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Impaired autophagy triggered by HDAC9 in mesenchymal stem cells accelerates bone mass loss
Yan Jin
College of Stomatology, Fourth Military Medical University, Research and Development Center for Tissue Engineering
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2586-1152
Wenjia Liu
Xi'an Jiaotong University Second Affiliated Hospital
Corresponding Author
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Stem Cell Research & Therapy.
Background: Bone mass loss in aging is linked with imbalanced lineage differentiation of bone marrow mesenchymal stem cells (BMMSCs). Recent studies have proved that histone deacetylases (HDACs) are regarded as key regulators of bone remodeling. However, HDACs involve in regulating BMMSCs bio-behaviors remain elusive. Here, we investigated ability of HDAC9 on modulation of autophagy and its significance in lineage differentiation of BMMSCs.
Methods: The effects of HDAC9 on lineage differentiation of BMMSCs and autophagic signaling were assessed by various biochemical (Western blot and ChIP assay), morphological (TEM and confocal microscopy) and microCT assays.
Results ：16-month mice manifested obvious bone mass loss and marrow fat increase, accompanied with decreased osteogenic differentiation and increased adipogenic differentiation of BMMSCs. Further, the expression of HDAC9 elevated in bone and BMMSCs. Importantly, HDAC9 inhibitors recovered the lineage differentiation abnormality of 16-month BMMSCs and reduced p53 expression. Mechanistically, we revealed that HDAC9 regulated the autophagy of BMMSCs by controlling H3K9 acetylation in the promoters of the autophagic genes, ATG7 , BECN1 , and LC3a/b, which subsequently affected their lineage differentiation. Finally, HDAC9 inhibition improved endogenous BMMSCs properties and promoted the bone mass recovery of 16-month mice.
Conclusions: Our data demonstrate that HDAC9 is a key regulator in variety of bone mass by regulating autophagic activity in BMMSCs and thus a potential target of age-related bone loss treatment.
Keywords
bone mass loss, HDACs, BMMSCs, autophagy, lineage differentiation
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Editorial decision: Major Revision
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Received 12 Apr, 2020
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Reviewer #4 agreed
On 06 Apr, 2020
Reviewer #2 agreed
On 05 Apr, 2020
Reviewer #3 agreed
On 05 Apr, 2020
Reviewers invited
Invitations sent on 04 Apr, 2020
Reviewer #1 agreed
On 04 Apr, 2020
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On 02 Apr, 2020
Editor invited
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This preprint is under consideration at Stem Cell Research & Therapy. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Impaired autophagy triggered by HDAC9 in mesenchymal stem cells accelerates bone mass loss
Yan Jin
College of Stomatology, Fourth Military Medical University, Research and Development Center for Tissue Engineering
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2586-1152
Wenjia Liu
Xi'an Jiaotong University Second Affiliated Hospital
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 2
Posted 29 May, 2020
Published
On 03 Jul, 2020
No community comments so far
Reviewer #1 agreed
On 20 May, 2020
Reviewer #2 agreed
On 20 May, 2020
Review #1 received
Received 20 May, 2020
Editor assigned
On 19 May, 2020
Reviewers invited
Invitations sent on 19 May, 2020
Submission checks complete
On 18 May, 2020
Editor invited
On 18 May, 2020
No comments provided
Review #1 received
Received 14 Apr, 2020
Editorial decision: Major Revision
On 14 Apr, 2020
Review #2 received
Received 12 Apr, 2020
Review #4 received
Received 12 Apr, 2020
Reviewer #4 agreed
On 06 Apr, 2020
Reviewer #2 agreed
On 05 Apr, 2020
Reviewer #3 agreed
On 05 Apr, 2020
Reviewers invited
Invitations sent on 04 Apr, 2020
Reviewer #1 agreed
On 04 Apr, 2020
Editor assigned
On 02 Apr, 2020
Editor invited
On 01 Apr, 2020
Submission checks complete
On 01 Apr, 2020
First submitted
On 31 Mar, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Stem Cell & Developmental Cell Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Stem Cell Research & Therapy.
Background: Bone mass loss in aging is linked with imbalanced lineage differentiation of bone marrow mesenchymal stem cells (BMMSCs). Recent studies have proved that histone deacetylases (HDACs) are regarded as key regulators of bone remodeling. However, HDACs involve in regulating BMMSCs bio-behaviors remain elusive. Here, we investigated ability of HDAC9 on modulation of autophagy and its significance in lineage differentiation of BMMSCs.
Methods: The effects of HDAC9 on lineage differentiation of BMMSCs and autophagic signaling were assessed by various biochemical (Western blot and ChIP assay), morphological (TEM and confocal microscopy) and microCT assays.
Results ：16-month mice manifested obvious bone mass loss and marrow fat increase, accompanied with decreased osteogenic differentiation and increased adipogenic differentiation of BMMSCs. Further, the expression of HDAC9 elevated in bone and BMMSCs. Importantly, HDAC9 inhibitors recovered the lineage differentiation abnormality of 16-month BMMSCs and reduced p53 expression. Mechanistically, we revealed that HDAC9 regulated the autophagy of BMMSCs by controlling H3K9 acetylation in the promoters of the autophagic genes, ATG7 , BECN1 , and LC3a/b, which subsequently affected their lineage differentiation. Finally, HDAC9 inhibition improved endogenous BMMSCs properties and promoted the bone mass recovery of 16-month mice.
Conclusions: Our data demonstrate that HDAC9 is a key regulator in variety of bone mass by regulating autophagic activity in BMMSCs and thus a potential target of age-related bone loss treatment.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6