Methylprednisolone (mPSL) pulse therapy is an essential treatment for systemic lupus erythematosus (SLE); however, it carries a risk of osteonecrosis of the femoral head (ONFH). The pathogenesis of ON Show more
Methylprednisolone (mPSL) pulse therapy is an essential treatment for systemic lupus erythematosus (SLE); however, it carries a risk of osteonecrosis of the femoral head (ONFH). The pathogenesis of ONFH involves neutrophil extracellular trap (NET)-mediated microcirculation disorders. In BALB/c mice with imiquimod (IMQ)-induced lupus, mPSL pulse elevated serum levels of prenylcysteine oxidase 1 (PCYOX1), an enzyme that produces NET inducers hydrogen peroxide and farnesal, resulting in increased NETs in vivo. Although ischemia was observed in the femoral head, IMQ + mPSL-treated BALB/c mice did not develop ONFH. PCYOX1 is abundant in very-low-density lipoproteins. This study aimed to demonstrate that hyperlipidemia exacerbates NET-mediated microcirculation disorders and leads to ONFH development following mPSL pulse in lupus mice. To address this, ApoE mutant hyperlipidemic and BALB/c mice with IMQ-induced lupus received mPSL pulse. NET-forming neutrophils in peripheral blood were detected by flow cytometry. ONFH was assessed microscopically. As a result, IMQ + mPSL-treated ApoE mutant but not BALB/c mice developed ONFH, exhibiting higher levels of PCYOX1 and NET-forming neutrophils in circulation. In addition, NET-forming neutrophils accumulated in the vessels surrounding the femoral head, accompanied by osteocyte necrosis. This study demonstrated that mPSL pulse in lupus mice with hyperlipidemia enhanced PCYOX1 levels and NET formation, resulting in ONFH development, suggesting that hyperlipidemia may be a risk factor for ONFH following mPSL pulse therapy in SLE. Show less