Pentosan polysulfate treatment counteracts the dysregulation of the cartilage matrix components caused by RRV infection. PPS treatment significantly reduced the early expression of aggrecan and collagen II and the expression of ADAMTS-5 and TIMP-3 at peak disease. Twenty-day-old C57BL/6 mice were infected s.c. with 104 PFU RRV or mock infected with diluent alone and then either treated daily i.p. with PPS at 3 mg/kg in 100 μl PBS or mock treated with PBS alone (Mock, mock infected mock treated; PPS, mock infected PPS treated; RRV, RRV infected mock treated; RRV+PPS, RRV infected PPS treated). At days 1, 3, and 10 p.i., joint tissues were removed, RNA extracted, and real-time PCR performed to evaluate gene regulation of key mediators of the proteoglycan matrix of joint cartilage. The results were normalized to the level of the housekeeping gene HPRT1 and are expressed as fold changes compared to the levels in the mock control samples. Each bar represents the mean ± standard error for 5 to 6 mice and is representative of two independent experiments. *, P < 0.05; **, P < 0.01; ***, P < 0.001; two-way ANOVA with Bonferroni posttest.