Propionate and butyrate attenuate macrophage pyroptosis and osteoclastogenesis induced by CoCrMo alloy particles

Abstract

Background Wear particles-induced osteolysis is a major long-term complication after total joint arthroplasty. Up to now, there is no effective treatment for wear particles-induced osteolysis except for the revision surgery, which is a heavy psychological and economic burden to patients. A metabolite of gut microbiota, short chain fatty acids (SCFAs), has been reported to be beneficial for many chronic inflammatory diseases. This study aimed to investigate the therapeutic effect of SCFAs on osteolysis. Methods A model of inflammatory osteolysis was established by applying CoCrMo alloy particles to mouse calvarium. After two weeks of intervention, the anti-inflammatory effects of SCFAs on wear particle-induced osteolysis were evaluated by Micro-CT analysis and immunohistochemistry staining. In vitro study, lipopolysaccharide (LPS) primed bone marrow-derived macrophages (BMDMs) and Tohoku Hospital Pediatrics-1 (THP-1) macrophages were stimulated with CoCrMo particles to activate inflammasome in the presence of acetate (C2), propionate (C3), and butyrate (C4). Western blotting, Enzyme-linked immunosorbent assay, and immunofluorescence were used to detect the activation of NLRP3 inflammasome. The effects of SCFAs on osteoclasts were evaluate by qRT-PCR, Western blotting, immunofluorescence, and tartrate-resistant acid phosphatase (TRAP) staining. Additionally, histone deacetylase (HDAC) inhibitors, agonists of GPR41, GPR43, and GPR109A were applied to confirm the underlying mechanism of SCFAs on the inflammasome activation of macrophages and osteoclastogenesis. Results C3 and C4 but not C2 could alleviate wear particles-induced osteolysis with fewer bone erosion pits (P < 0.001), higher level of bone volume to tissue volume (BV/TV, P < 0.001), bone mineral density (BMD, P < 0.001), and a lower total porosity (P < 0.001). C3 and C4 prevented CoCrMo alloy particles-induced ASC speck formation and nucleation-induced oligomerization, suppressing the cleavage of caspase-1 (P < 0.05) and IL-1β (P < 0.05) stimulated by CoCrMo alloy particles. C3 and C4 also inhibited the generation of Gasdermin D-N-terminal fragment (GSDMD-NT) to regulate pyroptosis. Besides, C3 and C4 have a negative impact on osteoclast differentiation (P < 0.05) and its function (P < 0.05), affecting the podosome arrangement and morphologically normal podosome belts formation. Conclusion Our work showed that C3 and C4 are qualified candidates for the treatment of wear particle-induced osteolysis.

Butyrate limits human natural killer cell effector function

“…Butyrate and propionate are known to signal through the G-protein coupled receptor, the free fatty acid receptor 3 (FFA3) while acetate preferentially signals though free fatty acid receptor 2 (FFAR2) 22 . Similar results were observed in macrophages, where propionate and butyrate but not acetate strongly inhibited inflammatory response 23 . Interestingly, butyrate and propionate also possess anti-inflammatory properties in other cell types such as iPSC-derived intestinal epithelia and periodontal tissue 24 , 25 .…”

ASPS Exhibits Anti‐Rheumatic Effects by Reprogramming Gut Microbiota and Increasing Serum γ‐Glutamylcysteine Level

“…NLRP3‐dependent caspase‐1 cleavage could specifically cleave GSDMD, which controls IL‐1 β release. [ 31 , 32 , 33 ] Correspondingly, GSDMD cleavage and IL‐1 β secretion were also blocked by GGC in a dose‐dependent manner (Figure 6C,D ). The expression levels of caspase‐1 and IL‐1 β were also detected in joint specimens.…”

D-Mannose prevents bone loss under weightlessness

“…It is widely acknowledged that bone homeostasis is maintained and orchestrated by osteoclast-mediated bone resorption and osteoblast-mediated bone formation [ 53 ]. Abundant studies have shown that under the influence of the space microgravity environment, bone homeostasis is unbalanced and osteoclast absorption becomes active, ultimately leading to bone loss [ 54 – 56 ]. Our results are consistent with these findings.…”