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.

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It has been shown that HtrA1, Ddr‐2 and Mmp‐13 are reliable biomarkers for osteoarthritis (OA), yet the exact mechanism for the upregulation of HtrA‐1 is not known. Some have shown that chondrocyte hypertrophy is associated with early indicators of inflammation including TFG‐β and the Receptor for Advanced Glycation End products (RAGE). The objective of this research is to examine the effects of TFG‐β and RAGE on the progression of osteoarthritis. Samples of wild type (WT) and RAGE knockout (KO) were assayed for Mmp‐13, Ddr‐2, HtrA‐1 and TGF‐β, and evaluated for cartilage degradation four weeks after a knee destabilization procedure. We observed consistent positive staining for Mmp‐13, Ddr‐2, and HtrA‐1 in both WT and RAGE KO mice with late OA, while TGF‐β staining was only positive in samples with early OA. Despite similar IHC staining profiles, RAGE KO mice exhibited significantly less cartilage degradation as compared to WT mice. In subsequent analyses, RAGE KO mice exhibited more chondrocytes and a lower percentage of cells staining positive for OA biomarkers. From our results, we hypothesize that TGF‐β is involved in the upregulation of HtrA‐1 and is subsequently inhibited by HtrA‐1, and further that the chondroprotection in RAGE KO samples is due to a decreased presence of Mmp‐13 and HtrA‐1 and consequent protection against cell death. This research has been supported by FAMRI and BYU MEG grants.

HtrA1 and Mmp‐13 are reliable biomarkers of osteoarthritis (OA) and are upregulated at days post knee destabilization surgery (Polur et al., 2010). While expression of RAGE and its ligands are suggested, the exact mechanism for HtrA1 upregulation is not known (Cecil et al., 2005; Loeser et al., 2005). Our objective was to examine biomarkers of OA in the presence (control mice) and absence (RAGE knock‐out) of RAGE. We performed right knee destabilization and sham surgery on 8 week old control and RAGE knock‐out (KO) mice. We assayed for HtrA1, Mmp‐13, RAGE and S‐100 at 3, 7, 14 and 28 days post‐surgery by immunohistochemistry on both knee joints. We did not detect biomarkers of OA including Mmp‐13 in any sham surgery mice. In RAGE KO mice, we observed negligible staining of HtrA1 and faint staining of S‐100 at 28 days post‐surgery but not Mmp‐13. In contrast, we detected the presence of S‐100, HtrA1 and Mmp‐13 at focal points 3 days post‐surgery in control mice. By 28 days post‐surgery HtrA1 and Mmp‐13 expression is uniformly expressed in articular cartilage in control mice. RAGE KO does not entirely prevent HtrA1 upregulation but does protect against Mmp‐13 activation. Since the expression of Mmp‐13 is a terminal event resulting in OA, we conclude that RAGE KO protects against the most vital component of articular cartilage degradation and subsequently, OA.