HDAC6/Trim21 aggravates macrophage inflammatory response and titanium-induced osteolysis via GSDMD signaling pathway

Total joint arthroplasty is the optimal method for end-stage osteoarticular diseases, but aseptic loosening reduces long-term success. Our prior research demonstrated that wear particles released from loosened prostheses activate macrophages to secrete proinflammatory cytokines, thereby promoting osteoclast formation and osteolysis. Gasdermin D (GSDMD), a key regulator of pyroptosis, is a core step in the production of inflammatory factors after stimulation of macrophage pattern recognition receptors together with downstream inflammatory pathways, and histone deacetylase 6 (HDAC6)/tripartite motif-containing protein 21 (Trim21) is important in regulating activation. Yet, the specific mechanism of HDAC6/Trim21/GSDMD in wear particle-induced aseptic loosening (AL) requires further illustration. Our study will clarify the mechanism by demonstrating how HDAC6/Trim21 regulates GSDMD-associated signaling pathways in vivo and in vitro. Sterile titanium particles (TiPs) of 1.2 to 10.0 μm were co-incubated with RAW264.7 macrophages. HDAC6 selective inhibitor tubastatin A, HDAC6 overexpressing lentivirus, and Trim21 small interfering RNA were utilized to explore activation of proinflammatory pathways and polarization of macrophages was related. The mouse cranial osteolysis model was constructed to demonstrate HDAC6 regulating TiP-induced osteolysis. Macrophages were stimulated by TiPs to produce interleukin-1β as well as interferon γ, exhibiting M1 polarization. HDAC6 directedly interacted with Trim21, promoting the multiple proinflammatory responses mentioned above via GSDMD, STING pathway, and NLRP3 pathway. In vivo, HDAC6 provoked TiP-induced mice calvaria osteolysis and IL-1β production. HDAC6/Trim21 aggravates macrophage inflammatory response and titanium-induced osteolysis via GSDMD signaling pathway.