PMID- 35996168 OWN - NLM STAT- MEDLINE DCOM- 20220824 LR - 20220906 IS - 2054-9369 (Electronic) IS - 2095-7467 (Print) IS - 2054-9369 (Linking) VI - 9 IP - 1 DP - 2022 Aug 23 TI - Propionate and butyrate attenuate macrophage pyroptosis and osteoclastogenesis induced by CoCrMo alloy particles. PG - 46 LID - 10.1186/s40779-022-00404-0 [doi] LID - 46 AB - 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-1beta (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. CI - (c) 2022. The Author(s). FAU - Wu, Yang-Lin AU - Wu YL AD - Department of Orthopaedics, Suzhou Dushu Lake Hospital, Dushu Lake Hospital Affiliated to Soochow University, Medical Centre of Soochow University, Suzhou, 215001, Jiangsu, China. AD - Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, Jiangsu, China. FAU - Zhang, Chen-Hui AU - Zhang CH AD - Department of Orthopaedics, Suzhou Dushu Lake Hospital, Dushu Lake Hospital Affiliated to Soochow University, Medical Centre of Soochow University, Suzhou, 215001, Jiangsu, China. FAU - Teng, Yun AU - Teng Y AD - Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, Jiangsu, China. FAU - Pan, Ying AU - Pan Y AD - Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. FAU - Liu, Nai-Cheng AU - Liu NC AD - Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, Jiangsu, China. FAU - Liu, Pei-Xin AU - Liu PX AD - Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, Jiangsu, China. FAU - Zhu, Xu AU - Zhu X AD - Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, Jiangsu, China. FAU - Su, Xin-Lin AU - Su XL AD - Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, Jiangsu, China. FAU - Lin, Jun AU - Lin J AUID- ORCID: 0000-0002-8094-5826 AD - Department of Orthopaedics, Suzhou Dushu Lake Hospital, Dushu Lake Hospital Affiliated to Soochow University, Medical Centre of Soochow University, Suzhou, 215001, Jiangsu, China. linjun@suda.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220823 PL - England TA - Mil Med Res JT - Military Medical Research JID - 101643181 RN - 0 (Alloys) RN - 0 (Butyrates) RN - 0 (Inflammasomes) RN - 0 (Propionates) SB - IM MH - Alloys/adverse effects MH - Animals MH - Butyrates/adverse effects MH - Humans MH - Inflammasomes/adverse effects/metabolism MH - Macrophages/metabolism MH - Mice MH - Osteogenesis MH - *Osteolysis/drug therapy/metabolism/prevention & control MH - Propionates/adverse effects MH - Pyroptosis PMC - PMC9396885 OTO - NOTNLM OT - NLRP3 inflammasome OT - Osteoclast OT - Osteolysis OT - Pyroptosis OT - Short chain fatty acids COIS- The authors declare that they have no competing interests. EDAT- 2022/08/23 06:00 MHDA- 2022/08/25 06:00 PMCR- 2022/08/23 CRDT- 2022/08/22 23:41 PHST- 2021/11/08 00:00 [received] PHST- 2022/07/21 00:00 [accepted] PHST- 2022/08/22 23:41 [entrez] PHST- 2022/08/23 06:00 [pubmed] PHST- 2022/08/25 06:00 [medline] PHST- 2022/08/23 00:00 [pmc-release] AID - 10.1186/s40779-022-00404-0 [pii] AID - 404 [pii] AID - 10.1186/s40779-022-00404-0 [doi] PST - epublish SO - Mil Med Res. 2022 Aug 23;9(1):46. doi: 10.1186/s40779-022-00404-0.