Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow
Abstract Excessive bone marrow adipocytes (BMAds) accumulation often occurs under diverse pathophysiological conditions associated with bone deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency pr...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-05-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-48255-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861848148017152 |
|---|---|
| author | Tongling Huang Zhaocheng Lu Zihui Wang Lixin Cheng Lu Gao Jun Gao Ning Zhang Chang-An Geng Xiaoli Zhao Huaiyu Wang Chi-Wai Wong Kelvin W. K. Yeung Haobo Pan William Weijia Lu Min Guan |
| author_facet | Tongling Huang Zhaocheng Lu Zihui Wang Lixin Cheng Lu Gao Jun Gao Ning Zhang Chang-An Geng Xiaoli Zhao Huaiyu Wang Chi-Wai Wong Kelvin W. K. Yeung Haobo Pan William Weijia Lu Min Guan |
| author_sort | Tongling Huang |
| collection | DOAJ |
| description | Abstract Excessive bone marrow adipocytes (BMAds) accumulation often occurs under diverse pathophysiological conditions associated with bone deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich bone marrow upon estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); yet positively modulates leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased leptin secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu. |
| format | Article |
| id | doaj-art-da0a9fae7c5c43eb81af269fd294bb66 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-da0a9fae7c5c43eb81af269fd294bb662025-02-09T12:43:49ZengNature PortfolioNature Communications2041-17232024-05-0115112010.1038/s41467-024-48255-8Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrowTongling Huang0Zhaocheng Lu1Zihui Wang2Lixin Cheng3Lu Gao4Jun Gao5Ning Zhang6Chang-An Geng7Xiaoli Zhao8Huaiyu Wang9Chi-Wai Wong10Kelvin W. K. Yeung11Haobo Pan12William Weijia Lu13Min Guan14Research Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesResearch Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesResearch Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesGuangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s HospitalResearch Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesResearch Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesNeuroscience Center, Shantou University Medical CollegeState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of SciencesResearch Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesResearch Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesGuangzhou Huazhen BiosciencesDepartment of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong KongResearch Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesFaculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesResearch Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesAbstract Excessive bone marrow adipocytes (BMAds) accumulation often occurs under diverse pathophysiological conditions associated with bone deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich bone marrow upon estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); yet positively modulates leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased leptin secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu.https://doi.org/10.1038/s41467-024-48255-8 |
| spellingShingle | Tongling Huang Zhaocheng Lu Zihui Wang Lixin Cheng Lu Gao Jun Gao Ning Zhang Chang-An Geng Xiaoli Zhao Huaiyu Wang Chi-Wai Wong Kelvin W. K. Yeung Haobo Pan William Weijia Lu Min Guan Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow Nature Communications |
| title | Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow |
| title_full | Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow |
| title_fullStr | Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow |
| title_full_unstemmed | Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow |
| title_short | Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow |
| title_sort | targeting adipocyte esrra promotes osteogenesis and vascular formation in adipocyte rich bone marrow |
| url | https://doi.org/10.1038/s41467-024-48255-8 |
| work_keys_str_mv | AT tonglinghuang targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT zhaochenglu targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT zihuiwang targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT lixincheng targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT lugao targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT jungao targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT ningzhang targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT changangeng targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT xiaolizhao targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT huaiyuwang targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT chiwaiwong targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT kelvinwkyeung targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT haobopan targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT williamweijialu targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow AT minguan targetingadipocyteesrrapromotesosteogenesisandvascularformationinadipocyterichbonemarrow |