Osteonecrosis development in a novel rat model characterized by a single application of oxidative stress

Ichiseki, Toru; Kaneuji, Ayumi; Ueda, Yoshimichi; Nakagawa, Shintaro; Mikami, Tomoaki; Fukui, Kiyokazu; Matsumoto, Tadami

doi:10.1002/art.30365

Cited by 41 publications

(35 citation statements)

References 33 publications

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“…36,37 Recently, we reported that differences in liver function were observed between patients with corticosteroidinduced ONFH and those without ONFH within 1 week after corticosteroid therapy. 38 Moreover, Ichiseki et al 39 reported that a disturbance in oxidative stress in the liver was observed within 24 h in an oxidative stress-induced ONFH rat model. These reports suggest that various changes in the liver in the early phase after treatment contribute to the development of ONFH.…”

Section: Discussionsupporting

confidence: 49%

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

Nagoya

Matsumoto

et al. 2015

Laboratory Investigation

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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.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. 9-13 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 treat...

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Section: Discussionsupporting

confidence: 49%

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

Nagoya

Matsumoto

et al. 2015

Laboratory Investigation

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“…However, this model shows metaphysic osteonecrosis and not the epiphysic necrosis that is observed in human patients. To overcome these limitations, a rat model has been developed in which osteonecrosis is induced by excessive MP [12-14]. The rats genome is 90 percent similar to the human genome, and thus the pathological characteristics of osteonecrosis in rats and human may be similar.…”

Section: Introductionmentioning

confidence: 99%

Immune response associated with Toll-like receptor 4 signaling pathway leads to steroid-induced femoral head osteonecrosis

Tian

Wen

Dang

et al. 2014

BMC Musculoskelet Disord

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BackgroundFemoral head osteonecrosis is frequently observed in patients treated with excessive corticosteroids. The objective of the current study was to establish a rat model to investigate the disruption of immune response in steroid-induced femoral head osteonecrosis via Toll-like receptor 4 (TLR4) signaling pathway.MethodsMale SD rats were divided into the treatment group (group A) and the model group (group B) consisting of 24 rats each, and were injected intramuscularly with 20 mg/kg methylprednisolone (MP) for 8 weeks, once a week. The rats in group A were injected intravenously with 7.5 mg/kg TAK242 before each MP administration. A control group (group N) consisted of 12 rats were received saline injection. All animals were sacrificed 8, 10 and 12 weeks from the first MP injection, respectively. Histopathological analysis was performed and the concentration of tartrate-resistant acid phosphatase (TRAP) in serum was tested. The signaling molecules including TLR4, MyD88, NF-κB p65 and MCP-1 were detected by immunohistochemistry, quantitative real-time PCR and Western blot.ResultsFemoral head osteonecrosis was observed in the model rats, and the concentration of TRAP and positive staining of all signaling molecules increased significantly in group B compared with that in group A and group N. Compare with the control group, the mRNA expressions and protein levels of all signaling molecules were enhanced significantly in group B, but no significant in group A.ConclusionsCorticosteroids can induce femoral head osteonecrosis by disturbing the immune response via TLR4 signaling pathway. These findings suggest that the disruption of immune response play a role in the pathogenesis of osteonecrosis.

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“…On the other hand, Ichiseki et al . reported oxidative stress‐induced ONFH in a rat model and demonstrated that glutathione level acts as an index of oxidative stress‐induced changes in the liver. Further, we previously reported that the disturbance of liver function was observed in patients with corticosteroid‐induced ONFH (Okazaki et al .…”

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confidence: 99%

Experimental rat model for alcohol‐induced osteonecrosis of the femoral head

Okazaki

Nagoya

Tateda

et al. 2013

Int J Experimental Path

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Alcohol-induced osteonecrosis of the femoral head (ONFH) is observed in alcohol abusers and patients with alcoholic fatty liver disease. It has been reported that Toll-like receptor 4 (TLR4) signalling plays a crucial role in the pathogenesis of alcoholic fatty liver disease. We previously reported a corticosteroid-induced ONFH rat model, and suggested that TLR4 signalling contributes to the pathogenesis of ONFH. Thus, it is thought that the pathogenesis of alcohol-induced ONFH is probably similar to that of corticosteroid-induced ONFH. The aim of this study was to develop a new animal model for alcohol-induced ONFH and to evaluate the relationship between the pro-inflammatory response via TLRs and the development of ONFH in rats. Male Wistar rats were fed a Lieber–DeCarli liquid diet containing 5% ethanol (experimental group) or dextran (control group) for 1–24 weeks. Histopathological and biochemical analyses were performed. Feeding the ethanol-containing liquid diet resulted in the development of ONFH with hepatic steatosis, hepatic dysfunction and hyperlipidaemia, whereas feeding the dextran-containing diet did not cause ONFH. However, we could not recognize any relationship between the pro-inflammatory response via TLR4 and the development of alcohol-induced ONFH. Thus in this study we have developed a new rat model for alcohol-induced ONFH based on the feeding of an ethanol liquid diet. ONFH was observed within seven days from the start of feeding with 5% ethanol-containing liquid diet. Although this was linked to hepatic steatosis, a TLR4 association was not a feature of this model.

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Osteonecrosis development in a novel rat model characterized by a single application of oxidative stress

Cited by 41 publications

References 33 publications

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

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

Immune response associated with Toll-like receptor 4 signaling pathway leads to steroid-induced femoral head osteonecrosis

Experimental rat model for alcohol‐induced osteonecrosis of the femoral head

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