JOURNAL OF BONE AND MINERAL RESEARCH
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2025
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IF 5.9
Liu Qian,Gan Ying,Hu Xingli,Liu Wei,Liao Xiaoxia,Zhang Jingyun,Li Xiaoxia,Zhou Jie,Wang Baoli
Lysine demethylase 6B (KDM6B) plays a role in regulating osteoblast differentiation and fetal bone ossification. Nevertheless, its involvement in regulating postnatal bone homeostasis and bone mass accrual remains unclear. In this study, we generated mice lacking Kdm6b gene specifically in mesenchyme and osteoprogenitor cells using a conditional strategy. The adult mice of both mutant strains had decreased cancellous bone mass. The absence of Kdm6b in mesenchyme led to decreased numbers of osteoblasts and osteoclasts, increased marrow adipocytes, as well as repressed bone formation and resorption. Additionally, Kdm6b-deficient bone marrow stromal cells (BMSCs) displayed impaired osteogenic differentiation and exerted an inhibitory effect on osteoclastogenesis. RNA-seq combined with gene expression analysis uncovered downregulation of collagen triple helix repeat containing 1 (CTHRC1) and a lower receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) ratio in BMSCs of the mutant mice. Further mechanistic explorations demonstrated that KDM6B epigenetically upregulated CTHRC1 expression by removing the repressive H3K27me3 mark from its promoter, thereby triggering PKCδ/MAPKs signaling to facilitate osteoblast differentiation. CTHRC1 was able to mitigate the dysregulated osteogenic and adipogenic differentiation induced by Kdm6b deficiency. This study provides evidence that KDM6B regulates postnatal bone homeostasis through balancing osteoblast and osteoclast differentiation. Given its predominant promotion of osteoblastic bone formation over osteoclastic bone resorption, KDM6B tends to promote postnatal bone mass accrual.
研究领域:
分子生物学
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骨骼发育
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Wenkai Yu,Xinyu Li,Chan Zhang,Pengpeng Niu,Jinghao Wu,Wenjun He,Kai Gao,Yuming Xu,Yusheng Li
Cerebral amyloid angiopathy (CAA) is a neurological disorder in the elderly, involving the deposition of vascular amyloid-β (Aβ). Sleep deprivation (SD) causes memory deficits during CAA. Lysine specific demethylase 6B (KDM6B) is a histone H3 lysine 27-specific demethylase associated with neuronal injury and inflammation. However, the role of KDM6B in CAA has yet to be studied. In the current study, the multi-platform over-water method was used to induce chronic SD in APP/PS1 mice. Pathological analysis revealed that SD exacerbated vascular lesions in this model, as manifested by extensive formation of Aβ-positive deposits. In addition, SD led to a significant increase in the expression of KDM6B in the cerebral cortex of APP/PS1 mice. Next, the effect of KDM6B on CAA progression was explored through loss of function. Further experiments illustrated that KDM6B knockdown diminished SD-induced memory impairment, neuronal injury and vascular lesions in vivo . Additionally, isolated primary cortical neurons were treated with 10 µM Aβ 1-42 for 48 h to induce the cell model. As expected, knockdown of KDM6B inhibited the Aβ 1-42 -induced cytotoxicity in primary neurons. Mechanistically, our results demonstrated that KDM6B knockdown downregulated poly (ADP-ribose) polymerase16 (PARP16) expression by increasing trimethylated lysine 27 on histone 3 (H3K27me3) levels, indicating that KDM6B epigenetically regulated PARP16 expression. Function recovery experiment results further proved that PARP16 overexpression negated the effect of KDM6B knockdown on Aβ 1-42 -induced cytotoxicity. Overall, our findings uncover an unanticipated role of KDM6B in CAA, and KDM6B may serve as a potential therapeutic target for CAA. Abbreviations: CAA, cerebral amyloid angiopathy; Aβ, amyloid-β; SD, sleep deprivation; KDM6B, lysine specific demethylase 6B; AD, Alzheimer’s disease; H3K27me3, trimethylated lysine 27 on histone 3; PARP16, poly (ADP-ribose) polymerase16; AAV2, adeno-associated virus 2; CHIP, chromatin immunoprecipitation; ANOVA, one-way analysis of variance.
