Lysine-specific demethylase 1 inhibitor rescues the osteogenic ability of mesenchymal stem cells under osteoporotic conditions by modulating H3K4 methylation

Lv, Longwei; Ge, Wenshu; Liu, Yunsong; Lai, Guanyou; Líu, Hao; Li, Wenyue; Zhou, Yongsheng

doi:10.1038/boneres.2016.37

Cited by 43 publications

(44 citation statements)

References 48 publications

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“…It has been reported that interventions entailing H3K4 modification may hold promise for the prevention of osteoporosis. Certain inhibitors of H3K4 demethylases were reported to upregulate H3K4 methylation at the osteogenesis-related genes in BMSCs of osteoporotic mice, thus promoting the osteogenic capability of BMSCs and rescuing bone loss [39,40]. In our research, both in vitro and ex vivo, we found that Ash1l promotes C3 cells osteogenesis.…”

Section: Discussionsupporting

confidence: 53%

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Epigenetic Control of Mesenchymal Stem Cell Fate Decision via Histone Methyltransferase Ash1l

Yin

Wang

et al. 2018

Stem Cells

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Previous research indicates that knocking out absent, small, or homeotic-like (Ash1l) in mice, a histone 3 lysine 4 (H3K4) trimethyltransferase, can result in arthritis with more severe cartilage and bone destruction. Research has documented the essential role of Ash1l in stem cell fate decision such as hematopoietic stem cells and the progenitors of keratinocytes. Following up on those insights, our research seeks to document the function of Ash1l in skeletal formation, specifically whether it controls the fate decision of mesenchymal progenitor cells. Our findings indicate that in osteoporotic bones, Ash1l was significantly decreased, indicating a positive correlation between bone mass and the expression of Ash1l. Silencing of Ash1l that had been markedly upregulated in differentiated C3H10T1/2 (C3) cells hampered osteogenesis and chondrogenesis but promoted adipogenesis. Consistently, overexpression of an Ash1l SET domain-containing fragment 3 rather than Ash1lΔN promoted osteogenic and chondrogenic differentiation of C3 cells and simultaneously inhibited adipogenic differentiation. This indicates that the role of Ash1l in regulating the differentiation of C3 cells is linked to its histone methyltransferase activity. Subcutaneous ex vivo transplantation experiments confirmed the role of Ash1l in the promotion of osteogenesis. Further experiments proved that Ash1l can epigenetically affect the expression of essential osteogenic and chondrogenic transcription factors. It exerts this impact via modifications in the enrichment of H3K4me3 on their promoter regions. Considering the promotional action of Ash1l on bone, it could potentially prompt new therapeutic strategy to promote osteogenesis. STEM CELLS 2019; 37:115-127 SIGNIFICANCE STATEMENTThe authors' research first discovered that Ash1l can epigenetically affect the expression of essential osteogenic and chondrogenic transcription factors via modifications in the enrichment of H3K4me3 on their promoter regions. These findings helped to further understand the role of Ash1l in the epigenetic regulation of C3H10T1/2 MSCs differentiation, which also makes it potential therapeutic target of bone diseases. Considering the promotional action of Ash1l on bone, it could potentially prompt new therapeutic strategy to promote osteogenesis.

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Section: Discussionsupporting

confidence: 53%

“…These findings are consistent with previous reports. In one relevant study, the total level of H3K4me3 was markedly decreased in BMSCs of OVX mice [39]. In Ras-induced senescence of IMR90 cells and in the astrocytes of aging rats, researchers detected a lower level of H3K4me3 compared with their counterparts [41,42].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Control of Mesenchymal Stem Cell Fate Decision via Histone Methyltransferase Ash1l

Yin

Wang

et al. 2018

Stem Cells

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“…Experiments using in vivo collagen scaffolds infused with hASCs implanted subcutaneously in nude mice showed that scaffolds with LSD1‐knockdown hASCs exhibited increased density and ossification compared with scrambled controls . Further, treatment with the LSD1 inhibitor pargyline helped restore the osteogenic capacity of ex vivo expanded BMSCs from aged osteoporotic mice and/or OVX mouse models . Our results demonstrated that MM cocultured with BMSCs enhanced the recruitment of LSD1 to epigenetically suppress Runx2 expression and the differentiation potential of OB progenitors .…”

