IL-6-induced endothelial microparticles exacerbate juvenile ischemic osteonecrosis by promoting Osteoclastogenesis: Implications for Perthes disease.

Perthes disease is a debilitating idiopathic osteonecrosis of the pediatric femoral head and is characterized by femoral head deformity driven by uncoupled bone remodelling, with excessive osteoclastic activity. However, the systemic signals orchestrating this localized bone destruction remain poorly understood. In this study, we found that circulating microparticles (MPs) isolated from the plasma of patients with Perthes disease at the necrotic stage exhibited a greater capacity to promote osteoclast differentiation than MPs from healthy controls. Given the elevated interleukin-6 (IL-6) levels observed in these patients, we characterized endothelial microparticles (EMPs) generated from human umbilical vein endothelial cells (HUVECs) stimulated with IL-6 (IL-6-induced EMPs). Functionally, IL-6-induced EMPs markedly enhanced monocyte-endothelial adhesion, were actively internalized by bone marrow-derived macrophages (BMMs), and potentiated RANKL-induced osteoclastogenesis. In vivo, using a juvenile ischemic osteonecrosis (JIO) model, fluorescence tracking revealed that systemically administered EMPs accumulated in the skeletal tissue, with preferential localization to the ischemic epiphysis. Furthermore, administration of IL-6-induced EMPs exacerbated epiphyseal deformity and trabecular deterioration, accompanied by increased TRAP-positive osteoclast accumulation at the necrotic site. Collectively, these findings elucidate a pathogenic cellular signaling axis wherein inflammation-induced endothelial vesicles act as systemic messengers to trigger localized bone destruction, highlighting the IL-6-EMPs-osteoclast axis as a potential therapeutic target.