In this study, we aimed to investigate the causal associations of brain structure with bone mineral density (BMD). Based on the genome-wide association study (GWAS) summary statistics of 1 325 brain imaging-derived phenotypes (BIDPs) of brain structure from the UK Biobank and GWAS summary datasets of 5 BMD locations, including the total body, femoral neck, lumbar spine, forearm, and heel from the GEFOS Consortium, linkage disequilibrium score regression (LDSC) was conducted to determine the genetic correlations, and Mendelian randomization (MR) was then performed to explore the causal relationship between the BIDPs and BMD. Several sensitivity analyses were performed to verify the strength and stability of the present MR outcomes. To increase confidence in our findings, we also performed confirmatory MR between BIDPs and osteoporosis. LDSC revealed that 1.93% of BIDPs, with a false discovery rate (FDR) < 0.01, were genetically correlated with BMD. Additionally, we observed that 1.31% of BIDPs exhibited a significant causal relationship with BMD (FDR < 0.01) through MR. Both the LDSC and MR results demonstrated that the BIDPs "Volume of normalized brain," "Volume of gray matter in Left Inferior Frontal Gyrus, pars opercularis," "Volume of Estimated Total Intra Cranial" and "Volume-ratio of brain segmentation/estimated total intracranial" had strong associations with BMD. Interestingly, our results showed that more left BIDPs were causally associated with BMD, especially within and around the left frontal region. In conclusion, a part of the brain structure causally influences BMD, which may provide important perspectives for the prevention of osteoporosis and offer valuable insights for further research on the brain-bone axis.
{"title":"Causal associations of brain structure with bone mineral density: a large-scale genetic correlation study.","authors":"Bin Guo, Chao Wang, Yong Zhu, Zhi Liu, Haitao Long, Zhe Ruan, Zhangyuan Lin, Zhihua Fan, Yusheng Li, Shushan Zhao","doi":"10.1038/s41413-023-00270-z","DOIUrl":"10.1038/s41413-023-00270-z","url":null,"abstract":"<p><p>In this study, we aimed to investigate the causal associations of brain structure with bone mineral density (BMD). Based on the genome-wide association study (GWAS) summary statistics of 1 325 brain imaging-derived phenotypes (BIDPs) of brain structure from the UK Biobank and GWAS summary datasets of 5 BMD locations, including the total body, femoral neck, lumbar spine, forearm, and heel from the GEFOS Consortium, linkage disequilibrium score regression (LDSC) was conducted to determine the genetic correlations, and Mendelian randomization (MR) was then performed to explore the causal relationship between the BIDPs and BMD. Several sensitivity analyses were performed to verify the strength and stability of the present MR outcomes. To increase confidence in our findings, we also performed confirmatory MR between BIDPs and osteoporosis. LDSC revealed that 1.93% of BIDPs, with a false discovery rate (FDR) < 0.01, were genetically correlated with BMD. Additionally, we observed that 1.31% of BIDPs exhibited a significant causal relationship with BMD (FDR < 0.01) through MR. Both the LDSC and MR results demonstrated that the BIDPs \"Volume of normalized brain,\" \"Volume of gray matter in Left Inferior Frontal Gyrus, pars opercularis,\" \"Volume of Estimated Total Intra Cranial\" and \"Volume-ratio of brain segmentation/estimated total intracranial\" had strong associations with BMD. Interestingly, our results showed that more left BIDPs were causally associated with BMD, especially within and around the left frontal region. In conclusion, a part of the brain structure causally influences BMD, which may provide important perspectives for the prevention of osteoporosis and offer valuable insights for further research on the brain-bone axis.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2023-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10359275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10234092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-06DOI: 10.1038/s41413-023-00268-7
Weizhao Lu, Yanhua Duan, Kun Li, Jianfeng Qiu, Zhaoping Cheng
A growing number of studies have demonstrated that the skeleton is an endocrine organ that is involved in glucose metabolism and plays a significant role in human glucose homeostasis. However, there is still a limited understanding of the in vivo glucose uptake and distribution across the human skeleton. To address this issue, we aimed to elucidate the detailed profile of glucose uptake across the skeleton using a total-body positron emission tomography (PET) scanner. A total of 41 healthy participants were recruited. Two of them received a 1-hour dynamic total-body 18F-fluorodeoxyglucose (18F-FDG) PET scan, and all of them received a 10-minute static total-body 18F-FDG PET scan. The net influx rate (Ki) and standardized uptake value normalized by lean body mass (SUL) were calculated as indicators of glucose uptake from the dynamic and static PET data, respectively. The results showed that the vertebrae, hip bone and skull had relatively high Ki and SUL values compared with metabolic organs such as the liver. Both the Ki and SUL were higher in the epiphyseal, metaphyseal and cortical regions of long bones. Moreover, trends associated with age and overweight with glucose uptake (SULmax and SULmean) in bones were uncovered. Overall, these results indicate that the skeleton is a site with significant glucose uptake, and skeletal glucose uptake can be affected by age and dysregulated metabolism.
