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.