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

Non-traumatic osteonecrosis of the femoral head (ONFH) often occurs after corticosteroid therapy in patients with inflammatory diseases. Recent studies suggest that toll-like receptor (TLR) signaling may contribute to the pathogenesis of inflammatory diseases, and that the reason for corticosteroid therapy for inflammatory diseases is related to the antiinflammatory activities of corticosteroids through the reduction of NF-kB. We hypothesized that the administration of TLR ligands in combination with corticosteroid causes ONFH and that transcription factors may contribute to the pathogenesis of ONFH. The aim of the study was to evaluate (1) the incidence of ONFH in rats after the administration of TLR7 or TLR9 ligands together with methylprednisolone (MPSL) and (2) whether transcription factors contribute to the development of ONFH. Male Wistar rats (n ¼ 148) were divided into five groups as follows: Group 1: Saline þ MPSL, Group 2: Imiquimod þ Saline, Group 3: Imiquimod þ MPSL, Group 4: CpG-C þ MPSL, Group 5: Imiquimod þ BAY11-7082 þ MPSL. As a result, ONFH was observed in 0 of 12 rats in Group 1, in 1 of 10 in Group 2, in 6 of 12 in Group 3, in 4 of 12 in Group 4, in 0 of 9 in Group 5. MPSL treatment did not significantly affect IRF7 activity, whereas NF-kB activity was significantly repressed in Group 2 and Group 3. Furthermore, the repression in interferon regulatory factor 7 (IRF7) activity by BAY11-7082 interfered with the development of ONFH simultaneously with the MPSL treatment-induced repression in NF-kB activity. In conclusion, in the present study, corticosteroid treatment after the administration of TLR7 or TLR9 ligands caused ONFH. Repression in NF-kB activity by corticosteroid treatment boosted the development of ONFH. High-dose corticosteroid therapy for inflammatory diseases, such as autoimmune disease, was reported to be a risk factor of non-traumatic osteonecrosis of the femoral head (ONFH). 1 On the other hand, it was reported that mega-dose corticosteroid therapy for traumatic spinal cord injury does not induce non-traumatic ONFH. 2 Thus, the role of corticosteroid in the pathogenesis of non-traumatic ONFH is poorly understood.