Stimulation of chondrocyte-mediated cartilage destruction by S100A8 in experimental murine arthritis
Corresponding Author
P. L. E. M. van Lent
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Department of Rheumatology, Radboud University Nijmegen Medical Centre, Building 850, Geert Grooteplein 26-28, 6500 HB Nijmegen, The NetherlandsSearch for more papers by this authorL. C. Grevers
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorA. B. Blom
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorO. J. Arntz
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorF. A. J. van de Loo
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorP. van der Kraan
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorS. Abdollahi-Roodsaz
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorG. Srikrishna
Burnham Institute for Medical Research, La Jolla, California
Drs. Srikrishna and Freeze have patent applications pending for monoclonal antibody GB3.1. The patents are licensed, but no fees have been received.
Search for more papers by this authorH. Freeze
Burnham Institute for Medical Research, La Jolla, California
Drs. Srikrishna and Freeze have patent applications pending for monoclonal antibody GB3.1. The patents are licensed, but no fees have been received.
Search for more papers by this authorA. Sloetjes
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorW. B. van den Berg
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorCorresponding Author
P. L. E. M. van Lent
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Department of Rheumatology, Radboud University Nijmegen Medical Centre, Building 850, Geert Grooteplein 26-28, 6500 HB Nijmegen, The NetherlandsSearch for more papers by this authorL. C. Grevers
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorA. B. Blom
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorO. J. Arntz
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorF. A. J. van de Loo
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorP. van der Kraan
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorS. Abdollahi-Roodsaz
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorG. Srikrishna
Burnham Institute for Medical Research, La Jolla, California
Drs. Srikrishna and Freeze have patent applications pending for monoclonal antibody GB3.1. The patents are licensed, but no fees have been received.
Search for more papers by this authorH. Freeze
Burnham Institute for Medical Research, La Jolla, California
Drs. Srikrishna and Freeze have patent applications pending for monoclonal antibody GB3.1. The patents are licensed, but no fees have been received.
Search for more papers by this authorA. Sloetjes
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorW. B. van den Berg
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorAbstract
Objective
To investigate whether S100A8 is actively involved in matrix metalloproteinase (MMP)–mediated chondrocyte activation.
Methods
S100A8 and S100A9 proteins were detected in inflamed knee joints from mice with various forms of murine arthritis, using immunolocalization. Murine chondrocyte cell line H4 was stimulated with proinflammatory cytokines or recombinant S100A8. Messenger RNA (mRNA) and protein levels were measured using reverse transcriptase–polymerase chain reaction and intracellular fluorescence-activated cell sorting (FACS). Breakdown of aggrecan on the pericellular surface of the chondrocytes was measured using VDIPEN and NITEGE antibodies and FACS, and breakdown in patellar cartilage was measured by immunolocalization.
Results
S100A8 and S100A9 proteins were abundantly expressed in and around chondrocytes in inflamed knee joints after induction of antigen-induced arthritis or onset of spontaneous arthritis in interleukin-1 (IL-1) receptor antagonist–knockout mice. Stimulation of chondrocytes by the proinflammatory cytokines tumor necrosis factor α, IL-1β, IL-17, and interferon-γ caused strong up-regulation of S100A8 mRNA and protein levels and up-regulation to a lesser extent of S100A9 levels. Stimulation of chondrocytes with S100A8 induced significant up-regulation of MMP-2, MMP-3, MMP-9, MMP-13, ADAMTS-4, and ADAMTS-5 mRNA levels (up-regulated 4, 4, 3, 16, 8, and 4 times, respectively). VDIPEN and NITEGE neoepitopes were significantly elevated in a concentration-dependent manner in chondrocytes treated with 0.2, 1, or 5 μg/ml of S100A8. (VDIPEN levels were elevated 17%, 67%, and 108%, respectively, and NITEGE levels were elevated 8%, 33%, and 67%, respectively.) S100A8 significantly increased the effect of IL-1β on MMP-3, MMP-13, and ADAMTS-5. Mouse patellae incubated with both IL-1β and S100A8 had elevated levels of NITEGE within the cartilage matrix when compared with patellae incubated with IL-1β or S100A8 alone.
Conclusion
These findings indicate that S100A8 and S100A9 are found in and around chondrocytes in experimental arthritis. S100A8 up-regulates and activates MMPs and aggrecanase-mediated pericellular matrix degradation.
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