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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Polyethylene (PE) remains the gold standard for the articulating surface in hip and knee arthroplasty. To increase arthroplasty longevity and improve wear resistance, newer versions of PE have been designed with resultantly different wear properties. Highly cross-linked polyethylene (HXLPE) is used in total hip arthroplasty with excellent outcomes; however, its use in total knee arthroplasty (TKA) remains conflicting. This review summarizes biomechanical and wear properties, clinical outcomes, and cost of polyethylene inserts in TKA. Simulation studies have convincingly shown decreased wear and oxidation rates with HXLPE when compared to conventional polyethylene (CPE). Registry results have been conflicting, and short-to midterm clinical studies have not demonstrated a significant difference between HXLPE and CPE. The cost of HXLPE inserts is higher than CPE. Long-term clinical data are lacking and further studies are warranted to evaluate the role of HXLPE in TKA.

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.

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

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.

ObjectiveIt has been previously shown that chondrocyte apoptosis is associated with the progression of osteoarthritis. The objective of this project was to examine the effects of S100, RAGE, Tgf‐β1, HtrA1 and NF κβ on apoptosis in the progression of osteoarthritis (OA).MethodsSamples of wild type (WT) and RAGE knockout (KO) were assayed for HtrA1, S100, RAGE, TGF‐β1, NF‐kB, TUNEL and evaluated for cartilage degradation four weeks after a knee destabilization procedure.ResultsWe observed positive staining for all biomarkers except TGF‐β1examined in both WT and RAGE KO mice with high Mankin score OA. All biomarkers assayed were present, except HtrA1, in samples with low Mankin score OA. We also observed varying degrees of TUNEL assay staining in both WT and RAGE KO mice. Remarkably, despite similar IHC staining profiles, RAGE KO mice exhibited significantly less cartilage degradation and chondrocyte apoptosis, assayed by TUNEL, compared to WT mice.ConclusionWe conclude that RAGE mediated upregulation of TGF β1 leads to an upregulation of HtrA1 and apoptosis associated with osteoarthritis. This suggests that an inhibition of inflammatory processes involving RAGE may attenuate chondrocyte apoptosis, and slow the progression of OA.