPAs) can trigger osteoclast activation and bone resorption in the bone marrow. However, data on the presence and role of ACPAs in human bone marrow are scarce. We investigated whether ACPAs can contribute to osteoclast activation and bone erosion in RA bone marrow. Anti-cyclic citrullinated peptide antibodies (anti-CCP Abs), osteoclast activation indicators–the tartrate-resistant acid phosphatase 5b (TRAP5b) and cathepsin K, and bone degradation marker–C-terminal telopeptide of type I collagen (CTX-I) were measured in the bone marrow and peripheral blood of RA patients using ELISAs. We found that ACPAs present in RA bone marrow was associated with increased amounts of TRAP5b, cathepsin K and CTX-I in this location. Levels of IL-8, the key mediator of anti-citrullinated protein antibody (ACPA)-induced bone resorption, were also elevated in bone marrow containing anti-CCP Abs and positively correlated with TRAP5b and cathepsin K concentrations. Higher levels of TRAP5b, cathepsin K, CTX-I and IL-8 in bone marrow compared to peripheral blood indicate local generation of these molecules. Our results complement data from animal studies and highlight the relevance of ACPAs and bone marrow in bone resorption in RA.

Anti-citrullinated Protein Antibody Generation, Pathogenesis, Clinical Application, and Prospects

“…Resting-state macrophages are usually located in synovial tissue. They are powerful immune effectors that can significantly promote the inflammatory response and joint destruction when stimulated ( 43 , 44 ). Furthermore, they can selectively activate the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways through direct interaction between the Fab variable region of ACPAs and citrullinated glucose regulatory protein 78, leading to the activation of NF-κB and promotion of TNF-α production ( 45 , 46 ).…”

Effects of Biological/Targeted Therapies on Bone Mineral Density in Inflammatory Arthritis

“…ACPAs are mainly produced by plasmablasts and plasma cells [17,18]. Recent animal studies have suggested that ACPAs may stimulate osteoclast differentiation and initiate bone change [19]. ACPAs enhance osteoclast differentiation from monocyte-derived or circulating CD1c+ dendritic cells (DCs) by increasing the release of IL-8 [20].…”

ACCP-negative rheumatoid arthritis – clinical and immunological features

“…По данным рентгенографии у АЦЦП-позитивных пациентов с РА отмечается более выраженный эрозивный процесс [110-113, 117, 118, 122, 129-133] даже при сопоставимой активности заболевания [134]. Известно, что АЦЦП ассоциированы с активацией остеокластов в костном мозге больных РА и индукцией костной резорбции [135]. Для АЦЦП-негативных больных РА темп дальнейшего рентгенологического прогрессирования коррелировал с количеством эрозий и суммарным Научно-практическая ревматология.…”