PMID- 35775626 OWN - NLM STAT- MEDLINE DCOM- 20220704 LR - 20220901 IS - 1530-6860 (Electronic) IS - 0892-6638 (Linking) VI - 36 IP - 8 DP - 2022 Aug TI - Mechanical force modulates macrophage proliferation via Piezo1-AKT-Cyclin D1 axis. PG - e22423 LID - 10.1096/fj.202200314R [doi] AB - Orthodontic tooth movement (OTM) is induced by biomechanical stimuli and facilitated by periodontal tissue remodeling, where multiple immune cells participate in this progression. It has been demonstrated that macrophage is essential for mechanical force-induced tissue remodeling. In this study, we first found that mechanical force significantly induced macrophage proliferation in human periodontal samples and murine OTM models. Yet, how macrophages perceive mechanical stimuli and thereby modulate their biological behaviors remain elusive. To illustrate the mechanisms of mechanical force-induced macrophage proliferation, we subsequently identified Piezo1, a novel mechanosensory ion channel, to modulate macrophage response subjected to mechanical stimuli. Mechanical force upregulates Piezo1 expression in periodontal tissues and cultured bone-marrow-derived macrophages (BMDMs). Remarkably, suppressing Piezo1 with GsMTx4 retarded OTM through reduced macrophage proliferation. Moreover, knockdown of Piezo1 effectively inhibited mechanical force-induced BMDMs proliferation. RNA sequencing was further performed to dissect the underlying mechanisms of Piezo1-mediated mechanotransduction utilizing mechanical stretch system. We revealed that Piezo1-activated AKT/GSK3beta signaling was closely associated with macrophage proliferation upon mechanical stimuli. Importantly, Cyclin D1 (Ccnd1) was authenticated as a critical downstream factor of Piezo1 that facilitated proliferation by enhancing Rb phosphorylation. We generated genetically modified mice in which Ccnd1 could be deleted in macrophages in an inducible manner. Conditional ablation of Ccnd1 inhibited periodontal macrophage proliferation and therefore delayed OTM. Overall, our findings highlight that proliferation driven by mechanical force is a key process by which macrophages infiltrate in periodontal tissue during OTM, where Piezo1-AKT-Ccnd1 axis plays a pivotal role. CI - (c) 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. FAU - Xu, Hao AU - Xu H AD - Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China. AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China. FAU - Guan, Jiani AU - Guan J AD - Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China. AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China. FAU - Jin, Zhichun AU - Jin Z AD - Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China. AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China. FAU - Yin, Cheng AU - Yin C AD - Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China. AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China. FAU - Wu, Shengnan AU - Wu S AD - Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China. AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China. FAU - Sun, Wen AU - Sun W AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. FAU - Zhang, Hanwen AU - Zhang H AD - School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China. AD - Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China. FAU - Yan, Bin AU - Yan B AUID- ORCID: 0000-0001-9169-4615 AD - Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China. AD - Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (CCND1 protein, human) RN - 0 (Ccnd1 protein, mouse) RN - 0 (Ion Channels) RN - 0 (PIEZO1 protein, human) RN - 0 (Piezo1 protein, mouse) RN - 136601-57-5 (Cyclin D1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Cell Proliferation MH - *Cyclin D1/genetics/metabolism MH - Humans MH - *Ion Channels/genetics/metabolism MH - *Macrophages/cytology/metabolism MH - Mechanotransduction, Cellular MH - Mice MH - *Proto-Oncogene Proteins c-akt/metabolism MH - Signal Transduction OTO - NOTNLM OT - cell proliferation OT - cyclin D1 OT - ion channel OT - macrophage OT - mechanobiology OT - orthodontics EDAT- 2022/07/02 06:00 MHDA- 2022/07/06 06:00 CRDT- 2022/07/01 06:53 PHST- 2022/05/21 00:00 [revised] PHST- 2022/02/24 00:00 [received] PHST- 2022/06/08 00:00 [accepted] PHST- 2022/07/01 06:53 [entrez] PHST- 2022/07/02 06:00 [pubmed] PHST- 2022/07/06 06:00 [medline] AID - 10.1096/fj.202200314R [doi] PST - ppublish SO - FASEB J. 2022 Aug;36(8):e22423. doi: 10.1096/fj.202200314R.