CoChat
Sign Up
Cited by 76Bone Metabolism and DiseasesCancer, Hypoxia, and MetabolismGenomics and Chromatin Dynamics

The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.

Lactate-induced histone lactylation by p300 promotes osteoblast differentiation

Open access
Minami, Erika, Sasa, Kiyohito, Yamada, Atsushi, Kawai, Ryota, Yoshida, Hiroshi, Nakano, Haruhisa, Maki, Koutaro, Kamijo, Ryutaro·2023·PLOS ONE
DOI 10.1371/journal.pone.0293676PMC PMC10697613
Open this paper in CoChat — free accountOpen PDF

Abstract

Lactate, which is synthesized as an end product by lactate dehydrogenase A (LDHA) from pyruvate during anaerobic glycolysis, has attracted attention for its energy metabolism and oxidant effects. A novel histone modification-mediated gene regulation mechanism termed lactylation by lactate was recently discovered. The present study examined the involvement of histone lactylation in undifferentiated cells that underwent differentiation into osteoblasts. C2C12 cells cultured in medium with a high glucose content (4500 mg/L) showed increases in marker genes (Runx2, Sp7, Tnap) indicating BMP-2-induced osteoblast differentiation and ALP staining activity, as well as histone lactylation as compared to those cultured in medium with a low glucose content (900 mg/L). Furthermore, C2C12 cells stimulated with the LDH inhibitor oxamate had reduced levels of BMP-2-induced osteoblast differentiation and histone lactylation, while addition of lactate to C2C12 cells cultured in low glucose medium resulted in partial restoration of osteoblast differentiation and histone lactylation. These results indicate that lactate synthesized by LDHA during glucose metabolism is important for osteoblast differentiation of C2C12 cells induced by BMP-2. Additionally, silencing of p300, a possible modifier of histone lactylation, also inhibited osteoblast differentiation and reduced histone lactylation. Together, these findings suggest a role of histone lactylation in promotion of undifferentiated cells to undergo differentiation into osteoblasts.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0293676

