Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Active Involvement of AlarminsS100A8 and S100A9 in Synovial Activation and Joint Destruction During Osteoarthritis
van Lent1, Peter, Blom1, Arjen, Roth2, Johannes, van den Berg1, Wim B.
Prominent proteins released by activated macrophages are the "alarmins" S100 A8 and A9. Both proteins accumulate in inflammatory synovial fluids and have been postulated to be involved in the pathogenesis of RA. S100A8 is assumed to be the active component whereas S100A9 functions as the regulatory subunit preventing S100A8 from degradation. The aim is to study the active involvement of S100A8/A9 in synovial activation and cartilage destruction in osteoarthritis.
Experimental OA was either induced by transection of the medial anterior meniscotibial ligament which leads to destabilisation of the medial meniscus (DMM) or by injection of collagenase into murine knee joints, which causes local instability. OA phenotypes were studied within 8 weeks after induction. Collagenase-induced-osteoarthritis involves chronic synovial activation in contrast to DMM. Synovial expression of S100A8 and S100A9 during the course of osteoarthritis was measured using immunolocalisation. Both models were induced in S100A9-/- deficient mice (myeloid cells also lack S100A8 at the protein level). Synovial activation and cartilage destruction was measured by histology. MMP-mediated cartilage destruction was measured with immunolocalisation using anti-VDIPEN antibodies.
Kinetic studies show that in the surgically induced DMM model, S100A8 and A9 was marginally expressed within the synovium, only evident at day 7 after induction and consistent with limited synovial thickening. In addition, cartilage destruction was measured in various cartilage surfaces (medial and lateral tibia and femur) of the knee joint. No differences in cartilage destruction were observed in S100A9-/- and WT mice at day 42 after induction of DMM.
In contrast, during the course of collagenase-induced osteoarthritis, S100A8 and S100A9 was strongly upregulated in synovium at day 7 and remained high at day 14,28 and 42. Expression of these proteins nicely correlated with thickening of the synovial lining layer comprising activated macrophages. When collagenase-induced-osteoarthritis was elicited in S100A9-/- mice, significantly lower synovial activation was observed when compared to WT mice. Synovial activation was 62% lower at day 42. Cartilage destruction was strongly and significantly lower in all surfaces and ranged from a 45% reduction in the lateral tibia to 73% reduction in the medial femur. In line with this, MMP-mediated cartilage destruction (VDIPEN) was clearly present in cartilage of osteoarthritic controls but markedly decreased in medial cartilage layers of day 42 osteoarthritic S100A9-/- mice, suggesting that S100A8/A9 are involved in activating MMPs.
Alarmins S100A8/A9 play a crucial role in synovial activation and cartilage destruction in an osteoarthritis model that shows clear synovial involvement. S100A8/A9 expression in the synovium causes pathology probably by stimulating MMP-mediated damage in the cartilage matrix.
To cite this abstract, please use the following information:
van Lent, Peter, Blom, Arjen, Roth, Johannes, van den Berg, Wim B.; Active Involvement of AlarminsS100A8 and S100A9 in Synovial Activation and Joint Destruction During Osteoarthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :146