Matthew Siebert, Spencer K. Wilhelm, Jeffrey Z Kartchner, David Mecham, Paul R. Reynolds and David L. Kooyman
Receptors for Advanced Glycation End Products (RAGE) and Toll Like Receptor 4 (TLR-4) have been shown to play a role in the development of Osteoarthritis (OA). We have previously shown that knocking out RAGE in mice slows the disease progression in articular cartilage of the knee. The objective of this study was to determine if application of the compound TAK-242, a TLR-4 specific inhibitor, in conjunction with knocking out RAGE could further attenuate the disease. Destabilization of the medial meniscus of RAGE KO and Wild Type (WT mice) was performed, and severity of OA was qualitatively analyzed through two standardized scoring systems (Mankin and OARSI). We also performed immunohistochemistry to analyze levels of HtrA1, Mmp-13 and Tgf-β1, known biomarkers for the disease. Surprisingly, addition of the TLR blocker did not offer additional protection against OA in mice when RAGE had been knocked out, and its application to WT mice exacerbated the severity of OA. We conclude that while blockage of the RAGE pathway alone is beneficial to the attenuation of OA, hampering the TLR-4 pathway offers no protective benefits.