{"title":"Glucose uptake and distribution across the human skeleton using state-of-the-art total-body PET/CT.","authors":"Weizhao Lu, Yanhua Duan, Kun Li, Jianfeng Qiu, Zhaoping Cheng","doi":"10.1038/s41413-023-00268-7","DOIUrl":"https://doi.org/10.1038/s41413-023-00268-7","url":null,"abstract":"<p><p>A growing number of studies have demonstrated that the skeleton is an endocrine organ that is involved in glucose metabolism and plays a significant role in human glucose homeostasis. However, there is still a limited understanding of the in vivo glucose uptake and distribution across the human skeleton. To address this issue, we aimed to elucidate the detailed profile of glucose uptake across the skeleton using a total-body positron emission tomography (PET) scanner. A total of 41 healthy participants were recruited. Two of them received a 1-hour dynamic total-body <sup>18</sup>F-fluorodeoxyglucose (<sup>18</sup>F-FDG) PET scan, and all of them received a 10-minute static total-body <sup>18</sup>F-FDG PET scan. The net influx rate (K<sub>i</sub>) and standardized uptake value normalized by lean body mass (SUL) were calculated as indicators of glucose uptake from the dynamic and static PET data, respectively. The results showed that the vertebrae, hip bone and skull had relatively high K<sub>i</sub> and SUL values compared with metabolic organs such as the liver. Both the K<sub>i</sub> and SUL were higher in the epiphyseal, metaphyseal and cortical regions of long bones. Moreover, trends associated with age and overweight with glucose uptake (SUL<sub>max</sub> and SUL<sub>mean</sub>) in bones were uncovered. Overall, these results indicate that the skeleton is a site with significant glucose uptake, and skeletal glucose uptake can be affected by age and dysregulated metabolism.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2023-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10322940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9802831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A distinct population of skeletal stem/progenitor cells (SSPCs) has been identified that is indispensable for the maintenance and remodeling of the adult skeleton. However, the cell types that are responsible for age-related bone loss and the characteristic changes in these cells during aging remain to be determined. Here, we established models of premature aging by conditional depletion of Zmpste24 (Z24) in mice and found that Prx1-dependent Z24 deletion, but not Osx-dependent Z24 deletion, caused significant bone loss. However, Acan-associated Z24 depletion caused only trabecular bone loss. Single-cell RNA sequencing (scRNA-seq) revealed that two populations of SSPCs, one that differentiates into trabecular bone cells and another that differentiates into cortical bone cells, were significantly decreased in Prx1-Cre; Z24f/f mice. Both premature SSPC populations exhibited apoptotic signaling pathway activation and decreased mechanosensation. Physical exercise reversed the effects of Z24 depletion on cellular apoptosis, extracellular matrix expression and bone mass. This study identified two populations of SSPCs that are responsible for premature aging-related bone loss. The impairment of mechanosensation in Z24-deficient SSPCs provides new insight into how physical exercise can be used to prevent bone aging.
