Krüppel-like factor 3 inhibition by mutated lncRNA<i>Reg1cp</i>results in human high bone mass syndrome

Yang, Mingzhi; Guo, Qi; Peng, Hui; Xiao, Yuzhong; Xiao, Ye; Huang, Yan; Li, Changjun; Su, Tian; Zhang, Yunlin; Lei, Minxiang; Chen, Huiling; Tong, Jiang; Luo, Xiang‐Hang

doi:10.1084/jem.20181554

Cited by 50 publications

(64 citation statements)

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“…Our previous studies have shown that KLF3 inhibited the expression of JUNB and VEGFA, and further repressed angiogenesis . We also demonstrated that specific knockout of Klf3 in endothelial cells increased the formation of CD31 hi EMCN hi vessels and increased bone formation . Here, we extended our study and confirmed that specific knockout of Klf3 in endothelial cells also could stimulate CD31 hi EMCN hi vessel formation after bone injury and could accelerate bone regeneration.…”

Section: Discussionsupporting

confidence: 85%

“…Chromatin immunoprecipitation-PCR (ChIP-PCR) assays showed that ophiopogonin D treatment affected the binding of KLF3 to the promoter of JUNB. 23 Western blotting also showed increased protein levels of JUNB and VEGFA in HMECs treated with ophiopogonin D, without affect the expression of KLF3 ( Figure 3H). We further confirmed the angiogenesis stimulating function of ophiopogonin D using migration and tube formation assays.…”

Section: Ophiopogonin D Acts As a Klf3 Inhibitor And Promotes Vessementioning

confidence: 90%

“…23 We also identified a natural compound from Radix Ophiopogon japonicus, ophiopogonin D, which acts as a KLF3 inhibitor to abolish the transcriptional repression function of KLF3 and further increase the expression of JUNB and VEGFA in endothelial cells. 23 As expected, we observed that CD31, EMCN, and JUNB and vessel growth factors (VEGFA, VEGFB, PDGFA (platelet derived growth factor subunit A), and PDGFB) transcripts were expressed at higher level in human microvascular endothelial cells (HMECs) treated with ophiopogonin D compared with that in DMSO control treated HMECs ( Figure 3A-G). Chromatin immunoprecipitation-PCR (ChIP-PCR) assays showed that ophiopogonin D treatment affected the binding of KLF3 to the promoter of JUNB.…”

Section: Ophiopogonin D Acts As a Klf3 Inhibitor And Promotes Vessementioning

confidence: 96%

“…We also identified a natural compound, ophiopogonin D, which functions as a KLF3 inhibitor. 23 Administration of ophiopogonin D increased the abundance of CD31 hi Emcn hi vessels and bone formation. 23 In the present study, we expanded our research and demonstrated that ophiopogonin D acts as a KLF3 inhibitor to promote vessel formation and further stimulate bone regeneration in young (3 months old) and middle-aged (12 months old) mice.…”

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confidence: 96%

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Ophiopogonin D promotes bone regeneration by stimulating CD31^hiEMCN^hi vessel formation

Yang

Xiao

et al. 2020

Cell Proliferation

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Objectives CD31hiEMCNhi vessels (CD31, also known as PECAM1 [platelet and endothelial cell adhesion molecule 1]; EMCN, endomucin), which are strongly positive for CD31 and endomucin, couple angiogenesis and osteogenesis. However, the role of CD31hiEMCNhi vessels in bone regeneration remains unknown. In the present study, we investigated the role of CD31hiEMCNhi vessels in the process of bone regeneration. Materials and Methods We used endothelial‐specific Krüppel like factor 3 (Klf3) knockout mice and ophiopogonin D treatment to interfere with CD31hiEMCNhi vessel formation. We constructed a bone regeneration model by surgical ablation of the trabecular bone. Immunofluorescence and micro‐computed tomography (CT) were used to detect CD31hiEMCNhi vessels and bone formation. Results CD31hiEMCNhi vessels participate in the process of bone regeneration, such that endothelial‐specific Klf3 knockout mice showed increased CD31hiEMCNhi vessels and osteoprogenitors in the bone regeneration area, and further accelerated bone formation. We also demonstrated that the natural compound, ophiopogonin D, acts as a KLF3 inhibitor to promote vessels formation both in vitro and in vivo. Administration of ophiopogonin D increased the abundance of CD31hiEmcnhi vessels and accelerated bone healing. Conclusions Our findings confirmed the important role of CD31hiEmcnhi vessels in bone regeneration and provided a new target to treat bone fracture or promote bone regeneration.

