Stepwise cell fate decision pathways during osteoclastogenesis at single-cell resolution

Tsukasaki, Masayuki; Huynh, Nam Cong-Nhat; Okamoto, Kazuo; Muro, Ryunosuke; Terashima, Asuka; Kurikawa, Yoshitaka; Komatsu, Noriko; Pluemsakunthai, Warunee; Nitta, Takeshi; Abe, Takaya; Kanazawa, Hiroshi; Okamura, Tadashi; Sakai, Mashito; Matsukawa, Toshiya; Matsumoto, Michihiro; Kobayashi, Yasuhiro; Penninger, Josef; Takayanagi, Hiroshi

doi:10.1038/s42255-020-00318-y

Cited by 79 publications

(80 citation statements)

References 57 publications

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“…Single-cell RNA sequencing of in vitro differentiated osteoclasts from bone marrow cells has provided more detailed insights into the various stages of osteoclast lineage commitment. The most immature committed monocytic precursor that is characterized by high expression of M-CSFR, RANK, CX3CR1, CCL2 and MAFB undergoes stepwise differentiation spanning four intermediate populations until the final mature osteoclast population with a high expression of cathepsin K, tartrate-resistant-acid phosphatase 5, matrix metalloproteinase 9, and dendritic cell-specific transmembrane protein (DC-STAMP) arises (34). Within the second population, cells show a dendritic cell-like expression pattern with a transient expression of CD11c.…”

Section: Accepted Articlementioning

confidence: 99%

“…Deficiency of RANK in CD11c+ cells inhibited osteoclast formation in vitro and in vivo indicating that this CD11c+ dendritic cell-like precursor population is important for proper osteoclastogenesis. Further, using RNA expression in single cells, Cited2 was identified as a novel critical factor driving terminal differentiation of osteoclasts, which previously has not been identified in bulk sequencing approaches (34). Given the limitations of extracting osteoclasts from in vivo samples, these single cell RNA outcomes are driven from in vitro differentiated osteoclasts derived from primary murine bone marrow, hence assumptions are made that these findings are relevant in vivo and in humans.…”

Section: Accepted Articlementioning

confidence: 99%

“…The most immature committed monocytic precursor that is characterized by high expression of M‐CSFR, RANK, C‐X3‐C motif chemokine receptor 1 (CX3CR1), C–C motif chemokine ligand 2 (CCL2), and MAF BZIP transcription factor b (MAFB) undergoes stepwise differentiation spanning four intermediate populations until the final mature osteoclast population with a high expression of cathepsin K, tartrate‐resistant‐acid phosphatase 5, matrix metalloproteinase 9, and dendritic cell‐specific transmembrane protein (DC‐STAMP) arises. ( 34 ) Within the second population, cells show a dendritic cell–like expression pattern with a transient expression of cluster of differentiation 11c (CD11c). Deficiency of RANK in CD11c+ cells inhibited osteoclast formation in vitro and in vivo, indicating that this CD11c+ dendritic cell‐like precursor population is important for proper osteoclastogenesis.…”

Section: Osteoclast Origin and Formationmentioning

confidence: 99%

“…Further, using RNA expression in single cells, CREB‐binding protein/p300‐interacting transactivator with Glu/Asp‐rich carboxy‐terminal domain 2 (CITED2) was identified as a novel critical factor driving terminal differentiation of osteoclasts, which previously has not been identified in bulk sequencing approaches. ( 34 ) Given the limitations of extracting osteoclasts from in vivo samples, these single‐cell RNA outcomes are driven from in vitro differentiated osteoclasts derived from primary murine bone marrow; hence, assumptions are made that these findings are relevant in vivo and in humans. Despite this limitation, however, considering the high plasticity of not only monocytes, macrophages, and dendritic cells, but also virtually all cell types that are now arising from single‐cell RNA sequencing data sets, it can be expected that several markers will be soon identified that more accurately characterize specific osteoclast (sub)‐populations.…”

Section: Osteoclast Origin and Formationmentioning

confidence: 99%

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New Insights Into Osteoclast Biology

et al. 2021

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Section: Accepted Articlementioning

confidence: 99%

Section: Accepted Articlementioning

confidence: 99%

Section: Osteoclast Origin and Formationmentioning

confidence: 99%

Section: Osteoclast Origin and Formationmentioning

confidence: 99%

See 2 more Smart Citations

New Insights Into Osteoclast Biology

et al. 2021

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“…The process whereby uncommitted monocytes develop into mature, active OCLs includes several distinct stages that are driven by M-CSF, which promotes the survival and proliferation of the monocyte OCL precursor cells, and RANKL, which provides the major pro-osteoclastogenic signals. The molecular events and transcriptional programs that are induced by both cytokines are essential and sufficient for inducing monocyte precursor cells to differentiate into mature, bone-resorbing OCLs ( Feng and Teitelbaum, 2013 ; Tsukasaki et al, 2020 ). Specifically, M-CSF activates its receptor tyrosine kinase, c-Fms, which, in turn, activates ERK1/2, PI3K, and Src signaling.…”

Section: Introductionmentioning

confidence: 99%

Sorting Nexin 10 as a Key Regulator of Membrane Trafficking in Bone-Resorbing Osteoclasts: Lessons Learned From Osteopetrosis

Elson

Stein

Rabie

et al. 2021

Front. Cell Dev. Biol.

