PMID- 34805177 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20211123 IS - 2296-634X (Print) IS - 2296-634X (Electronic) IS - 2296-634X (Linking) VI - 9 DP - 2021 TI - Geranylgeraniol Restores Zoledronic Acid-Induced Efferocytosis Inhibition in Bisphosphonate-Related Osteonecrosis of the Jaw. PG - 770899 LID - 10.3389/fcell.2021.770899 [doi] LID - 770899 AB - Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe side effect of long-term administration of bisphosphonates such as zoledronic acid (ZA), but its pathogenesis remains unclear. Impairment of the clearance of apoptotic cells (termed "efferocytosis") by ZA may be associated with the pathogenesis of BRONJ. The aim of this study was to investigate whether ZA might inhibit macrophage efferocytosis and promote osteocytic apoptosis, and the underlying mechanisms responsible for the disturbing balance between clean and generation of osteocytic apoptosis. We found that ZA significantly promoted the apoptosis of osteocyte and pre-osteoblast via BRONJ mouse models and in vitro MC3T3-E1 but also inhibited the efferocytosis of macrophage on apoptotic cells. Moreover, supplement with geranylgeraniol (GGOH), a substrate analog for geranylgeranylation of Rac1, could restore Rac1 homeostasis and rescue macrophage efferocytosis. GGOH partially inhibits MC3T3-E1 apoptosis induced by ZA via downregulation of Rac1/JNK pathway. We also examined the Rac1 distribution and activation conditions in bone marrow-derived macrophages (BMDMs) and MC3T3-E1 under ZA treatment, and we found that ZA impaired Rac1 migration to BMDM membrane, leading to round appearance with less pseudopodia and efferocytosis inhibition. Moreover, ZA simultaneously activated Rac1, causing overexpression of P-JNK and cleaved caspase 3 in MC3T3-E1. Finally, the systemic administration of GGOH decreased the osteocytic apoptosis and improved the bone healing of the extraction sockets in BRONJ mouse models. Taken together, our findings provided a new insight and experimental basis for the application of GGOH in the treatment of BRONJ. CI - Copyright (c) 2021 Chen, Zhu, Xu, Shen, Fu, Cheng, Liu and Jiang. FAU - Chen, Xin AU - Chen X AD - Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China. AD - Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China. AD - Department of Stomatology, Jiangyin People's Hospital, Wuxi, China. FAU - Zhu, Weiwen AU - Zhu W AD - Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China. AD - Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China. FAU - Xu, Rongyao AU - Xu R AD - Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China. AD - Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China. FAU - Shen, Xin AU - Shen X AD - Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China. FAU - Fu, Yu AU - Fu Y AD - Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China. AD - Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China. FAU - Cheng, Jie AU - Cheng J AD - Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China. FAU - Liu, Laikui AU - Liu L AD - Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China. AD - Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China. FAU - Jiang, Hongbing AU - Jiang H AD - Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China. AD - Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China. AD - Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China. LA - eng PT - Journal Article DEP - 20211103 PL - Switzerland TA - Front Cell Dev Biol JT - Frontiers in cell and developmental biology JID - 101630250 PMC - PMC8595285 OTO - NOTNLM OT - apoptosis OT - bisphosphonate-related osteonecrosis of the jaw OT - macrophages OT - phagocytosis OT - zoledronic acid COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/11/23 06:00 MHDA- 2021/11/23 06:01 PMCR- 2021/01/01 CRDT- 2021/11/22 06:53 PHST- 2021/09/05 00:00 [received] PHST- 2021/10/06 00:00 [accepted] PHST- 2021/11/22 06:53 [entrez] PHST- 2021/11/23 06:00 [pubmed] PHST- 2021/11/23 06:01 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fcell.2021.770899 [doi] PST - epublish SO - Front Cell Dev Biol. 2021 Nov 3;9:770899. doi: 10.3389/fcell.2021.770899. eCollection 2021.