Development of non-traumatic osteonecrosis of the femoral head requires toll-like receptor 7 and 9 stimulations and is boosted by repression on nuclear factor kappa B in rats

Okazaki, Shunichiro; Nagoya, Satoshi; Matsumoto, Hiroshi; Mizuo, Keisuke; Sasaki, Mikito; Watanabe, Satoshi; Yamashita, Toshihiko; Inoue, Hiromasa

We previously reported that the toll-like receptor (TLR) 4 signaling pathway, which induces inflammatory status, contributes to the pathogenesis of non-traumatic ONFH in rats. [3] [4] [5] TLRs were identified as receptors related to the innate immune system in 1997. 6 Recently, TLRs have been reported to play a crucial role in autoimmunity. 7, 8 In particular, TLRs contribute to the pathogenesis of underlying diseases, such as systemic lupus erythematodes (SLE), nephrotic syndrome, polymyositis/dermatmyositis, bronchial asthma, and thrombocytopenic purpura, in patients with corticosteroidinduced ONFH. [9] [10] [11] [12] [13] The signaling pathway via TLR7 or TLR9 and type I interferon may, in particular, contribute to the pathogenesis of systemic autoimmune diseases, such as SLE, 9, 14 and some inhibitors such as biologics were developed to downregulate these signaling pathways for the treatment of inflammatory diseases. 15, 16 The reason for using corticosteroid therapy for inflammatory diseases is related to the anti-inflammatory and immunosuppressive activities of corticosteroids, 17 and it was reported that the reduction of nuclear factor kappa B (NF-kB) activity via glucocorticoid receptors has a central role in these activities. 18 NF-kB and interferon regulatory factor 7 (IRF7) are signal transcription factors related to the proinflammatory response via TLR7 or TLR9 and the MyD88-dependent pathway. Thus, we hypothesized that the administration of these TLR7 or TLR9 ligands and subsequent treatment with methylprednisolone (MPSL) leads to ONFH in rats, and that these transcription factors may contribute to the pathogenesis of ONFH via the TLRs. In the present study, to verify this hypothesis, we investigated (1) the incidence of ONFH in rats after the administration of TLR7 or TLR9 ligands in combination with MPSL and (2) whether NF-kB and IRF7 contributed to the pathogenesis of ONFH after MPSL treatment.