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Bone homeostasis is a complex, multi-step process, which is based primarily on a tightly orchestrated interplay between bone formation and bone resorption that is executed by osteoblasts and osteoclasts (OCLs), respectively. The essential physiological balance between these cells is maintained and controlled at multiple levels, ranging from regulated gene expression to endocrine signals, yet the underlying cellular and molecular mechanisms are still poorly understood. One approach for deciphering the mechanisms that regulate bone homeostasis is the characterization of relevant pathological states in which this balance is disturbed. In this article we describe one such “error of nature,” namely the development of acute recessive osteopetrosis (ARO) in humans that is caused by mutations in sorting nexin 10 (SNX10) that affect OCL functioning. We hypothesize here that, by virtue of its specific roles in vesicular trafficking, SNX10 serves as a key selective regulator of the composition of diverse membrane compartments in OCLs, thereby affecting critical processes in the sequence of events that link the plasma membrane with formation of the ruffled border and with extracellular acidification. As a result, SNX10 determines multiple features of these cells either directly or, as in regulation of cell-cell fusion, indirectly. This hypothesis is further supported by the similarities between the cellular defects observed in OCLs form various models of ARO, induced by mutations in SNX10 and in other genes, which suggest that mutations in the known ARO-associated genes act by disrupting the same plasma membrane-to-ruffled border axis, albeit to different degrees. In this article, we describe the population genetics and spread of the original arginine-to-glutamine mutation at position 51 (R51Q) in SNX10 in the Palestinian community. We further review recent studies, conducted in animal and cellular model systems, that highlight the essential roles of SNX10 in critical membrane functions in OCLs, and discuss possible future research directions that are needed for challenging or substantiating our hypothesis.

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Role of Lysine‐Specific Demethylase 1 in Metabolically Integrating Osteoclast Differentiation and Inflammatory Bone Resorption Through Hypoxia‐Inducible Factor 1α and E2F1

Doi

Murata

Ito

et al. 2022

Arthritis & Rheumatology

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Objective. Hypoxia occurs in tumors, infections, and sites of inflammation, such as in the affected joints of patients with rheumatoid arthritis (RA). It alleviates inflammatory responses and increases bone resorption in inflammatory arthritis by enhancing osteoclastogenesis. The mechanism by which the hypoxia response is linked to osteoclastogenesis and inflammatory bone resorption is unclear. This study was undertaken to evaluate whether the protein lysinespecific demethylase 1 (LSD1) metabolically integrates inflammatory osteoclastogenesis and bone resorption in a state of inflammatory arthritis.Methods. LSD1-specific inhibitors and gene silencing with small interfering RNAs were used to inhibit the expression of LSD1 in human osteoclast precursor cells derived from CD14-positive monocytes, with subsequent assessment by RNA-sequencing analysis. In experimental mouse models of arthritis, inflammatory osteolysis, or osteoporosis, features of accelerated bone loss and inflammatory osteolysis were analyzed. Furthermore, in blood samples from patients with RA, cis-acting expression quantitative trait loci (cis-eQTL) were analyzed for association with the expression of hypoxiainducible factor 1α (HIF-1α), and associations between HIF-1α allelic variants and extent of bone erosion were evaluated.Results. In human osteoclast precursor cells, RANKL induced the expression of LSD1 in a mechanistic target of rapamycin-dependent manner. Expression of LSD1 was higher in synovium from RA patients than in synovium from osteoarthritis patients. Inhibition of LSD1 in human osteoclast precursors suppressed osteoclast differentiation. Results of transcriptome analysis identified several LSD1-mediated hypoxia and cell-cycle pathways as key genetic pathways involved in human osteoclastogenesis. Furthermore, HIF-1α protein, which is rapidly degraded by the proteasome in a normoxic environment, was found to be expressed in RANKL-stimulated osteoclast precursor cells. Induction of LSD1 by RANKL stabilized the expression of HIF-1α protein, thereby promoting glycolysis, in conjunction with up-regulation of the transcription factor E2F1. Analyses of cis-eQTL revealed that higher HIF-1α expression was associated with increased bone erosion in patients with RA. Inhibition of LSD1 decreased pathologic bone resorption in mice, both in models of accelerated osteoporosis and models of arthritis and inflammatory osteolysis.Conclusion. LSD1 metabolically regulates osteoclastogenesis in an energy-demanding inflammatory environment. These findings provide potential new therapeutic strategies targeting osteoclasts in the management of inflammatory arthritis, including in patients with RA.

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Stepwise cell fate decision pathways during osteoclastogenesis at single-cell resolution

Cited by 79 publications

References 57 publications

New Insights Into Osteoclast Biology

New Insights Into Osteoclast Biology

Sorting Nexin 10 as a Key Regulator of Membrane Trafficking in Bone-Resorbing Osteoclasts: Lessons Learned From Osteopetrosis

Role of Lysine‐Specific Demethylase 1 in Metabolically Integrating Osteoclast Differentiation and Inflammatory Bone Resorption Through Hypoxia‐Inducible Factor 1α and E2F1

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