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Section: Discussionsupporting

confidence: 85%

Section: Ophiopogonin D Acts As a Klf3 Inhibitor And Promotes Vessementioning

confidence: 90%

Section: Ophiopogonin D Acts As a Klf3 Inhibitor And Promotes Vessementioning

confidence: 96%

mentioning

confidence: 96%

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Ophiopogonin D promotes bone regeneration by stimulating CD31^hiEMCN^hi vessel formation

Yang

Xiao

et al. 2020

Cell Proliferation

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“…Bone homeostasis tightly depends on the balance between bone resorption and bone formation . A perturbation of this balance will lead to some bone metabolic diseases including osteoporosis and osteopetrosis .…”

Section: Introductionmentioning

confidence: 99%

Osteoclastogenesis inhibition by mutated IGSF23 results in human osteopetrosis

et al. 2019

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Objectives Osteopetrosis is a rare inherited skeletal disease characterized by increased bone mineral density due to the loss of osteoclast function or differentiation potential. Materials and Methods The study involved a Chinese patient with osteopetrosis (the proband) and her immediate family members and 180 controls without osteopetrosis. Bone density of the femoral neck, lumbar spine and total body was measured using dual‐energy x‐ray absorptiometry. Osteoclast differentiation by the participants’ peripheral blood mononuclear cells (PBMCs) was investigated using tartrate‐resistant acid phosphatase (TRAP) staining. Osteoblast differentiation was examined with Alizarin Red S staining. Reverse transcription‐quantitative PCR was used to amplify immunoglobulin superfamily member 23 (IGSF23), c‐FOS and nuclear factor of activated T cells 1 (NFATC1). Results We found a homozygous mutation (c.295C>T) in the IGSF23 gene in two osteopetrosis samples. The mutation led to the formation of a stop codon, causing loss of the immunoglobulin‐like domain and the whole transmembrane domain. PBMCs from the proband (IGSF23−/−) exhibited poor ability for differentiating into mature osteoclasts in vitro. Overexpression of IGSF23 rescued the ability of IGSF23−/− PBMCs to differentiate into osteoclasts. Moreover, knockdown of IGSF23 reversed the bone loss in OVX mice by injecting AAV‐shIGSF23 into mice femoral bone marrow cavity. Furthermore, we also found that the IGSF23 mutation led to decreased c‐Fos and NFATC1 expression levels by inhibiting the mitogen‐activated protein kinase signalling pathways. Conclusions IGSF23‐mediated osteoclast differentiation of PBMCs may serve as a potential target in osteoporosis therapy.

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The role of autophagy in bone homeostasis

Guo

Yang

et al. 2021

Journal Cellular Physiology

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Autophagy is an evolutionarily conserved intracellular process and is considered one of the main catabolism pathways. In the process of autophagy, cells are digested nonselectively or selectively to recover nutrients and energy, so it is regarded as an antiaging process. In addition to the essential role of autophagy in cellular homeostasis, autophagy is a stress response mechanism for cell survival. Here, we review recent literature describing the pathway of autophagy and its role in different bone cell types, including osteoblasts, osteoclasts, and osteocytes. Also discussed is the mechanism of autophagy in bone diseases associated with bone homeostasis, including osteoporosis and Paget's disease. Finally, we discuss the application of autophagy regulators in bone diseases. This review aims to introduce autophagy, summarize the understanding of its relevance in bone physiology, and discuss its role and therapeutic potential in the pathogenesis of bone diseases such as osteoporosis.

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Krüppel-like factor 3 inhibition by mutated lncRNAReg1cpresults in human high bone mass syndrome

Cited by 50 publications

References 51 publications

Ophiopogonin D promotes bone regeneration by stimulating CD31^hiEMCN^hi vessel formation

Ophiopogonin D promotes bone regeneration by stimulating CD31^hiEMCN^hi vessel formation

Osteoclastogenesis inhibition by mutated IGSF23 results in human osteopetrosis

The role of autophagy in bone homeostasis

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Krüppel-like factor 3 inhibition by mutated lncRNAReg1cpresults in human high bone mass syndrome

Cited by 50 publications

References 51 publications

Ophiopogonin D promotes bone regeneration by stimulating CD31hiEMCNhi vessel formation

Ophiopogonin D promotes bone regeneration by stimulating CD31hiEMCNhi vessel formation

Osteoclastogenesis inhibition by mutated IGSF23 results in human osteopetrosis

The role of autophagy in bone homeostasis

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Ophiopogonin D promotes bone regeneration by stimulating CD31^hiEMCN^hi vessel formation

Ophiopogonin D promotes bone regeneration by stimulating CD31^hiEMCN^hi vessel formation