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  • Bone- and cartilage-protective effects of a monoclonal antibody against colony-stimulating factor 1 receptor in experimental arthritis.

Bone- and cartilage-protective effects of a monoclonal antibody against colony-stimulating factor 1 receptor in experimental arthritis.

Arthritis & rheumatology (Hoboken, N.J.) (2014-03-14)
Myew-Ling Toh, Jean-Yves Bonnefoy, Nathalie Accart, Sandrine Cochin, Sandy Pohle, Hélène Haegel, Micael De Meyer, Christophe Zemmour, Xavier Preville, Christine Guillen, Christine Thioudellet, Philippe Ancian, Anja Lux, Bettina Sehnert, Falk Nimmerjahn, Reinhard E Voll, Georg Schett
ABSTRACT

Colony-stimulating factor 1 receptor (CSF-1R) essentially modulates monocyte proliferation, migration, and activation, which are considered important for the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine CSF-1R expression in human RA as well as the efficacy of a specific anti-CSF-1R monoclonal antibody (AFS98) in 2 different animal models of RA. CSF-1R expression was examined in blood, synovium, and bone samples from RA patients, osteoarthritis (OA) patients, and healthy subjects. The efficacy of AFS98 was examined by clinical assessment, histology, and bone histomorphometry in collagen-induced arthritis (CIA) and serum-transfer arthritis. CSF-1R expression was increased in the synovium of RA patients compared to OA patients and healthy controls in fibroblast-like synoviocytes, follicular dendritic cells, macrophages, and osteoclasts. Circulating RA monocytes and neutrophils but not lymphocytes were CSF-1R+. In mice, blockade of CSF-1R abrogated cartilage damage, bone erosion, and systemic bone loss, and this was associated with the depletion of osteoclasts in both models. While blockade of CSF-1R did not affect inflammation in passive serum-transfer arthritis, it significantly reduced inflammation in CIA, and this was associated with the absence of synovial macrophages and reduced splenic CD11b+Gr-1- monocytes. CSF-1R was broadly expressed in human RA. Blockade of CSF-1R protected against bone and cartilage destruction in both mouse models and also showed significant antiinflammatory effects in the CIA model. These data provide evidence for CSF-1R as a therapeutic target in RA.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cyclosporin A, from Tolypocladium inflatum, ≥95% (HPLC), solid
Sigma-Aldrich
Cyclosporin A, 97.0-101.5% (on dried basis)
Supelco
Cyclosporin A, VETRANAL®, analytical standard
Sigma-Aldrich
Cyclosporin A, BioReagent, from Tolypocladium inflatum, for molecular biology, ≥95%
Sigma-Aldrich
Hematoxylin
Sigma-Aldrich
Hematoxylin, certified by the Biological Stain Commission
Supelco
Cyclosporine, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
DAPI, for nucleic acid staining
Sigma-Aldrich
Toluidine Blue, 8.74% (ZN (THEORY)), for microscopy (Hist., Vit.)