Section: Epigenetic Targeting As Treatment Of Mmbdmentioning

confidence: 67%

“…Several studies reported that LSD1 inhibits osteogenic and supports adipogenic differentiation . LSD1 inhibitors, pargyline and CBB1007, have been shown to enhance alkaline phosphatase activity and extracellular matrix mineralization by hASCs without apparent cellular toxicity . Further analysis showed that LSD1i rescued osteogenic differentiation by enhancing the dimethylation level of H3K4 at the promoter regions of osteogenesis‐related genes .…”

Section: Epigenetic Targeting As Treatment Of Mmbdmentioning

confidence: 99%

“…LSD1 inhibitors, pargyline and CBB1007, have been shown to enhance alkaline phosphatase activity and extracellular matrix mineralization by hASCs without apparent cellular toxicity . Further analysis showed that LSD1i rescued osteogenic differentiation by enhancing the dimethylation level of H3K4 at the promoter regions of osteogenesis‐related genes . Experiments using in vivo collagen scaffolds infused with hASCs implanted subcutaneously in nude mice showed that scaffolds with LSD1‐knockdown hASCs exhibited increased density and ossification compared with scrambled controls .…”

Section: Epigenetic Targeting As Treatment Of Mmbdmentioning

confidence: 99%

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Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

2019

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Multiple myeloma (MM) bone disease is characterized by the development of osteolytic lesions, which cause severe complications affecting the morbidity, mortality, and treatment of myeloma patients. Myeloma tumors seeded within the bone microenvironment promote hyperactivation of osteoclasts and suppression of osteoblast differentiation. Because of this prolonged suppression of bone marrow stromal cells’ (BMSCs) differentiation into functioning osteoblasts, bone lesions in patients persist even in the absence of active disease. Current antiresorptive therapy provides insufficient bone anabolic effects to reliably repair MM lesions. It has become widely accepted that myeloma‐exposed BMSCs have an altered phenotype with pro‐inflammatory, immune‐modulatory, anti‐osteogenic, and pro‐adipogenic properties. In this review, we focus on the role of epigenetic‐based modalities in the establishment and maintenance of myeloma‐induced suppression of osteogenic commitment of BMSCs. We will focus on recent studies demonstrating the involvement of chromatin‐modifying enzymes in transcriptional repression of osteogenic genes in MM‐BMSCs. We will further address the epigenetic plasticity in the differentiation commitment of osteoprogenitor cells and assess the involvement of chromatin modifiers in MSC‐lineage switching from osteogenic to adipogenic in the context of the inflammatory myeloma microenvironment. Lastly, we will discuss the potential of employing small molecule epigenetic inhibitors currently used in the MM research as therapeutics and bone anabolic agents in the prevention or repair of osteolytic lesions in MM. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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MiR‐137 knockdown promotes the osteogenic differentiation of human adipose‐derived stem cells via the LSD1/BMP2/SMAD4 signaling network

Fan

Wang

et al. 2019

Journal Cellular Physiology

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MicroRNAs are a group of endogenous regulators that participate in several cellular physiological processes. However, the role of miR-137 in the osteogenic differentiation of human adipose-derived stem cells (hASCs) has not been reported. This study verified a general downward trend in miR-137 expression during the osteogenic differentiation of hASCs. MiR-137 knockdown promoted the osteogenesis of hASCs in vitro and in vivo. Mechanistically, inhibition of miR-137 activated the bone morphogenetic protein 2 (BMP2)-mothers against the decapentaplegic homolog 4 (SMAD4) pathway, whereas repressed lysine-specific histone demethylase 1 (LSD1), which was confirmed as a negative regulator of osteogenesis in our previous studies. Furthermore, LSD1 knockdown enhanced the expression of BMP2 and SMAD4, suggesting the coordination of LSD1 in the osteogenic regulation of miR-137. This study indicated that miR-137 negatively regulated the osteogenic differentiation of hASCs via the LSD1/BMP2/SMAD4 signaling network, revealing a new potential therapeutic target of hASC-based bone tissue engineering.

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Lysine-specific demethylase 1 inhibitor rescues the osteogenic ability of mesenchymal stem cells under osteoporotic conditions by modulating H3K4 methylation

Cited by 43 publications

References 48 publications

Epigenetic Control of Mesenchymal Stem Cell Fate Decision via Histone Methyltransferase Ash1l

Epigenetic Control of Mesenchymal Stem Cell Fate Decision via Histone Methyltransferase Ash1l

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

MiR‐137 knockdown promotes the osteogenic differentiation of human adipose‐derived stem cells via the LSD1/BMP2/SMAD4 signaling network

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