Retinoic Acid Receptor Gamma (RAR) Promotes Cartilage Destruction through Positive Feedback Activation of NF-B Pathway in Human Osteoarthritis.

Osteoarthritis (OA) is a severe inflammation-related disease which leads to cartilage destruction. The retinoic acid receptor gamma (RAR) has been indicated to be involved in many inflammation processes. However, the role and mechanism of RAR in cartilage destruction caused by inflammation in OA are still unknown. Here, we demonstrated that the RAR was highly expressed in chondrocytes of OA patients compared with healthy people and was positively correlated with the damage degree of cartilage in OA. Cytokine TNF- promoted the transcription and expression of RAR through activating the NF-B pathway in OA cartilage. In addition, the overexpression of RAR resulted in the upregulation of matrix degradation and inflammation associated genes and downregulation of differentiation and collagen production genes in human normal chondrocyte C28/I2 cells. Mechanistically, overexpression of RAR could increase the level of p-IB and p-P65 to regulate the expression of downstream genes. RAR and IB also could interact with each other and had the same localization in C28/I2 cells. Moreover, the SD rats OA model induced by monosodium iodoacetate indicated that CD437 (RAR agonist) and TNF- accelerated the OA progression, including more severe cartilage layer destruction, larger knee joint diameter, and higher serum ALP levels, while LY2955303 (RAR inhibitor) showed the opposite result. RAR was also highly expressed in OA group and even higher in TNF- group. In conclusion, RAR/NF-B positive feedback loop was activated by TNF- in chondrocyte to promote cartilage destruction. Our data not only propose a novel and precise molecular mechanism for OA disease but also provide a prospective strategy for the treatment.