Lithium Modified Mesoporous Hydroxyapatite Nanoparticles Mediate the Polarization of M2 Macrophages to Promote Bone Defect Repair in Glucocorticoid-Induced Osteonecrosis of the Femoral Head

Abstract

Glucocorticoid (GC)-induced osteonecrosis of femoral head(GI-ONFH) is a chronic inflammatory disease characterized by abnormal activation of macrophages and infiltration of necrotic sites. However, previous studies on osteonecrosis repair have neglected the immunomodulatory effect of bone, which leads to the failure of bone repair. Therefore, in this study, we produced an immunomodulatory bone repair material with lithium (Li)-modified mesoporous hydroxyapatite nanoparticles (Li-mHANP) that has the potential to enhance bone regeneration by manipulating macrophage (M) polarization to create an immunomodulatory microenvironment that promotes bone healing in GIONFH. In order to investigate whether Li incorporation into mHANP can synergistically improve bone formation and repair osteonecrosis by changing the polarization of macrophages, we evaluated Li-mHANP and macrophages in the process of GIONFH bone regeneration through in vitro and in vivo biological tests. We found that, compared with mHANP, Li-mHANP activated the JAK1/STAT6/STAT3 signaling pathway and promoted the transformation of macrophages to M2 phenotype. In addition, Li-mHANP-treated macrophages promote osteogenesis of BMSCs and endothelial cell angiogenesis in vitro. After Li-mHANP nanoparticles were implanted into the model of GIONFH, we found that Li-mHANP mediated the transformation of pro-inflammatory M1 macrophages into pro-tissue repair M2 phenotype, restored the M2/M1 ratio to normal levels, effectively alleviated inflammation, and ultimately promoted osteoblast differentiation and bone regeneration, compared with mHANP without Li modified. In conclusion, these findings suggest that Li-mHANP is an immunomodulatory material that can direct immunoregulatory bone repair related to tissue repair and regeneration and promote bone regeneration of bone defect in the condition of GIONFH. Funding Information: This study was supported by The National Natural Science Foundation of China (grant no. 81974333) and Science and Technology Program of Chengdu (grant no.2019-YF05-01188-SN). Declaration of Interests: The authors declare no competing financial interest. Ethics Approval Statement: All animal operations were approved by the Animal Research Committee of West China Hospital of Sichuan University (Chengdu, China).