Inflammatory markers associated with osteoarthritis after destabilization surgery in young mice with and without Receptor for Advanced Glycation End-products (RAGE)

Abstract

HtrA1, Ddr-2, and Mmp-13 are reliable biomarkers for osteoarthritis (OA), yet the exact mechanism for the upregulation of HtrA-1 is unknown. Some have shown that chondrocyte hypertrophy is associated with early indicators of inflammation including TGF-β and the Receptor for Advanced Glycation End-products (RAGE). To examine the correlation of inflammation with the expression of biomarkers in OA, we performed right knee destabilization surgery on 4-week-old-wild type and RAGE knock-out (KO) mice. We assayed for HtrA-1, TGF-β1, Mmp-13, and Ddr-2 in articular cartilage at 3, 7, 14, and 28 days post-surgery by immunohistochemistry on left and right knee joints. RAGE KO and wild type mice both showed staining for key OA biomarkers. However, RAGE KO mice were significantly protected against OA compared to controls. We observed a difference in the total number of chondrocytes and percentage of chondrocytes staining positive for OA biomarkers between RAGE KO and control mice. The percentage of cells staining for OA biomarkers correlated with severity of cartilage degradation. Our results indicate that the absence of RAGE did protect against the development of advanced OA. We conclude that HtrA-1 plays a role in lowering TGF-β1 expression in the process of making articular cartilage vulnerable to damage associated with OA progression.

Effect of Pharmacological Blocking of TLR-4 on Osteoarthritis in Mice

“…Additionally, RAGE KO mice experienced a dose-dependent increase in both TGF-B1 and HtrA1 upon TAK-242 treatment, a finding which is contrary to our previous results which showed a reciprocal relationship between these two biomarkers [3]. These data could indicate that a shared downstream product of the RAGE and TLR-4 is responsible for HtrA1 induced inhibition of Tgf-B1.…”

“…Our previous studies have demonstrated that even when RAGE is knocked out, TGF-B levels are not significantly different from wild type (WT) mice [3]. This observation suggests an alternate transduction mechanism that results in production of Tgf-B.…”

“…Indeed, we have previously shown that early expression of Tgf-B1 in OA leads to an initial surge of chondrocyte proliferation. This response is, however, overwhelmed by expression of catabolic proteins such as HtrA1 which are induced by elevated levels of Tgf-B1 [3,10]. The Receptor for Advanced Glycation End-products (RAGE) is a cellsurface receptor expressed in a wide array of cell types.…”

“…We and others have previously demonstrated the importance of Tgf-B1, HtrA1 and Mmp-13 in the progression of OA [3][4][5][6]. As part of the inflammatory pathway driving OA progression, matrix degrading proteases HtrA1 and Mmp-13 are secreted by chondrocytes into the pericellular and extracellular matrix, resulting in reduced matrix integrity and function.…”

Identification of the Tidemark Line of Calcification in Osteoarthritic Cartilage Using a Stain for Alkaline Phosphatase

“…It has also been shown that inflammation can be related to the onset of OA [24][25][26]. Inflammation is associated with the upregulation of HtrA1 which degrades aggrecan and other proteoglycans in the pericellular matrix (PCM) [27].…”