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 and TGF‐β1, known biomarkers for the disease. Surprisingly, addition of the TLR blocker disrupted the protection afforded by knocking out RAGE, and its application to WT mice had no protective effect. 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. We hypothesize that blocking TLR‐4 receptor mitigates the beneficial effects of knocking out RAGE on OA.
We have previously shown that knockout (KO) mice lacking the Receptor for Advanced Glycation End Products (RAGE) demonstrate attenuated osteoarthritis (OA) in articular cartilage of the knee. The objective of this research is to discover if knocking out RAGE has a similar protective effect in the condylar cartilage of the Temporomandibular joint (TMJ). Misalignment of the TMJ of Wild‐type (WT) and RAGE KO mice was performed, and severity of OA was assessed along with immunohistochemical staining of several known biomarkers of OA. An inverse relationship is known to exist between the expression of Htra1 and TGF‐B 1 in association with OA. We observed a reciprocal expression of these two proteins in WT but not RAGE KO mice. Condylar cartilage, unlike articular cartilage, has been shown to self‐repair when stress is applied. We hypothesize that the WT mice expressed higher levels of TGF‐B 1 as a result of natural repair processes. In contrast, RAGE KO mice lacked this pattern, suggesting that this receptor may play a role in the natural repair of condylar cartilage of the TMJ.
Prior research has indicated that a pathway exists in the molecular progression of Osteoarthritis (OA) involving key biomarkers HtrA1, Ddr‐2 and Mmp‐13. We and others have recently shown, by immunohisotchemical staining, that HtrA1 and TGF‐β1 show a unique, inverse relationship in OA. The objective of this research is to provide supporting data and clarification to this interaction via Enzyme‐Linked Immunosorbent Assay (ELISA) and quantitative Polymerase Chain Reaction (qPCR) analysis. Cartilage samples from the hip and synovial fluid samples form the knee of wild type (WT) mice, treated to induce OA, were assayed for quantitative presence of TGF‐β1 biomarker using ELISA and quantitative mRNA presence using qRTPCR. We observed initially high levels of TGF‐β1 protein that subsequently decreased 50% as OA progressed and became more severe over time. We hypothesize that TGF‐β1, as a cytokine growth factor, is over expressed in early OA resulting in an increased expression of HtrA1, a serine protease, which subsequently impairs TGF‐β1 cell maintenance activity and dooms the cell to apoptosis.
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