{"title":"Premature aging of skeletal stem/progenitor cells rather than osteoblasts causes bone loss with decreased mechanosensation.","authors":"Ruici Yang, Dandan Cao, Jinlong Suo, Lingli Zhang, Chunyang Mo, Miaomiao Wang, Ningning Niu, Rui Yue, Weiguo Zou","doi":"10.1038/s41413-023-00269-6","DOIUrl":"https://doi.org/10.1038/s41413-023-00269-6","url":null,"abstract":"<p><p>A distinct population of skeletal stem/progenitor cells (SSPCs) has been identified that is indispensable for the maintenance and remodeling of the adult skeleton. However, the cell types that are responsible for age-related bone loss and the characteristic changes in these cells during aging remain to be determined. Here, we established models of premature aging by conditional depletion of Zmpste24 (Z24) in mice and found that Prx1-dependent Z24 deletion, but not Osx-dependent Z24 deletion, caused significant bone loss. However, Acan-associated Z24 depletion caused only trabecular bone loss. Single-cell RNA sequencing (scRNA-seq) revealed that two populations of SSPCs, one that differentiates into trabecular bone cells and another that differentiates into cortical bone cells, were significantly decreased in Prx1-Cre; Z24<sup>f/f</sup> mice. Both premature SSPC populations exhibited apoptotic signaling pathway activation and decreased mechanosensation. Physical exercise reversed the effects of Z24 depletion on cellular apoptosis, extracellular matrix expression and bone mass. This study identified two populations of SSPCs that are responsible for premature aging-related bone loss. The impairment of mechanosensation in Z24-deficient SSPCs provides new insight into how physical exercise can be used to prevent bone aging.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2023-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10322990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9804170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-29DOI: 10.1038/s41413-023-00273-w
Fei Wei, Zewen Kelvin Tuong, Mahmoud Omer, Christopher Ngo, Jackson Asiatico, Michael Kinzel, Abinaya Sindu Pugazhendhi, Annette R Khaled, Ranajay Ghosh, Melanie Coathup
Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone. Presently, no effective countermeasure exists, and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity. The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy. Our studies revealed that P7C3 repressed ionizing radiation (IR)-induced osteoclastic activity, inhibited adipogenesis, and promoted osteoblastogenesis and mineral deposition in vitro. We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened, osteoporotic bone. However, the administration of P7C3 significantly inhibited osteoclastic activity, lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area, architecture, and mechanical strength. Our findings revealed significant enhancement of cellular macromolecule metabolic processes, myeloid cell differentiation, and the proteins LRP-4, TAGLN, ILK, and Tollip, with downregulation of GDF-3, SH2B1, and CD200. These proteins are key in favoring osteoblast over adipogenic progenitor differentiation, cell matrix interactions, and shape and motility, facilitating inflammatory resolution, and suppressing osteoclastogenesis, potentially via Wnt/β-catenin signaling. A concern was whether P7C3 afforded similar protection to cancer cells. Preliminarily, and remarkably, at the same protective P7C3 dose, a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro. Together, these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy, leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications. Our data uncover a new approach for the prevention of radiation-induced bone damage, and further work is needed to investigate its ability to selectively drive cancer cell death.
{"title":"A novel multifunctional radioprotective strategy using P7C3 as a countermeasure against ionizing radiation-induced bone loss.","authors":"Fei Wei, Zewen Kelvin Tuong, Mahmoud Omer, Christopher Ngo, Jackson Asiatico, Michael Kinzel, Abinaya Sindu Pugazhendhi, Annette R Khaled, Ranajay Ghosh, Melanie Coathup","doi":"10.1038/s41413-023-00273-w","DOIUrl":"https://doi.org/10.1038/s41413-023-00273-w","url":null,"abstract":"<p><p>Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone. Presently, no effective countermeasure exists, and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity. The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy. Our studies revealed that P7C3 repressed ionizing radiation (IR)-induced osteoclastic activity, inhibited adipogenesis, and promoted osteoblastogenesis and mineral deposition in vitro. We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened, osteoporotic bone. However, the administration of P7C3 significantly inhibited osteoclastic activity, lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area, architecture, and mechanical strength. Our findings revealed significant enhancement of cellular macromolecule metabolic processes, myeloid cell differentiation, and the proteins LRP-4, TAGLN, ILK, and Tollip, with downregulation of GDF-3, SH2B1, and CD200. These proteins are key in favoring osteoblast over adipogenic progenitor differentiation, cell matrix interactions, and shape and motility, facilitating inflammatory resolution, and suppressing osteoclastogenesis, potentially via Wnt/β-catenin signaling. A concern was whether P7C3 afforded similar protection to cancer cells. Preliminarily, and remarkably, at the same protective P7C3 dose, a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro. Together, these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy, leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications. Our data uncover a new approach for the prevention of radiation-induced bone damage, and further work is needed to investigate its ability to selectively drive cancer cell death.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2023-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10310858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9746498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Author Correction: Reversal of the diabetic bone signature with anabolic therapies in mice.","authors":"Silvia Marino, Nisreen Akel, Shenyang Li, Meloney Cregor, Meghan Jones, Betiana Perez, Gaston Troncoso, Jomeeka Meeks, Scott Stewart, Amy Y Sato, Intawat Nookaew, Teresita Bellido","doi":"10.1038/s41413-023-00274-9","DOIUrl":"https://doi.org/10.1038/s41413-023-00274-9","url":null,"abstract":"","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10264430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9639373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-09DOI: 10.1038/s41413-023-00264-x
Zhengtian Lyu, Yongfei Hu, Yuming Guo, Dan Liu
The gut microbiota (GM) plays a crucial role in maintaining the overall health and well-being of the host. Recent studies have demonstrated that the GM may significantly influence bone metabolism and degenerative skeletal diseases, such as osteoporosis (OP). Interventions targeting GM modification, including probiotics or antibiotics, have been found to affect bone remodeling. This review provides a comprehensive summary of recent research on the role of GM in regulating bone remodeling and seeks to elucidate the regulatory mechanism from various perspectives, such as the interaction with the immune system, interplay with estrogen or parathyroid hormone (PTH), the impact of GM metabolites, and the effect of extracellular vesicles (EVs). Moreover, this review explores the potential of probiotics as a therapeutic approach for OP. The insights presented may contribute to the development of innovative GM-targeted therapies for OP.
