PMID- 38477755 OWN - NLM STAT- Publisher LR - 20240313 IS - 1523-4681 (Electronic) IS - 0884-0431 (Linking) DP - 2024 Mar 11 TI - The chromatin remodeling factor Arid1a cooperates with Jun/Fos to promote osteoclastogenesis by epigenetically upregulating Siglec15 expression. LID - zjae042 [pii] LID - 10.1093/jbmr/zjae042 [doi] AB - Osteoporosis is characterized by an imbalance between osteoclast-mediated bone resorption and osteoblast-related bone formation, particularly increased osteoclastogenesis. However, the mechanisms by which epigenetic factors regulate osteoclast precursor differentiation during osteoclastogenesis remain poorly understood. Here, we show that the specific knockout of the chromatin remodeling factor Arid1a in bone marrow-derived macrophages (BMDMs) results in increased bone mass. The loss of Arid1a in BMDM inhibits cell-cell fusion and maturation of osteoclast precursors, thereby suppressing osteoclast differentiation. Mechanistically, Arid1a increases the chromatin access in the gene promoter region of sialic acid-binding Ig-like lectin 15 (Siglec15) by transcription factor Jun/Fos, which results in the upregulation of Siglec15 and promotion of osteoclast differentiation. However, the loss of Arid1a reprograms the chromatin structure to restrict Siglec15 expression in osteoclast precursors, thereby inhibiting BMDM differentiation into mature osteoclasts. Deleting Arid1a after ovariectomy (a model for postmenopausal bone loss) alleviated bone loss and maintained bone mass. In summary, epigenetic reprogramming mediated by Arid1a loss suppresses osteoclast differentiation and may serve as a promising therapeutic strategy for treating bone loss diseases. CI - (c) The Author(s) [2024]. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. FAU - Zhang, Yongxing AU - Zhang Y AD - Department of Orthopedics, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China. AD - Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China. AD - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China. AD - Clinical Research Center of Motor System Disease of Zhejiang Province, PR China. FAU - Sun, Hangxiang AU - Sun H AD - Department of Orthopedics, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China. AD - Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China. AD - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China. AD - Clinical Research Center of Motor System Disease of Zhejiang Province, PR China. FAU - Huang, Fei AU - Huang F AD - MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou City, Zhejiang Province, PR China. FAU - Chen, Yang AU - Chen Y AD - Department of Ultrasound, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China. FAU - Ding, Xiying AU - Ding X AD - Department of Ultrasound, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China. FAU - Zhou, Chenhe AU - Zhou C AD - Department of Orthopedics, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China. AD - Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China. AD - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China. AD - Clinical Research Center of Motor System Disease of Zhejiang Province, PR China. FAU - Wu, Yan AU - Wu Y AD - Department of Orthopedics, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China. AD - Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China. AD - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China. AD - Clinical Research Center of Motor System Disease of Zhejiang Province, PR China. FAU - Zhang, Qing AU - Zhang Q AD - Research Institute of Artificial Intelligence, Zhejiang Lab, Hangzhou City, Zhejiang Province, PR China. FAU - Ma, Xiao AU - Ma X AD - Research Institute of Artificial Intelligence, Zhejiang Lab, Hangzhou City, Zhejiang Province, PR China. FAU - Wang, Jun AU - Wang J AD - Research Institute of Artificial Intelligence, Zhejiang Lab, Hangzhou City, Zhejiang Province, PR China. FAU - Yue, Rui AU - Yue R AD - Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, PR China. AD - Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, PR China. FAU - Shen, Li AU - Shen L AD - MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou City, Zhejiang Province, PR China. AD - Hangzhou Innovation Center, Zhejiang University, Hangzhou City, Zhejiang Province, PR China. FAU - Sun, Xuxu AU - Sun X AD - Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China. FAU - Ye, Zhaoming AU - Ye Z AD - Department of Orthopedics, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China. AD - Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China. AD - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China. AD - Clinical Research Center of Motor System Disease of Zhejiang Province, PR China. LA - eng PT - Journal Article DEP - 20240311 PL - England TA - J Bone Miner Res JT - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JID - 8610640 SB - IM OAB - Osteoporosis is a common disease, usually diagnosed by decreased bone density and increased fragility. The people with osteoporosis has higher risk of fractures. Nearly one third of the aged people will suffer from osteoporosis-related fractures and even lose their lives because of this. Therefore, there is an urgent need for early intervention and effective treatment options for osteoporosis in the aging population. Bone tissue is a highly dynamic tissue that undergoes continuous remodeling throughout an individual's entire life. The balance of remodeling depends on the bone formation mediated by osteoblasts and bone resorption by osteoclasts. When this balance is disrupted, osteoporosis occurs. Thus, the aim of our research is to explore the behind mechanism of this imbalance. Here, we demonstrate that the loss of Arid1a, a chromatin remodeler, leads to chromatin reprogramming that restricts access to promoters by transcription factors such as Jun/Fos, thereby suppressing osteoclast activation and bone resorption. Our findings offer insights into the epigenetic mechanisms underlying osteoporosis and suggest potential strategies for its prevention and treatment. OABL- eng OTO - NOTNLM OT - Arid1a OT - Chromatin remodeling OT - Osteoclast differentiation OT - Osteoporosis OT - Siglec15 EDAT- 2024/03/13 12:47 MHDA- 2024/03/13 12:47 CRDT- 2024/03/13 10:44 PHST- 2023/06/23 00:00 [received] PHST- 2024/02/09 00:00 [revised] PHST- 2024/03/08 00:00 [accepted] PHST- 2024/03/13 12:47 [medline] PHST- 2024/03/13 12:47 [pubmed] PHST- 2024/03/13 10:44 [entrez] AID - 7625513 [pii] AID - 10.1093/jbmr/zjae042 [doi] PST - aheadofprint SO - J Bone Miner Res. 2024 Mar 11:zjae042. doi: 10.1093/jbmr/zjae042.