Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
S100A8 Enhances Osteoclastic Bone Resorption in Experimental Antigen-Induced Arthritis.
Grevers3, Lilyanne C., de Vries1, Teun J., Everts1, Vincent, Sloetjes3, Annet W., Vogl2, Thomas, Roth2, Johannes, van den Berg3, Wim B.
Department of Oral Cell Biology, ACTA, UVA and VU University Amsterdam, Amsterdam, The Netherlands
Institute of Experimental Dermatology, University of Münster, Muenster, Germany
Radboud University Nijmegen, Medical Centre, Nijmegen, The Netherlands
Rheumatoid Arthritis (RA) is characterized by bone destruction in the joints caused by enhanced formation and activity of osteoclasts. In RA, local inflammatory mediators produce many factors that stimulate osteoclastogenesis. The "alarmins" S100A8 and S100A9 are the most up-regulated proteins present in RA synovial fluid and significantly correlate with joint destruction. The aim of the present study was to investigate the role of S100A8 on osteoclastic bone resorption in murine antigen-induced arthritis (AIA).
Bone destruction was analyzed 7 and 21 days after AIA induction in knee joints of S100A9-/- mice, which also lack S100A8 expression, and wild type controls. Bone marrow precursors from S100A9-/- and wild type mice were differentiated into osteoclasts in-vitro. Additionally, osteoclast precursors were stimulated with recombinant S100A8 (rS100A8) during osteoclastogenesis. Receptor involvement was investigated using an anti-RAGE blocking antibody or TLR4-/- osteoclast precursors. In-vitro experiments were analyzed for the formation of TRACP-positive multinucleated cells (TRACP+ MNCs), actin ring formation by immunolocalization, mRNA expression levels of osteoclast markers, and resorption pit formation on bone.
Bone erosions were significantly suppressed in S100A9-/-mice 7 and 21 days after AIA induction. In-vitro, bone marrow-derived precursors from S100A9-/- mice developed normally into functional osteoclasts. Stimulation of osteoclast differentiation with rS100A8 resulted in increased numbers of predominantly smaller sized TRACP+ MNCs (35 nuclei per cell), as compared to unstimulated controls. mRNA expression of DC-STAMP, an important cell-cell fusion factor was moderately down-regulated (ddCt =-1.39), which might explain the smaller size of the osteoclasts. The expression of TRACP, cathepsin K and calcitonin receptor was not changed. Furthermore, actin ring formation, essential for the bone resorptive capacity of osteoclasts, was enhanced and bone resorption levels were significantly increased in S100A8 stimulated osteoclasts (50% versus 35% in unstimulated controls, P<0.03) The stimulatory effects of S100A8 on osteoclast maturation and function could not be inhibited by RAGE blockade, whereas the increased osteoclast numbers, actin ring formation and resorption pit formation were completely abrogated using TLR4-/- osteoclasts.
This study demonstrates that S100A8 stimulates osteoclast formation and activity and indicates that both S100A8 and TLR4 are important factors in mediating osteoclastic bone destruction in experimental arthritis.
To cite this abstract, please use the following information:
Grevers, Lilyanne C., de Vries, Teun J., Everts, Vincent, Sloetjes, Annet W., Vogl, Thomas, Roth, Johannes, et al; S100A8 Enhances Osteoclastic Bone Resorption in Experimental Antigen-Induced Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1495