{"title":"Modulation of bone remodeling by the gut microbiota: a new therapy for osteoporosis.","authors":"Zhengtian Lyu, Yongfei Hu, Yuming Guo, Dan Liu","doi":"10.1038/s41413-023-00264-x","DOIUrl":"https://doi.org/10.1038/s41413-023-00264-x","url":null,"abstract":"<p><p>The gut microbiota (GM) plays a crucial role in maintaining the overall health and well-being of the host. Recent studies have demonstrated that the GM may significantly influence bone metabolism and degenerative skeletal diseases, such as osteoporosis (OP). Interventions targeting GM modification, including probiotics or antibiotics, have been found to affect bone remodeling. This review provides a comprehensive summary of recent research on the role of GM in regulating bone remodeling and seeks to elucidate the regulatory mechanism from various perspectives, such as the interaction with the immune system, interplay with estrogen or parathyroid hormone (PTH), the impact of GM metabolites, and the effect of extracellular vesicles (EVs). Moreover, this review explores the potential of probiotics as a therapeutic approach for OP. The insights presented may contribute to the development of innovative GM-targeted therapies for OP.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2023-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10256815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9610899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
As the major cell precursors in osteogenesis, mesenchymal stem cells (MSCs) are indispensable for bone homeostasis and development. However, the primary mechanisms regulating osteogenic differentiation are controversial. Composed of multiple constituent enhancers, super enhancers (SEs) are powerful cis-regulatory elements that identify genes that ensure sequential differentiation. The present study demonstrated that SEs were indispensable for MSC osteogenesis and involved in osteoporosis development. Through integrated analysis, we identified the most common SE-targeted and osteoporosis-related osteogenic gene, ZBTB16. ZBTB16, positively regulated by SEs, promoted MSC osteogenesis but was expressed at lower levels in osteoporosis. Mechanistically, SEs recruited bromodomain containing 4 (BRD4) at the site of ZBTB16, which then bound to RNA polymerase II-associated protein 2 (RPAP2) that transported RNA polymerase II (POL II) into the nucleus. The subsequent synergistic regulation of POL II carboxyterminal domain (CTD) phosphorylation by BRD4 and RPAP2 initiated ZBTB16 transcriptional elongation, which facilitated MSC osteogenesis via the key osteogenic transcription factor SP7. Bone-targeting ZBTB16 overexpression had a therapeutic effect on the decreased bone density and remodeling capacity of Brd4fl/fl Prx1-cre mice and osteoporosis (OP) models. Therefore, our study shows that SEs orchestrate the osteogenesis of MSCs by targeting ZBTB16 expression, which provides an attractive focus and therapeutic target for osteoporosis. Without SEs located on osteogenic genes, BRD4 is not able to bind to osteogenic identity genes due to its closed structure before osteogenesis. During osteogenesis, histones on osteogenic identity genes are acetylated, and OB-gain SEs appear, enabling the binding of BRD4 to the osteogenic identity gene ZBTB16. RPAP2 transports RNA Pol II from the cytoplasm to the nucleus and guides Pol II to target ZBTB16 via recognition of the navigator BRD4 on SEs. After the binding of the RPAP2-Pol II complex to BRD4 on SEs, RPAP2 dephosphorylates Ser5 at the Pol II CTD to terminate the transcriptional pause, and BRD4 phosphorylates Ser2 at the Pol II CTD to initiate transcriptional elongation, which synergistically drives efficient transcription of ZBTB16, ensuring proper osteogenesis. Dysregulation of SE-mediated ZBTB16 expression leads to osteoporosis, and bone-targeting ZBTB16 overexpression is efficient in accelerating bone repair and treating osteoporosis.
