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IL-6-induced endothelial microparticles exacerbate juvenile ischemic osteonecrosis by promoting Osteoclastogenesis:
Shijie Liao1, Zhendi Wei2, Jianhong Liu2
1Department of Orthopedic Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China; Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning 530021, China.
Insights
Circulating microparticles (MPs) from Perthes disease patients promote osteoclast formation. Interleukin-6 (IL-6) induced endothelial microparticles (EMPs) worsen bone destruction, revealing a key pathogenic pathway.
Area of Science:
- Pediatric Orthopedics
- Vascular Biology
- Bone Biology
Background:
- Perthes disease involves femoral head osteonecrosis and deformity due to abnormal bone remodeling.
- Systemic factors driving localized bone destruction in Perthes disease are not well understood.
- Elevated IL-6 levels are noted in Perthes disease patients.
Purpose of the Study:
- To investigate the role of circulating microparticles (MPs) in Perthes disease pathogenesis.
- To characterize the function of IL-6-induced endothelial microparticles (EMPs) in osteoclastogenesis and bone destruction.
- To elucidate the IL-6-EMPs-osteoclast signaling axis in Perthes disease.
Main Methods:
- Isolated MPs from Perthes disease patients and healthy controls for functional assays.
- Generated IL-6-induced EMPs from HUVECs and assessed their effects on monocyte-endothelial adhesion and macrophage internalization.
- Evaluated EMPs' role in RANKL-induced osteoclastogenesis in vitro.
- Utilized a juvenile ischemic osteonecrosis (JIO) mouse model to track EMPs in vivo and assess their impact on epiphyseal deformity and bone structure.
Main Results:
- MPs from Perthes disease patients enhanced osteoclast differentiation compared to controls.
- IL-6-induced EMPs promoted monocyte-endothelial adhesion, were internalized by macrophages, and potentiated osteoclastogenesis.
- In vivo, administered EMPs localized to ischemic skeletal tissue and exacerbated epiphyseal deformity and bone deterioration.
- Increased TRAP-positive osteoclasts were observed at the necrotic site following EMP administration.
Conclusions:
- Inflammation-induced endothelial microparticles (EMPs) act as systemic messengers in Perthes disease.
- The IL-6-EMPs-osteoclast axis contributes to localized bone destruction and femoral head deformity.
- This axis represents a potential therapeutic target for managing Perthes disease.
Abstract:
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.
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