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

onecrosis. Therefore, present findings suggest that the administration of TLR ligands in combination with subsequent corticosteroid treatment are required to trigger the onset of primary corticosteroid-induced ONFH in rats, and that the pathogenesis of underlying diseases treated with corticosteroids contributes to the development of corticosteroid-induced ONFH. High-dose corticosteroid treatment for severe acute respiratory syndrome (SARS) infection was reported to be a risk factor of ONFH. 31 SARS virus is a single-stranded RNA virus, which is one of the ligands of TLR7. 32 Consequently, we believe that the pathogenesis of ONFH in Imiquimod þ MPSL group resembles the pathogenesis of ONFH after corticosteroid treatment for SARS infection. Although ONFH was not found in the Saline þ MPSL group rats, the fact that the Imiquimod þ Saline rats, to which no alcohol or corticosteroids were given, developed ONFH at a lower rate indicates that this group resembled idiopathic ONFH. This result suggests that TLR7 signaling contributes to the development of idiopathic ONFH, and indicates that infection by a single-stranded RNA virus, which was one of the ligands for TLR7, could be a risk factor for idiopathic ONFH. Infection with human immunodeficiency virus, a single-stranded RNA virus, has already been reported as an isolated risk factor for idiopathic ONFH. 33 Therefore, our results may explain the pathogenesis of idiopathic ONFH in patients infected with single-stranded RNA viruses. Among the underlying diseases treated with corticosteroids, SLE was reported to be frequently observed in ONFH patients. 25 The incidence of ONFH in SLE patients after corticosteroid therapy was reported to be 10-50%. 34, 35 In the present study, 33-50% of the Imiquimod þ MPSL and CpG-C þ MPSL group rats developed ONFH, which is similar to the incidence of ONFH in patients with SLE.