A Novel Long Noncoding RNA in Osteocytes Regulates Bone Formation through the Wnt/β-Catenin Signaling Pathway
The vast majority of transcribed RNAs are noncoding RNAs. Among noncoding RNAs, long noncoding RNAs (lncRNAs), which contain hundreds to thousands of bases, have received attention in many fields. The vast majority of the constituent cells in bone tissue are osteocytes, but their regulatory mechanis...
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| Format: | Article |
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MDPI AG
2023-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/17/13633 |
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| author | Makoto Arai Hiroki Ochi Satoko Sunamura Nobuaki Ito Masaomi Nangaku Shu Takeda Shingo Sato |
| author_facet | Makoto Arai Hiroki Ochi Satoko Sunamura Nobuaki Ito Masaomi Nangaku Shu Takeda Shingo Sato |
| author_sort | Makoto Arai |
| collection | DOAJ |
| description | The vast majority of transcribed RNAs are noncoding RNAs. Among noncoding RNAs, long noncoding RNAs (lncRNAs), which contain hundreds to thousands of bases, have received attention in many fields. The vast majority of the constituent cells in bone tissue are osteocytes, but their regulatory mechanisms are incompletely understood. Considering the wide range of potential contributions of lncRNAs to physiological processes and pathological conditions, we hypothesized that lncRNAs in osteocytes, which have not been reported, could be involved in bone metabolism. Here, we first isolated osteocytes from femurs of mice with osteocyte-specific GFP expression. Then, through RNA-sequencing, we identified osteocyte-specific lncRNAs and focused on a novel lncRNA, 9530026P05Rik (lncRNA953Rik), which strongly suppressed osteogenic differentiation. In the IDG-SW3 osteocyte line with lncRNA953Rik overexpression, the expression of <i>Osterix</i> and its downstream genes was reduced. RNA pull-down and subsequent LC-MS/MS analysis revealed that lncRNA953Rik bound the nuclear protein CCAR2. We demonstrated that CCAR2 promoted Wnt/β-catenin signaling and that lncRNA953Rik inhibited this pathway. lncRNA953Rik sequestered CCAR2 from HDAC1, leading to deacetylation of H3K27 in the <i>Osterix</i> promoter and consequent transcriptional downregulation of <i>Osterix</i>. This research is the first to clarify the role of a lncRNA in osteocytes. Our findings can pave the way for novel therapeutic options targeting lncRNAs in osteocytes to treat bone metabolic diseases such as osteoporosis. |
| first_indexed | 2024-03-10T23:20:06Z |
| format | Article |
| id | doaj.art-07bd614f706043cc980d6283c36b3415 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:20:06Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-07bd614f706043cc980d6283c36b34152023-11-19T08:20:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124171363310.3390/ijms241713633A Novel Long Noncoding RNA in Osteocytes Regulates Bone Formation through the Wnt/β-Catenin Signaling PathwayMakoto Arai0Hiroki Ochi1Satoko Sunamura2Nobuaki Ito3Masaomi Nangaku4Shu Takeda5Shingo Sato6Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo 113-8655, JapanDepartment of Rehabilitation for Motor Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities, Tokorozawa 359-8555, JapanDepartment of Orthopaedic Surgery, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo 113-8519, JapanDivision of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo 113-8655, JapanDivision of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo 113-8655, JapanDivision of Endocrinology, Toranomon Hospital Endocrine Center, Tokyo 105-8470, JapanCenter for Innovative Cancer Treatment, Tokyo Medical and Dental University (TMDU), Tokyo 113-8519, JapanThe vast majority of transcribed RNAs are noncoding RNAs. Among noncoding RNAs, long noncoding RNAs (lncRNAs), which contain hundreds to thousands of bases, have received attention in many fields. The vast majority of the constituent cells in bone tissue are osteocytes, but their regulatory mechanisms are incompletely understood. Considering the wide range of potential contributions of lncRNAs to physiological processes and pathological conditions, we hypothesized that lncRNAs in osteocytes, which have not been reported, could be involved in bone metabolism. Here, we first isolated osteocytes from femurs of mice with osteocyte-specific GFP expression. Then, through RNA-sequencing, we identified osteocyte-specific lncRNAs and focused on a novel lncRNA, 9530026P05Rik (lncRNA953Rik), which strongly suppressed osteogenic differentiation. In the IDG-SW3 osteocyte line with lncRNA953Rik overexpression, the expression of <i>Osterix</i> and its downstream genes was reduced. RNA pull-down and subsequent LC-MS/MS analysis revealed that lncRNA953Rik bound the nuclear protein CCAR2. We demonstrated that CCAR2 promoted Wnt/β-catenin signaling and that lncRNA953Rik inhibited this pathway. lncRNA953Rik sequestered CCAR2 from HDAC1, leading to deacetylation of H3K27 in the <i>Osterix</i> promoter and consequent transcriptional downregulation of <i>Osterix</i>. This research is the first to clarify the role of a lncRNA in osteocytes. Our findings can pave the way for novel therapeutic options targeting lncRNAs in osteocytes to treat bone metabolic diseases such as osteoporosis.https://www.mdpi.com/1422-0067/24/17/13633long noncoding RNAosteocytebone formation |
| spellingShingle | Makoto Arai Hiroki Ochi Satoko Sunamura Nobuaki Ito Masaomi Nangaku Shu Takeda Shingo Sato A Novel Long Noncoding RNA in Osteocytes Regulates Bone Formation through the Wnt/β-Catenin Signaling Pathway International Journal of Molecular Sciences long noncoding RNA osteocyte bone formation |
| title | A Novel Long Noncoding RNA in Osteocytes Regulates Bone Formation through the Wnt/β-Catenin Signaling Pathway |
| title_full | A Novel Long Noncoding RNA in Osteocytes Regulates Bone Formation through the Wnt/β-Catenin Signaling Pathway |
| title_fullStr | A Novel Long Noncoding RNA in Osteocytes Regulates Bone Formation through the Wnt/β-Catenin Signaling Pathway |
| title_full_unstemmed | A Novel Long Noncoding RNA in Osteocytes Regulates Bone Formation through the Wnt/β-Catenin Signaling Pathway |
| title_short | A Novel Long Noncoding RNA in Osteocytes Regulates Bone Formation through the Wnt/β-Catenin Signaling Pathway |
| title_sort | novel long noncoding rna in osteocytes regulates bone formation through the wnt β catenin signaling pathway |
| topic | long noncoding RNA osteocyte bone formation |
| url | https://www.mdpi.com/1422-0067/24/17/13633 |
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