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.
Alarmins S100A8 and A9 Are Expressed in Synovium of Early OA Patients and Regulate Synovial Activation and Joint Destruction during Experimental Osteoarthritis.
van Lent1, Peter, Blom1, Arjen, Schelbergen1, Rik, Sloetjes1, Annet, Vogl2, Thomas, Roth2, Johannes, van den Berg1, Wim
Prominent proteins released by activated macrophages are the "alarmins" S100 A8 and A9. There is increasing belief that synovial tissue activation contributes to OA cartilage pathology The aim is to evaluate the presence of S100A8/S100A9 in synovia of patients with early OA and to explore active involvement of S100A8/A9 in cartilage destruction in experimental osteoarthritis models that differ in degree of synovial activation.
Arthroscopic biopsies were taken from 30 early OA patients. mRNA levels (RT-PCR) and immunolocalisation was determined and related to joint destruction (Kellgren Lawrence score). 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 overall ligament damage and broad instability. Collagenase-induced-osteoarthritis involves chronic synovial activation in contrast to DMM. Synovial expression of S100A8 and S100A9 was measured using immunolocalisation. Both models were induced in S100A9-/- deficient mice (myeloid cells also lack S100A8 at the protein level). Primary chondrocytes were stimulated with S100A8 and A9 and MMP levels were measured using RT-PCR
mRNA and protein levels of S100A8 and A9 were significantly higher in synovial biopsies of early OA patients when compared to control joints. S100A8 and A9 was predominantly found in synovial macrophages. Of great interest, high levels correlated to increased joint destruction (KL score). The function of S100A8 and S100A9 was further studied in experimental OA models. Kinetic studies show that in 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. The degree of OA cartilage pathology in the knee joint was similar 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 days 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 significantly lower in all surfaces and ranged from a 45% reduction in the lateral tibia to 73% reduction in the medial femur. When primary mouse chondrocytes were stimulated with S100A8 or S100A9, a strong upregulation of particularly MMP-3 mRNA level was found indicating a direct role of S100A8/A9 in cartilage destruction.
Alarmins S100A8/S100A9 are expressed by macrophages in biopsies of early OA patients. 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, Schelbergen, Rik, Sloetjes, Annet, Vogl, Thomas, Roth, Johannes, et al; Alarmins S100A8 and A9 Are Expressed in Synovium of Early OA Patients and Regulate Synovial Activation and Joint Destruction during Experimental Osteoarthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :845