PMID- 31543513 OWN - NLM STAT- MEDLINE DCOM- 20200923 LR - 20210614 IS - 2041-4889 (Electronic) VI - 10 IP - 10 DP - 2019 Sep 23 TI - MicroRNA-29a represses osteoclast formation and protects against osteoporosis by regulating PCAF-mediated RANKL and CXCL12. PG - 705 LID - 10.1038/s41419-019-1942-1 [doi] LID - 705 AB - Osteoporosis deteriorates bone mass and biomechanical strength, becoming a life-threatening cause to the elderly. MicroRNA is known to regulate tissue remodeling; however, its role in the development of osteoporosis remains elusive. In this study, we uncovered that silencing miR-29a expression decreased mineralized matrix production in osteogenic cells, whereas osteoclast differentiation and pit formation were upregulated in bone marrow macrophages as co-incubated with the osteogenic cells in transwell plates. In vivo, decreased miR-29a expression occurred in ovariectomy-mediated osteoporotic skeletons. Mice overexpressing miR-29a in osteoblasts driven by osteocalcin promoter (miR-29aTg/OCN) displayed higher bone mineral density, trabecular volume and mineral acquisition than wild-type mice. The estrogen deficiency-induced loss of bone mass, trabecular morphometry, mechanical properties, mineral accretion and osteogenesis of bone marrow mesenchymal cells were compromised in miR-29aTg/OCN mice. miR-29a overexpression also attenuated the estrogen loss-mediated excessive osteoclast surface histopathology, osteoclast formation of bone marrow macrophages, receptor activator nuclear factor-kappa ligand (RANKL) and C-X-C motif chemokine ligand 12 (CXCL12) expression. Treatment with miR-29a precursor improved the ovariectomy-mediated skeletal deterioration and biomechanical property loss. Mechanistically, miR-29a inhibited RANKL secretion in osteoblasts through binding to 3'-UTR of RANKL. It also suppressed the histone acetyltransferase PCAF-mediated acetylation of lysine 27 in histone 3 (H3K27ac) and decreased the H3K27ac enrichment in CXCL12 promoters. Taken together, miR-29a signaling in osteogenic cells protects bone tissue from osteoporosis through repressing osteoclast regulators RANKL and CXCL12 to reduce osteoclastogenic differentiation. Arrays of analyses shed new light on the miR-29a regulation of crosstalk between osteogenic and osteoclastogenic cells. We also highlight that increasing miR-29a function in osteoblasts is beneficial for bone anabolism to fend off estrogen deficiency-induced excessive osteoclastic resorption and osteoporosis. FAU - Lian, Wei-Shiung AU - Lian WS AD - Core Laboratory for Phenomics and Diagnostic, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. AD - Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. FAU - Ko, Jih-Yang AU - Ko JY AD - Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. FAU - Chen, Yu-Shan AU - Chen YS AD - Core Laboratory for Phenomics and Diagnostic, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. AD - Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. FAU - Ke, Huei-Jing AU - Ke HJ AD - Core Laboratory for Phenomics and Diagnostic, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. AD - Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. FAU - Hsieh, Chin-Kuei AU - Hsieh CK AD - Core Laboratory for Phenomics and Diagnostic, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. AD - Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. FAU - Kuo, Chung-Wen AU - Kuo CW AD - Core Laboratory for Phenomics and Diagnostic, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. AD - Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. FAU - Wang, Shao-Yu AU - Wang SY AD - Core Laboratory for Phenomics and Diagnostic, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. AD - Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. FAU - Huang, Bo-Wun AU - Huang BW AD - Department of Mechanical Engineering, Cheng Shiu University, Kaohsiung, Taiwan. FAU - Tseng, Jung-Ge AU - Tseng JG AD - Department of Leisure and Sports Management, Cheng Shiu University, Kaohsiung, Taiwan. FAU - Wang, Feng-Sheng AU - Wang FS AD - Core Laboratory for Phenomics and Diagnostic, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. wangfs@ms33.hinet.net. AD - Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. wangfs@ms33.hinet.net. AD - Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan. wangfs@ms33.hinet.net. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190923 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Chemokine CXCL12) RN - 0 (Cxcl12 protein, mouse) RN - 0 (MIRN29a microRNA, human) RN - 0 (MicroRNAs) RN - 0 (RANK Ligand) RN - 0 (Tnfsf11 protein, mouse) RN - EC 2.3.1.48 (p300-CBP Transcription Factors) RN - EC 2.3.1.48 (p300-CBP-associated factor) SB - IM MH - Animals MH - Biomechanical Phenomena MH - Bone and Bones/cytology/metabolism MH - Cell Communication/physiology MH - Cell Differentiation/physiology MH - Chemokine CXCL12/*genetics MH - Female MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - MicroRNAs/genetics/*metabolism MH - Osteoclasts/cytology/*metabolism MH - Osteoporosis/*genetics MH - Ovariectomy MH - RANK Ligand/*genetics/metabolism MH - p300-CBP Transcription Factors/genetics/*metabolism PMC - PMC6755134 COIS- The authors declare that they have no conflict of interest. EDAT- 2019/09/24 06:00 MHDA- 2020/09/24 06:00 PMCR- 2019/09/23 CRDT- 2019/09/24 06:00 PHST- 2019/04/01 00:00 [received] PHST- 2019/08/26 00:00 [accepted] PHST- 2019/08/20 00:00 [revised] PHST- 2019/09/24 06:00 [entrez] PHST- 2019/09/24 06:00 [pubmed] PHST- 2020/09/24 06:00 [medline] PHST- 2019/09/23 00:00 [pmc-release] AID - 10.1038/s41419-019-1942-1 [pii] AID - 1942 [pii] AID - 10.1038/s41419-019-1942-1 [doi] PST - epublish SO - Cell Death Dis. 2019 Sep 23;10(10):705. doi: 10.1038/s41419-019-1942-1.