Histone demethylase LSD1 is critical for endochondral ossification during bone fracture healing

Sun, Jun; Feng, Heng; Xing, Wenhui; Han, Yujiao; Suo, Jinlong; Yallowitz, Alisha R.; Qian, Nan; Shi, Yujiang Geno; Greenblatt, Matthew B.; Zou, Weiguo

doi:10.1126/sciadv.aaz1410

Cited by 19 publications

(17 citation statements)

References 44 publications

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“…Bone is a highly vascularized organ. During bone modeling and remodeling, bone formation and vessel angiogenesis are inseparable and coupled (Peng et al, 2020;Sun et al, 2020). CD31 hi EMCN hi or type H vessels have proven to be a specific endothelial feature identified in the murine skeletal system and exhibit potent osteogenic function (Wang et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

miR-29cb2 promotes angiogenesis and osteogenesis by inhibiting HIF-3α in bone

Ouyang

Sun

et al. 2022

iScience

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Coordination between osteogenesis and angiogenesis is required for bone homeostasis. Here, we show that miR-29cb2 is a bone-specific miRNA and plays critical roles on angiogenesis-osteogenesis coupling during bone remodeling. Mice with deletion of miR-29cb2 exhibit osteopenic phenotypes and osteoblast impairment, accompanied by pronounced decreases in specific H vessels. The decrease in bone miR-29cb2 was associated with pathological ovariectomy stimuli. Mechanistically, hypoxia-inducible factor (HIF)-3a, as a target for miR-29cb2, inhibits HIF-1a activity by competitively bonding with HIF-1b. Notably, miR-29cb2 in peripheral blood (PB) nearly is undetectable in sham and significantly increases in ovariectomy mice. Further evaluation from osteoporosis patients demonstrates similar signatures. ROC analysis shows miR-29cb2 in PB has higher sensitivity and specificity for diagnosing osteoporosis when compared with four clinical biomarkers. Collectively, these findings reveal that miR-29cb2 is essential for bone remodeling by inhibiting HIF-3a and elevated bone-specific miR-29cb2 in PB, which may be a promising biomarker for bone loss

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Section: Discussionmentioning

confidence: 99%

miR-29cb2 promotes angiogenesis and osteogenesis by inhibiting HIF-3α in bone

Ouyang

Sun

et al. 2022

iScience

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“…A genome-wide methylation analysis among osteoporotic and osteoarthritic populations identified unique methylation sites, suggesting a role of epigenetic regulation in the two bone pathologies [78]. A histone lysine-specific demethylase, LSD1 has been reported to be essential for endochondral ossification during fracture healing [79]. LSD1 also regulates bone accrual by controlling the expression of Wnt7b and BMP2 [80].…”

Section: Epigenetic Alterationsmentioning

confidence: 99%

Skeletal Aging and Osteoporosis: Mechanisms and Therapeutics

Chandra

Rajawat

2021

IJMS

117

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Bone is a dynamic organ maintained by tightly regulated mechanisms. With old age, bone homeostasis, which is maintained by an intricate balance between bone formation and bone resorption, undergoes deregulation. Oxidative stress-induced DNA damage, cellular apoptosis, and cellular senescence are all responsible for this tissue dysfunction and the imbalance in the bone homeostasis. These cellular mechanisms have become a target for therapeutics to treat age-related osteoporosis. Genetic mouse models have shown the importance of senescent cell clearance in alleviating age-related osteoporosis. Furthermore, we and others have shown that targeting cellular senescence pharmacologically was an effective tool to alleviate age- and radiation-induced osteoporosis. Senescent cells also have an altered secretome known as the senescence associated secretory phenotype (SASP), which may have autocrine, paracrine, or endocrine function. The current review discusses the current and potential pathways which lead to a senescence profile in an aged skeleton and how bone homeostasis is affected during age-related osteoporosis. The review has also discussed existing therapeutics for the treatment of osteoporosis and rationalizes for novel therapeutic options based on cellular senescence and the SASP as an underlying pathogenesis of an aging bone.

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“…Within the MAO family, LSD1 has been extensively studied in stem cell biology and development [ 43 , 44 ], and has also been implicated in the differentiation of a number of cell types including neurons [ 45 , 46 ], adipocytes [ 47 ], chondrocytes [ 48 , 49 ] and hematopoietic cells [ 50 , 51 ]. In adipose tissue, LSD1 plays a major role in thermogenesis and in regulating brown adipocyte phenotype [ 52 , 53 ].…”

Section: Introductionmentioning

confidence: 99%

Lysine-Specific Demethylase 1 (LSD1) epigenetically controls osteoblast differentiation

et al. 2022

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Epigenetic mechanisms regulate osteogenic lineage differentiation of mesenchymal stromal cells. Histone methylation is controlled by multiple lysine demethylases and is an important step in controlling local chromatin structure and gene expression. Here, we show that the lysine-specific histone demethylase Kdm1A/Lsd1 is abundantly expressed in osteoblasts and that its suppression impairs osteoblast differentiation and bone nodule formation in vitro. Although Lsd1 knockdown did not affect global H3K4 methylation levels, genome-wide ChIP-Seq analysis revealed high levels of Lsd1 at gene promoters and its binding was associated with di- and tri-methylation of histone 3 at lysine 4 (H3K4me2 and H3K4me3). Lsd1 binding sites in osteoblastic cells were enriched for the Runx2 consensus motif suggesting a functional link between the two proteins. Importantly, inhibition of Lsd1 activity decreased osteoblast activity in vivo. In support, mesenchymal-targeted knockdown of Lsd1 led to decreased osteoblast activity and disrupted primary spongiosa ossification and reorganization in vivo. Together, our studies demonstrate that Lsd1 occupies Runx2-binding cites at H3K4me2 and H3K4me3 and its activity is required for proper bone formation.

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Histone demethylase LSD1 is critical for endochondral ossification during bone fracture healing

Cited by 19 publications

References 44 publications

miR-29cb2 promotes angiogenesis and osteogenesis by inhibiting HIF-3α in bone

miR-29cb2 promotes angiogenesis and osteogenesis by inhibiting HIF-3α in bone

Skeletal Aging and Osteoporosis: Mechanisms and Therapeutics

Lysine-Specific Demethylase 1 (LSD1) epigenetically controls osteoblast differentiation

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