The Role Of IL-34 And Particle-induced Macrophage Autophage In The Pathogenesis Of Aseptic Loosening

Total joint replacemant is thought to be one of the most commonly performed and successful operations in orthopaedics as defined by clinical outcomes and implant survivorship. However, aseptic loosening following periprosthetic osteolysis, induced by wear particles, is the major reason for total joint arthroplasty failure and surgical revision. Various particles stimulate macrophages and other mesenchymal cells to secrete abundant pro-inflammatory cytokines and chemokines, which mediates the activation of osteoclasts and disturbs the balance between bone formation and resorption.Recently, a new cytokine interleukin-34 (IL-34) was identified as an alternative ligand for CSF1R. Previous studies have confirmed the expression of IL-34 in gingival fibroblasts, osteoblasts and the synovial tissue of patients with arthritis, and it can promote osteoclastogenesis with the same efficiency as M-CSF. As a downstream effector of TNF-a and IL-1β, IL-34 may contribute to inflammation and bone destruction in inflammatory bone diseases. However, whether IL-34 contributes to the pathogenesis of aseptic loosening remains unknown. In our present study, we find that IL-34 is expressed in the peri-implant membrane of patients with aseptic loosening and that wear particles stimulate its expression via the JNK and p44/42 MAPK signaling pathways in vitro. Furthermore, the administration of IL-34 and RANKL is able to increase osteoclastogenesis in vitro. Collectively, our study reveals that IL-34 is involved in the pathological process of particle-induced aseptic loosening and may be a potential therapeutic target for inhibiting osteoclastogenesis.Our previous studies showed that the expression of autophagy marker protein was up-regulated by wear particles in macrophages. The expression of TNF-a in macrophages induced by wear particles were down-regulated when autophagy was inhibited. With cellular, animal models and patients pathological specimens, our study will further clarify that wear partilces can stimulate autophagy in macrophages; investigate the effect of autophagy in macrophages secreting inflammatory cytokines and undergoing osteoclasts differrentiation; clarify the mechanism of secreting inflammatory cytokines and osteoclastogenesis; reveal the effect of autophagy in the pathological process in cellular/animals/patients levels. In our present study, we demonstrated that TiPs activited autophage in macrophages and particle-induced osteolysis animal models as well as periprosthetic membranes of patients with aseptic loosening. The autophagy inhibitor 3-MA (3-methyladenine) could dramatically reduce TiPs-induced TNF-a expression both in macrophages and in membranes from animal models. Furthermore, inhibition of autophagy with 3-MA ameliorated the severity of osteolysis in PIO animal models. Collectively, these results suggest that autophagy plays a key role in TiPs-induced osteolysis by promoting TNF-a expression and that blocking autophagy may represent a potential therapeutic approach for treating particle-induced peri-implant osteolysis.