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.
The objective of this study is to understand the pathogenesis of osteoarthritis (OA) in the temporomandibular joint (TMJ) by testing for the presence of established biomarkers present in OA of the knee.
Six wild‐type mice (M. musculus) and six mice heterozygous for the chondrodysplasia gene mutation (cho/+) were used in this study. The mice were euthanized at three months of age, and their TMJs were isolated, fixed, decalcified, embedded in paraffin, and sectioned at 6µ thickness. Fifteen sections of each mouse were stained with Safranin O and Fast Green to determine the extent of OA. Fifteen additional sections of each mouse were immunohistochemically stained for the presence of TGFß1 and HTRA1.
Using the Modified Mankin and OARSI scoring systems, it was determined that OA is present in the TMJ of cho/+ mice but not in the wild type. Also, staining for TGFß1 and HTRA1 was positive in cho/+ TMJs and absent in the wild type.
We have established that at three months of age, i.e., when early signs of OA histopathology are detectable, TGFß1 and HTRA1 are upregulated in the TMJ articular cartilage of cho/+ mice. We propose that TGFß1 is a biomarker for OA and can be used as an early diagnostic tool of TMJ OA. This finding is of clinical significance in light of the current practice to use TGFß1 as a therapeutic agent of TMJ OA. Despite the lack of type II collagen in TMJ articular cartilage relative to that of the knee joint, the presence of HTRA1 here suggests that the degenerative changes involve the same pathogenetic mechanism as in the knee joint.
Grant Funding Source: NIH grant 1‐R15‐AR056861‐01A1
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.