Cites

27 of 27 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig 1 High glucose concentration promoted osteoblast differentiation and increased histone lactylation levels in C2C12 cells. C2C12 cells were incubated for 72 (a right, b, c) or 24 (a left, d) hours after addition of BMP-2 (150 ng/ml) into medium with a high (4500 mg/L) or low (900 mg/L) glucose concentration. Amounts of (a) lactate, and (b) ALP staining and activity are shown. (c) Osteoblast differentiation marker genes were determined using real-time RT-PCR. (d) Expression of lactyl lysine after addition of BMP-2 was evaluated by western blotting. Data are expressed as mean ± SD (n = 3–5). *, **Significantly different from control group (*p <0.05, **p <0.01).
Fig 1 High glucose concentration promoted osteoblast differentiation and increased histone lactylation levels in C2C12 cells. C2C12 cells were incubated for 72 (a right, b, c) or 24 (a left, d) hours after addition of BMP-2 (150 ng/ml) into medium with a high (4500 mg/L) or low (900 mg/L) glucose concentration. Amounts of (a) lactate, and (b) ALP staining and activity are shown. (c) Osteoblast differentiation marker genes were determined using real-time RT-PCR. (d) Expression of lactyl lysine after addition of BMP-2 was evaluated by western blotting. Data are expressed as mean ± SD (n = 3–5). *, **Significantly different from control group (*p <0.05, **p <0.01).CC BY · PubMed Central
Fig 2 Inhibition of LDHA reduced osteoblast differentiation and lactyl lysine levels. C2C12 cells were incubated for 72 (a right, b, c) or 24 (a left, d) hours after addition of BMP-2 with oxamate. Amounts of (a) lactate, and (b) ALP staining and activity are shown. (c) Osteoblast differentiation marker genes were determined using real-time RT-PCR. (d) Expression of lactyl lysine after addition of BMP-2 and oxamate was evaluated by western blotting. Data are expressed as mean ± SD (n = 3). *, **Significantly different from control group (*p <0.05, **p <0.01). NS, not significant.
Fig 2 Inhibition of LDHA reduced osteoblast differentiation and lactyl lysine levels. C2C12 cells were incubated for 72 (a right, b, c) or 24 (a left, d) hours after addition of BMP-2 with oxamate. Amounts of (a) lactate, and (b) ALP staining and activity are shown. (c) Osteoblast differentiation marker genes were determined using real-time RT-PCR. (d) Expression of lactyl lysine after addition of BMP-2 and oxamate was evaluated by western blotting. Data are expressed as mean ± SD (n = 3). *, **Significantly different from control group (*p <0.05, **p <0.01). NS, not significant.CC BY · PubMed Central
Fig 3 Lactate recovered suppression of osteoblast differentiation and decreased histone lactylation levels caused by low glucose. C2C12 cells were incubated for 72 (a right, b, c) or 24 (a left, d) hours after placing in medium with a high or low glucose concentration in the absence or presence of lactate. Amounts of (a) lactate, and (b) ALP staining and activity are shown. (c) Osteoblast differentiation marker genes were determined using real-time RT-PCR. (d) Expression of lactyl lysine under the same conditions was evaluated by western blotting. Data are expressed as mean ± SD (n = 3–4). *, **Significantly different from control group (*p <0.05, **p <0.01). ND: not detected.
Fig 3 Lactate recovered suppression of osteoblast differentiation and decreased histone lactylation levels caused by low glucose. C2C12 cells were incubated for 72 (a right, b, c) or 24 (a left, d) hours after placing in medium with a high or low glucose concentration in the absence or presence of lactate. Amounts of (a) lactate, and (b) ALP staining and activity are shown. (c) Osteoblast differentiation marker genes were determined using real-time RT-PCR. (d) Expression of lactyl lysine under the same conditions was evaluated by western blotting. Data are expressed as mean ± SD (n = 3–4). *, **Significantly different from control group (*p <0.05, **p <0.01). ND: not detected.CC BY · PubMed Central
Fig 4 Ep300 siRNA suppressed osteoblast differentiation and decreased histone lactylation levels. Following introduction of Ep300 siRNA, C2C12 cells were cultured for 72 (a right, b, c) or 24 (a left, d) hours after addition of BMP-2 to the medium. Amounts of (a) lactate, and (b) ALP staining and activity are shown. (c) Osteoblast differentiation marker genes were determined using real-time RT-PCR. (d) Expression of lactyl lysine under the same conditions was evaluated by western blotting. Data are expressed as mean ± SD (n = 3–5). *, **Significantly different from control group (*p <0.05, **p <0.01). NS, not significant.
Fig 4 Ep300 siRNA suppressed osteoblast differentiation and decreased histone lactylation levels. Following introduction of Ep300 siRNA, C2C12 cells were cultured for 72 (a right, b, c) or 24 (a left, d) hours after addition of BMP-2 to the medium. Amounts of (a) lactate, and (b) ALP staining and activity are shown. (c) Osteoblast differentiation marker genes were determined using real-time RT-PCR. (d) Expression of lactyl lysine under the same conditions was evaluated by western blotting. Data are expressed as mean ± SD (n = 3–5). *, **Significantly different from control group (*p <0.05, **p <0.01). NS, not significant.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 27 references

Research works printed but not linked: 1

  1. T Katagiri, 1994, Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage, J Cell Biol, 127, 1755

Cited by

Sorted by citations

See all 76

Related

See all

Metadata

Authors
Minami, E., Sasa, K., Yamada, A., Kawai, R., Yoshida, H., Nakano, H., Maki, K., & Kamijo, R.
Affiliations
SHOWA Medical University (JP)
Corresponding author
Sasa, Kiyohito
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2023-12-05
Volume
18
Issue
12
Pages
e0293676
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0293676
PMC
PMC10697613
OpenAlex
W4389331757
Cited by
73
References
27
Citations by year
2026: 31 · 2025: 35 · 2024: 7
FWCI
6.50
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Japan Society for the Promotion of Science (21K16936, 23K09128)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
histone lactylation, lactate, P300, osteogenic differentiation, LDHA, BMP-2, high glucose, C2C12 myoblasts, Runx2, Osterix, tissue-nonspecific alkaline phosphatase, osteoblastogenesis, histone modifications, gene expression regulation
MeSH terms
Cell Differentiation, Glucose, Histones, Osteoblasts, Lactic Acid

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Lactate-induced histone lactylation by p300 promotes osteoblast differentiation. https://app.cochat.ai/papers/10.1371/journal.pone.0293676
The paper
Minami, E., Sasa, K., Yamada, A., Kawai, R., Yoshida, H., Nakano, H., Maki, K., & Kamijo, R. (2023). Lactate-induced histone lactylation by p300 promotes osteoblast differentiation. PLOS ONE. https://doi.org/10.1371/journal.pone.0293676