Parathyroid Hormone Administration Improves Bone Marrow Microenvironment and Partially Rescues Haematopoietic Defects in Bmi1-Null Mice

Lu, Ruinan; Wang, Qian; Han, Yongli; Li, Jianyong; Yang, Xiang-Jiao; Miao, Dengshun

doi:10.1371/journal.pone.0093864

Cited by 14 publications

(15 citation statements)

References 44 publications

(70 reference statements)

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“…VC is an actively regulated process that is similar to osteogenesis (25,26). BMP2, a member of the transforming growth factor-β superfamily, regulates osteoblast differentiation and bone formation (27).…”

Section: Discussionmentioning

confidence: 99%

Parathyroid hormone promotes osteoblastic differentiation of endothelial cells via the extracellular signal‑regulated protein kinase 1/2 and nuclear factor‑κB signaling pathways

Cheng

Ling³

et al. 2017

Exp Ther Med

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Abstract. Vascular calcification (VC) occurs in patients with chronic kidney disease (CKD) and contributes to cardiovascular dysfunction and mortality. Parathyroid hormone (PTH) is a crucial regulator of VC. High PTH serum levels constitute as a major risk factor for patients with CKD. However, the effect and mechanism of PTH on osteoblastic differentiation in endothelial cells have not been fully elucidated. In the present study, the role of PTH in VC was investigated using an in vitro calcification model. Endothelial cells were stimulated with PTH in the femto-to picomolar range. As determined by western blot analysis and ELISA, osteoblastic differentiation, as indicated by the BMP2 marker, occurred with maximum effect at 1x10 -10 mmol/l PTH. The results indicate that PTH promotes osteoblastic differentiation of endothelial cells, as demonstrated by the increased expression of bone morphogenetic protein (BMP) 2 and BMP4. In addition, western blot analysis revealed that PTH activated the extracellular signal-regulated protein kinase (Erk)1/2 and nuclear factor (NF)-κB signaling pathways. However, reverse transcription-quantitative polymerase chain reaction demonstrated that inhibitors specific to Erk1/2 and NF-κB eradicated the effect of PTH treatment on BMP2, BMP4, ALP and RUNX2 expression. These results demonstrate that PTH promotes the osteoblastic differentiation of endothelial cells via the Erk1/2 and NF-κB signaling pathways, which suggests a potential role of PTH in the promotion of VC. These findings provide an insight into the association between PTH and cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Parathyroid hormone promotes osteoblastic differentiation of endothelial cells via the extracellular signal‑regulated protein kinase 1/2 and nuclear factor‑κB signaling pathways

Cheng

Ling³

et al. 2017

Exp Ther Med

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“…In this context, PTH 1-34 administration partially rescued hematopoietic defects in Bmi 1-null mice and reestablished the HSC niche microenvironment. Furthermore, PTH partially reversed the premature osteoporosis that occurs in the Bmi 1 knockout mice [64]. These results highlight the many ways PTH maintains niche functionality through MSC and HSC interdependency.…”

Section: The Role Of Pth In Hsc Niche Regulation Pth Influences Hscs mentioning

confidence: 64%

Role of PTH in Bone Marrow Niche and HSC Regulation

et al. 2017

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Purpose of Review. The bone marrow microenvironment hosts a multicellular complex that is extraordinary in its interdependence and function. The composite machinery within the axial and long bones is involved in the homing, maintenance, differentiation, and egress of hematopoietic/ progenitors stem cells (HSCS) as well as mesenchymal/ stromal stem cells (MSCs) that dwell in specific anatomical areas inside the marrow space, described as niches. The need for more efficient hematopoietic stem cell transplantation protocols and bonemarrow manipulation techniques has motivated scientists to identify effective niche regulators such as the parathyroid hormone (PTH). Recent Findings PTH treatment is increasingly used with promising outcomes in autologous and allogeneic transplantation of HSCs, because PTH operates as a significant mediator in HSC engraftment, expansion, and mobilization. In addition to the well-established anti-osteoporotic effect of PTH,\ud there is evidence that it may also coordinate hematopoietic stem cell activities.\ud Summary. This report provides up-to-date information about PTH action within marrow niches and highlights the importance of this hormone in the behavior of hematopoietic elements in the bone marrow

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“…Future studies may provide further insights into the precise role of the FANCD2-FANCI heterodimer in resolving the R-loop-mediated replication stresses. Lastly, BMI1 knockout mice display significant defects in the hematopoietic system and bone marrow development (56, 57), a phenotype reminiscent of the Fanconi Anemia pathway deficiency. Although the phenotype could be majorly contributed by de-repression of BMI1 target genes (e.g.…”

Section: Discussionmentioning

confidence: 99%

Transcription-replication conflicts as a source of common fragile site instability caused by BMI1-RNF2 deficiency

Sanchez

Vivo

Tonzi

et al. 2019

Preprint

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Common fragile sites (CFSs) are breakage-prone genomic loci, and are considered to be hotspots for genomic rearrangements frequently observed in cancers. Understanding the underlying mechanisms for CFS instability will lead to better insight on cancer etiology. Here we show that Polycomb group proteins BMI1 and RNF2 are suppressors of transcription-replication conflicts (TRCs) and CFS instability. Cells depleted of BMI1 or RNF2 showed slower replication forks and elevated fork stalling. These phenotypes are associated with increase occupancy of RNA Pol II (RNAPII) at CFSs, suggesting that the BMI1-RNF2 complex regulate RNAPII elongation at these fragile regions. Using proximity ligase assays, we showed that depleting BMI1 or RNF2 causes increased associations between RNAPII with EdU-labeled nascent forks and replisomes, suggesting increased TRC incidences. Increased occupancy of a fork protective factor FANCD2 and R-loop resolvase RNH1 at CFSs are observed in RNF2 CRISPR-KO cells, which are consistent with increased transcription-associated replication stress in RNF2-deficient cells. Depleting FANCD2 or FANCI proteins further increased genomic instability and cell death of the RNF2-deficient cells, suggesting that in the absence of RNF2, cells depend on these fork-protective factors for survival. These data suggest that the Polycomb proteins have non-canonical roles in suppressing TRC and preserving genomic integrity.Author summaryIncreasing evidence suggest that instabilities at common fragile sites (CFSs), breakage-prone genomic loci, may be source of genomic aberration seen in cancer cells. Among the proposed mechanisms that can cause CFSs instabilities is the conflict between transcription and replication, and the mechanisms or factors that resolve the possible conflicts are only beginning to be understood. Here we found that deficiency in the Polycomb group proteins BMI1 or RNF2 leads to the CFS instability, and is associated with transcription-associated replication fork stresses. We further found that in the absence of RNF2, cells depend on the Fanconi Anemia fork-protective proteins for genome maintenance and survival. These results underscore that the Polycomb proteins are important for genome maintenance.

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Parathyroid Hormone Administration Improves Bone Marrow Microenvironment and Partially Rescues Haematopoietic Defects in Bmi1-Null Mice

Cited by 14 publications

References 44 publications

Parathyroid hormone promotes osteoblastic differentiation of endothelial cells via the extracellular signal‑regulated protein kinase 1/2 and nuclear factor‑κB signaling pathways

Parathyroid hormone promotes osteoblastic differentiation of endothelial cells via the extracellular signal‑regulated protein kinase 1/2 and nuclear factor‑κB signaling pathways

Role of PTH in Bone Marrow Niche and HSC Regulation

Transcription-replication conflicts as a source of common fragile site instability caused by BMI1-RNF2 deficiency

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