间充质干细胞(mesenchymal stem cells, MSCs)作为成骨过程中主要的细胞前体,在骨稳态和发育中起着不可缺少的作用。然而,调控成骨分化的主要机制存在争议。超级增强子由多个成分增强子组成,是一种功能强大的顺式调控元件,可识别确保序列分化的基因。本研究表明,se在MSC成骨过程中不可或缺,并参与骨质疏松症的发生。通过综合分析,我们确定了最常见的se靶向和骨质疏松相关的成骨基因ZBTB16。受SEs正调控的ZBTB16促进MSC成骨,但在骨质疏松症中表达水平较低。从机制上说,se在ZBTB16位点招募含溴结构域4 (BRD4),然后与RNA聚合酶II相关蛋白2 (RPAP2)结合,将RNA聚合酶II (POL II)转运到细胞核中。随后,BRD4和RPAP2协同调控POL II羧基末端结构域(CTD)磷酸化,启动ZBTB16转录延伸,通过关键成骨转录因子SP7促进MSC成骨。骨靶向ZBTB16过表达对Brd4fl/fl Prx1-cre小鼠和骨质疏松症(OP)模型骨密度和重塑能力下降有治疗作用。因此,我们的研究表明,SEs通过靶向ZBTB16的表达来调控MSCs的成骨,这为骨质疏松症的治疗提供了一个有吸引力的焦点和治疗靶点。如果没有位于成骨基因上的se, BRD4在成骨前结构封闭,无法与成骨身份基因结合。成骨过程中,成骨识别基因上的组蛋白乙酰化,OB-gain se出现,使BRD4与成骨识别基因ZBTB16结合。RPAP2将RNA Pol II从细胞质转运到细胞核,并通过识别SEs上的导航BRD4引导Pol II靶向ZBTB16。RPAP2-Pol II复合物在SEs上与BRD4结合后,RPAP2使Pol II CTD上的Ser5去磷酸化以终止转录暂停,BRD4使Pol II CTD上的Ser2磷酸化以启动转录延伸,从而协同驱动ZBTB16的高效转录,确保正常的成骨。se介导的ZBTB16表达失调导致骨质疏松,骨靶向ZBTB16过表达可有效加速骨修复,治疗骨质疏松。
{"title":"Super enhancers targeting ZBTB16 in osteogenesis protect against osteoporosis.","authors":"Wenhui Yu, Zhongyu Xie, Jinteng Li, Jiajie Lin, Zepeng Su, Yunshu Che, Feng Ye, Zhaoqiang Zhang, Peitao Xu, Yipeng Zeng, Xiaojun Xu, Zhikun Li, Pei Feng, Rujia Mi, Yanfeng Wu, Huiyong Shen","doi":"10.1038/s41413-023-00267-8","DOIUrl":"https://doi.org/10.1038/s41413-023-00267-8","url":null,"abstract":"<p><p>As the major cell precursors in osteogenesis, mesenchymal stem cells (MSCs) are indispensable for bone homeostasis and development. However, the primary mechanisms regulating osteogenic differentiation are controversial. Composed of multiple constituent enhancers, super enhancers (SEs) are powerful cis-regulatory elements that identify genes that ensure sequential differentiation. The present study demonstrated that SEs were indispensable for MSC osteogenesis and involved in osteoporosis development. Through integrated analysis, we identified the most common SE-targeted and osteoporosis-related osteogenic gene, ZBTB16. ZBTB16, positively regulated by SEs, promoted MSC osteogenesis but was expressed at lower levels in osteoporosis. Mechanistically, SEs recruited bromodomain containing 4 (BRD4) at the site of ZBTB16, which then bound to RNA polymerase II-associated protein 2 (RPAP2) that transported RNA polymerase II (POL II) into the nucleus. The subsequent synergistic regulation of POL II carboxyterminal domain (CTD) phosphorylation by BRD4 and RPAP2 initiated ZBTB16 transcriptional elongation, which facilitated MSC osteogenesis via the key osteogenic transcription factor SP7. Bone-targeting ZBTB16 overexpression had a therapeutic effect on the decreased bone density and remodeling capacity of Brd4<sup>fl/fl</sup> Prx1-cre mice and osteoporosis (OP) models. Therefore, our study shows that SEs orchestrate the osteogenesis of MSCs by targeting ZBTB16 expression, which provides an attractive focus and therapeutic target for osteoporosis. Without SEs located on osteogenic genes, BRD4 is not able to bind to osteogenic identity genes due to its closed structure before osteogenesis. During osteogenesis, histones on osteogenic identity genes are acetylated, and OB-gain SEs appear, enabling the binding of BRD4 to the osteogenic identity gene ZBTB16. RPAP2 transports RNA Pol II from the cytoplasm to the nucleus and guides Pol II to target ZBTB16 via recognition of the navigator BRD4 on SEs. After the binding of the RPAP2-Pol II complex to BRD4 on SEs, RPAP2 dephosphorylates Ser5 at the Pol II CTD to terminate the transcriptional pause, and BRD4 phosphorylates Ser2 at the Pol II CTD to initiate transcriptional elongation, which synergistically drives efficient transcription of ZBTB16, ensuring proper osteogenesis. Dysregulation of SE-mediated ZBTB16 expression leads to osteoporosis, and bone-targeting ZBTB16 overexpression is efficient in accelerating bone repair and treating osteoporosis.