Phosphocitrate reduced cartilage degeneration in non-calcification induced osteoarthritis

s / Osteoarthritis and Cartilage 23 (2015) A82eA416 A396 Figure 2. Mean histological scores of the tibia plateaus. Left bar group: Mean histological scores of the medial tibia plateaus of the rights knees in the untreated and PC-treated guinea pigs. Right bar group: Mean histological scores of the lateral tibia plateaus of the right knees in the untreated and PC-treated guinea pigs. * 1⁄4 P 1.5-fold by IL1b compared to baseline. IL-1b treatment in the presence of either JQ1 or Flavopiridol alone prevented the induction of many genes. However, a combination of both drugs prevented the induction of most IL-1b response genes. (Fig.1) IL1b treatment of cartilage explants induced significant release of GAG within 3-6 days. GAG release was effectively prevented when IL-1b treatment in the presence of either or both drugs. (Fig2) In PTOAmouse model, knee injury caused significant increases of IL1b and IL6 expression in the injured joint. All 3 treatments showed effect to prevent increases of these cytokines and drug combination was more effective than single drugs. (Fig3A, B) MMP activity in injured knee was suppressed by all 3 treatment similarly at 24h and 48h after injury. (Fig3C, D) Conclusions: JQ1 and Flavopiridol are each able to effectively repress a panel of pro-inflammatory and catabolic genes in chondrocytes induced by inflammatory stimulus. We found that the combination of the 2 drugs showed a synergistic interaction, with similar or better repression achieved at reduced drug doses. Although previous reports indicated that Brd4 and CDK9 control mRNA transcription by regulating a common checkpoint, microarray analysis showed that there were also inflammatory genes only affected by each drug individually. Ex vivo and in vivo study also demonstrated the combination of lower dose of the drugs has similar or better intensity of effect. This indicates that using both drugs together may be able to suppress inflammation after trauma with preventing side effects induced by overdose, leading to novel treatment for PTOA.