Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


Colony Stimulating Factor 1 Receptor Inhibition Has Anti-Inflammatory and Potent Early Onset Bone and Cartilage Protective Effects.

Toh1,  Myew-Ling, Bonnefoy1,  Jean-Yves, Accart1,  Nathalie, Cochin1,  Sandrine, Zemmour1,  Christophe, Haegel1,  Helene, Ancian1,  Philippe

Transgene SA, Illkirch, France
Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
Erlangen, Germany
Freiburg, Germany

Background/Purpose:

The colony stimulating factor 1 (CSF-1)/CSF-1 receptor (CSF-1R) network plays a key role in macrophage and osteoclast differentiation which are current therapeutic targets in rheumatoid arthritis (RA). We determined CSF-1R expression in human RA synovium/bone, and the efficacy of CSF-1R antagonism using a humanized anti-CSF-1R monoclonal antibody (mAb) and an anti-murine CSF-1R MAb in arthritis models.

Methods:

CSF-1R immunostaining was performed with a murine anti-human CSF-1R MAb (murine CXIIG6) in RA, osteoarthritis (OA) and healthy human synovium/bone. The efficacy of a humanized anti-CSF-1R MAb (H27K15) or anti-murine CSF-1R MAb (clone AFS98) was examined in a human osteoclast differentiation assay from CD34+ bone marrow precursors (TRAP5b activity, CTX levels) in vitro or collagen-induced and serum transfer induced arthritis in vivo respectively.

Results:

CSF-1R expression was increased in RA synovium/bone compared to OA or healthy controls, in predominantly lining and sublining CD68+ macrophages, TRAP+ multinucleated mature osteoclasts and a small proportion of vimentin+ RA fibroblast-like synoviocytes and CD21+ follicular dendritic cells in germinal centre-like structures. CSF-1R expression was not detected in osteoblasts, T cells, B cells or immature or mature DC. In vitro, H27K15 significantly inhibited osteoclast differentiation and activity. In vivo, an anti-murine CSF-1R MAb reduced arthritis scores and synovial inflammation within 14 days of arthritis onset, associated with rapid inhibition in serum TRAP5b activity and complete abrogation of local bone and cartilage erosion in collagen-induced arthritis. Complete abrogation of serum TRAP5b activity and local bone erosion was confirmed in serum transfer-induced arthritis.

Conclusion:

CSF-1R expression was abundant in macrophages and mature osteoclasts in human RA synovium/bone, and a humanized anti-CSF-1R MAb markedly inhibited human osteoclast differentiation and activity. We demonstrate an anti-inflammatory as well as early onset potent bone and cartilage protection by a specific anti-CSF-1R MAb in murine arthritis models. This supports evidence for CSF-1R as a therapeutic target in arthritis, inflammatory bone loss and other diseases associated with osteoclastic bone damage.

To cite this abstract, please use the following information:
Toh, Myew-Ling, Bonnefoy, Jean-Yves, Accart, Nathalie, Cochin, Sandrine, Zemmour, Christophe, Haegel, Helene, et al; Colony Stimulating Factor 1 Receptor Inhibition Has Anti-Inflammatory and Potent Early Onset Bone and Cartilage Protective Effects. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1140
DOI:

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