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2023-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10244438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9685985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dysregulated lineage commitment of mesenchymal stem cells (MSCs) contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and osteoporosis. The intrinsic cellular mechanism that regulates MSC commitment remains unclear. Here, we identified Cullin 4B (CUL4B) as a critical regulator of MSC commitment. CUL4B is expressed in bone marrow MSCs (BMSCs) and downregulated with aging in mice and humans. Conditional knockout of Cul4b in MSCs resulted in impaired postnatal skeletal development with low bone mass and reduced bone formation. Moreover, depletion of CUL4B in MSCs aggravated bone loss and marrow adipose accumulation during natural aging or after ovariectomy. In addition, CUL4B deficiency in MSCs reduced bone strength. Mechanistically, CUL4B promoted osteogenesis and inhibited adipogenesis of MSCs by repressing KLF4 and C/EBPδ expression, respectively. The CUL4B complex directly bound to Klf4 and Cebpd and epigenetically repressed their transcription. Collectively, this study reveals CUL4B-mediated epigenetic regulation of the osteogenic or adipogenic commitment of MSCs, which has therapeutic implications in osteoporosis.
{"title":"CUL4B orchestrates mesenchymal stem cell commitment by epigenetically repressing KLF4 and C/EBPδ.","authors":"Ruiqi Yu, Hong Han, Shuxian Chu, Yijun Ding, Shiqi Jin, Yufeng Wang, Wei Jiang, Yuting Liu, Yongxin Zou, Molin Wang, Qiao Liu, Gongping Sun, Baichun Jiang, Yaoqin Gong","doi":"10.1038/s41413-023-00263-y","DOIUrl":"https://doi.org/10.1038/s41413-023-00263-y","url":null,"abstract":"<p><p>Dysregulated lineage commitment of mesenchymal stem cells (MSCs) contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and osteoporosis. The intrinsic cellular mechanism that regulates MSC commitment remains unclear. Here, we identified Cullin 4B (CUL4B) as a critical regulator of MSC commitment. CUL4B is expressed in bone marrow MSCs (BMSCs) and downregulated with aging in mice and humans. Conditional knockout of Cul4b in MSCs resulted in impaired postnatal skeletal development with low bone mass and reduced bone formation. Moreover, depletion of CUL4B in MSCs aggravated bone loss and marrow adipose accumulation during natural aging or after ovariectomy. In addition, CUL4B deficiency in MSCs reduced bone strength. Mechanistically, CUL4B promoted osteogenesis and inhibited adipogenesis of MSCs by repressing KLF4 and C/EBPδ expression, respectively. The CUL4B complex directly bound to Klf4 and Cebpd and epigenetically repressed their transcription. Collectively, this study reveals CUL4B-mediated epigenetic regulation of the osteogenic or adipogenic commitment of MSCs, which has therapeutic implications in osteoporosis.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2023-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9564885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}