RNA Sequencing Evidences the Prevention of Oxidative Stress is Effective in Injury-Induced Heterotopic Ossification Treatment

Heterotopic ossification is a bona fide bone formation outside the normal skeleton. Traumatic injury and genetic mutations are the important risk factors of HO. Both injury-induced HO and hereditary HO severely affect human life quality. However, there were no effect therapies treating HO. Here, we performed the RNA-sequencing assay to examine dynamic process during HO initiation and development. Moreover, we found that oxidation-reduction process were significantly dysregulated following HO formation. Further, we characterized that Nuclear factor erythroid 2-related factor 2 (NRF2) expression conferred antioxidant property in macrophages and then helped chondrocytes formation. Instead, 3-Nitrotyrosine is expressed by T-lymphocytes, but not macrophages, causing deficient adaptive immunity. Inhibition of NRF2 markedly alleviated HO. Finally, we identified that PI3K/AKT signaling pathway is responsible for whole HO process, but ERK signaling is activated only in early stage. ERK pathway blockade effectively prevented HO. These findings revealed that oxidative stress induced by early immune response can be targeted in HO treatment.