Osteonecrosis occurs when, under continuous stimulation by adverse factors such as glucocorticoids or alcohol, the death of local bone and marrow cells leads to abnormal osteoimmune function. This creates a chronic inflammatory microenvironment, which interferes with bone regeneration and repair. In a variety of bone tissue diseases, innate immune cells and adaptive immune cells interact with bone cells, and their effects on bone metabolic homeostasis have attracted more and more attention, thus developing into a new discipline - osteoimmunology. Immune cells are the most important regulator of inflammation, and osteoimmune disorder may be an important cause of osteonecrosis. Elucidating the chronic inflammatory microenvironment regulated by abnormal osteoimmune may help develop potential treatments for osteonecrosis. This review summarizes the inflammatory regulation of bone immunity in osteonecrosis, explains the pathophysiological mechanism of osteonecrosis from the perspective of osteoimmunology, and provides new ideas for the treatment of osteonecrosis.

The British Editorial Society of Bone & Joint Surgery

Steroid‐induced osteoblast apoptosis is a crucial pathological process in steroid‐induced osteonecrosis of the femoral head (SONFH). Autophagy can resist apoptosis and AMPK plays an important role in autophagy regulation. Aucubin from the small tree Eucommia ulmoides Oliv., which has a long history of use in orthopaedics and traumatology in Asian medicine, can promote bone formation, but whether it can slow or prevent steroid‐osteoblast apoptosis is unclear. Therefore, we investigated the pathogenesis of SONFH and how the osteoblast responds to aucubin under the dexamethasone stimulation. In human femoral head osteonecrosis specimens, we found that the autophage and apoptosis level were increased, and the AMPK signalling was crucial to autophagy. We observed that aucubin could prevent dexamethasone‐induced apoptosis in osteoblasts by enhancing the level of autophagy. Further, we confirmed that the regulatory effect of aucubin on autophagy and apoptosis was achieved by activating AMPK signalling. We have demonstrated a mechanism of disease progression and shown that aucubin could enhance autophagy through AMPK signalling to prevent osteoblast apoptosis. These findings provide a basis for the further investigation of the potential therapeutic role of aucubin in the SONFH.

Senescent nucleus pulposus mesenchymal stem cells (NPMSCs) are key instigators of local chronic inflammation and disruptions in nucleus pulposus tissue repair in intervertebral disc degeneration (IVDD). This study aimed to investigate the interplay between EZH2 and NPMSCs senescence-associated inflammation. Nucleus pulposus samples were collected from IVDD patients (n = 15, F/M = 7/8, average age 47.9 (21-72) year-old). Multiplex immunohistochemistry was conducted to detect the expression of EZH2 and the cGAS/STING pathway. Subsequently, NPMSCs were isolated from 7 patients (n = 7, F/M = 4/3, average age 49.4 (36-68) year-old). After treatment with tert-butyl hydroperoxide and lentivirus-overexpression-EZH2 (Lv-OE-EZH2), real time fluorescent quantitative PCR, immunofluorescence, western blot, and ChIP were used to detect the expression of EZH2 and the cGAS/STING pathway. Micro-CT, magnetic resonance imaging, and histological staining were performed to assess the therapeutic effects of Lv-OE-EZH2 and a STING inhibitor on rat IVDD. All experiment designs were independent. In both human nucleus pulposus tissues and an in vitro cell model, EZH2 expression decreased while the cGAS/STING pathway became activated in senescent NPMSCs. ChIP assays and Lv-OE-EZH2 experiments validated that EZH2 epigenetically inhibited STING expression via H3K27me3, thereby impairing the cGAS/STING pathway and attenuating senescence-associated inflammation. Moreover, overexpression of EZH2 (Pfirrmann grade means difference -1.375, p = 0.0089) and inhibition of STING effectively attenuated rat IVDD. The decreased expression of EZH2 in senescent NPMSCs promotes senescence-associated inflammation and the progression of IVDD, possibly by relieving the transcriptional inhibition of STING and enabling the activation of the cGAS/STING pathway.