NRF2 is a critical regulator and therapeutic target of metal implant particle-incurred bone damage.

Aseptic metal implant loosening due to wear particle-induced bone damage is a major complication of total joint arthroplasty often leading to revision surgery, of which the key regulators mediating the processes are not clearly defined. Here we reported that in a mouse model of calvarial osteolysis, titanium particles (TiPs) and cobalt-chromium-molybdenum particles induced severe osteolysis accompanied by marked suppression of a master redox transcriptional factor NRF2 (Nuclear factor erythroid derived 2-related factor 2). Nfe2l2 knockout mice treated with TiPs developed worse osteolytic alterations compared with wild-type mice. On the contrary, NRF2 restoration by an NRF2 agonist TBHQ (tert-butylhydroquinone) effectively alleviated the osteolysis and the abnormal expression of NRF2 downstream antioxidant enzymes, inflammatory cytokines and osteogenic factors. Further, TiPs induced adverse osteoblastogenesis and osteoclastogenesis in cultured bone cells, which were substantially blocked by TBHQ in an NRF2 inhibition-sensitive manner. Consistently, the osteoprotective effects of TBHQ observed in wild-type mice were largely limited in Nfe2l2 knockout mice. Collectively, our data suggest that NRF2 suppression is a critical causal event of metal wear particle-incurred osteolysis, and the strategies reinstating NRF2 are effective to lessen the bone damage and potentially reduce the incidence of metal implant loosening.