The suppression of TRIM21 and the accumulation of IFN-α play crucial roles in the pathogenesis of osteonecrosis of the femoral head

Abstract

Osteonecrosis of the femoral head (ONFH), the pathogenesis of which remains unclear, has been observed in autoimmune disease patients treated with corticosteroids. Recently, it has been shown that anti-tripartite motif-containing 21 (TRIM21) autoantibodies, which are often present in patients with systemic lupus erythematosis and Sjögren's syndrome, inhibit the E3 ligase activity of TRIM21. TRIM21 negatively regulates nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs) 3 and 7, three downstream transcription factors, via toll-like receptor 4 signaling. The aim of this study was to clarify the role of TRIM21 in the pathogenesis of ONFH using an animal model. Male Wistar rats were injected with lipopolysaccharide (LPS) twice and with methylprednisolone (MPSL) or saline three times. N-acetyl cysteine (NAC) was administered either concurrently with MPSL or once daily for the 3 days following the last MPSL injection. The incidence of ONFH in the MPSL group was 23.5%. Co-treatment of NAC and MPSL increased the incidence of ONFH to 55.6%. MPSL treatment decreased the activity of NF-κB in the liver and significantly increased the activity of both IRF3 and IRF7. No significant differences were observed in the activity of any of these three transcription factors between the MPSL and the co-treatment groups. In the femoral head, co-treatment with NAC and MPSL significantly decreased the expression of TRIM21 at 3 h and significantly increased the expression of interferon (IFN)-α at 24 h when compared with the MPSL group. IFN-α is known to induce cell death. These findings suggest that the suppression of TRIM21 in the femoral head causes an accumulation of IFN-α, which in turn leads to the development of ONFH. In conclusion, the suppression of TRIM21 resulting from altered NF-κB and IRF homeostasis accelerates the ONFH in rats treated with corticosteroids following LPS administration.

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

“…13 These reports showed that innate immune signaling via TLRs contributes to the pathogenesis of underlying diseases in patients with corticosteroid-induced ONFH. We previously reported that [3][4][5] In the present study, we showed that the administration of TLR7 and TLR9 ligands in combination with MPSL treatment resulted in the development of ONFH in rats. In contrast, it was reported that mega-dose corticosteroid therapy, recommended under the national acute spinal cord injury protocol for spinal cord injury, resulting from trauma did not induce ONFH.…”

“…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.…”

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

“…The tissues were then processed for routine haematoxylin and eosin staining. Osteonecrosis was defined as the presence of diffuse empty lacunae or pyknotic osteocytic nuclei in the bone trabeculae accompanied by and surrounding bone marrow cell necrosis, as described previously (Yamamoto et al 1997;Ichiseki 2006;Okazaki et al 2009;Tateda et al 2012).…”

Nontraumatic Osteonecrosis of the Femoral Head: Where Do We Stand Today?

“…Corticosteroids and alcohol lead to cell apoptosis along with precursor cell suppression 25,26 . In addition, there have been reports of several biomarkers and genes that may play a role in osteonecrosis development (see Appendix) [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] .…”