研究领域:
神经科学
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分子生物学
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病理学
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药理学
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DOI
PubMed
高影响因子
MOLECULAR MEDICINE
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2022
·Vol. 28
·期 1
·1-14
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IF 6.376
Zhao Fei,Ke Jinjing,Pan Wensheng,Pan Hanghai,Shen Miao
Background The increasing incidence of non-alcoholic fatty liver disease (NAFLD) has been reported worldwide, which urges understanding of its pathogenesis and development of more effective therapeutical methods for this chronic disease. In this study, we aimed to investigate the effects of a LIM homeodomain transcription factor, islet1 (ISL1) on NAFLD. Methods Male C57BL/6J mice were fed with a diet high in fat content to produce NAFLD models. These models were then treated with overexpressed ISL1 (oe-ISL1), oe-Lysine-specific demethylase 6B (KDM6B), oe-SNAI1, or short hairpin RNA against SNAI1. We assessed triglyceride and cholesterol contents in the plasma and liver tissues and determined the expressions of ISL1, KDM6B and SNAI1 in liver tissues. Moreover, the in vitro model of lipid accumulation was constructed using fatty acids to explore the in vitro effect of ISL1/KDM6B/SNAI1 in NAFLD. Results The results showed that the expressions of ISL1, KDM6B, and SNAI1 where decreased, but contents of triglyceride and cholesterol increased in mice exposed to high-fat diet. ISL1 inhibited lipogenesis and promoted lipolysis and exhibited a synergizing effect with KDM6B to upregulate the expression of SNAI1. Moreover, both KDM6B and SNAI1 could inhibit lipogenesis and induce lipolysis. Importantly, the therapeutic effects of ISL1 on in vitro model of lipid accumulations was also confirmed through the modulation of KDM6B and SNAI1. Conclusions Taken together, these findings highlighted that ISL1 effectively ameliorated NAFLD by inducing the expressions of KDM6B and SNAI1, which might be a promising drug for the treatment of NAFLD.
研究领域:
分子生物学
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肝病学
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转化医学
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DOI
PubMed
高影响因子
ACS Nano
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2023
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IF 17.1
Lang Chen,Chenyan Yu,Wanting Xu,Yuan Xiong,Peng Cheng,Ze Lin,Zhenhe Zhang,Leonard Knoedler,Adriana C. Panayi,Samuel Knoedler,Junqing Wang,Bobin Mi,Guohui Liu
Ongoing research has highlighted the significance of the cross-play of macrophages and mesenchymal stem cells (MSCs). Lysine-specific demethylase 6B (KDM6B) has been shown to control osteogenic differentiation of MSCs by depleting trimethylated histone 3 lysine 27 (H3K27me3). However, to date, the role of KDM6B in bone marrow-derived macrophages (BMDMs) remains controversial. Here, a chromatin immunoprecipitation assay (ChIP) proved that KDM6B derived from osteogenic-induced BMSCs could bind to the promoter region of BMDMs’ brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1) gene in a coculture system and activate BMAL1. Transcriptome sequencing and experiments in vitro showed that the overexpression of BMAL1 in BMDM could inhibit the TLR2/NF-κB signaling pathway, reduce pyroptosis, and decrease the M1/M2 ratio, thereby promoting osteogenic differentiation of BMSCs. Furthermore, bone and macrophage dual-targeted GSK-J4 (KDM6B inhibitor)-loaded nanodiscs were synthesized via binding SDSSD-apoA-1 peptide analogs (APA) peptide, which indirectly proved the critical role of KDM6B in osteogenesis in vivo. Overall, we demonstrated that KDM6B serves as a positive circulation trigger during osteogenic differentiation by decreasing the ratio of M1/M2 both in vitro and in vivo. Collectively, these results provide insight into basic research in the field of osteoporosis and bone repair.
研究领域:
干细胞生物学
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免疫学
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骨生物学
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分子生物学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
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