Bromodomain Protein BRD4 Accelerates Glucocorticoid Dysregulation of Bone Mass and Marrow Adiposis by Modulating H3K9 and Foxp1

Glucocorticoid provokes bone mass loss and fatty marrow, accelerating osteoporosis development. Bromodomain protein BRD4, an acetyl–histone-binding chromatin reader, regulates stem cell and tissue homeostasis. We uncovered that glucocorticoid inhibited acetyl Lys-9 at the histone 3 (H3K9ac)-binding Runx2 promoter and decreased osteogenic differentiation, whereas bromodomain protein 4 (BRD4) and adipocyte formation were upregulated in bone-marrow mesenchymal progenitor cells. BRD4 knockdown improved H3K9ac occupation at the Runx2 promoter and osteogenesis, but attenuated glucocorticoid-mediated adipocyte formation together with the unaffected H3K9ac-binding PPARγ2 promoter. BRD4 regulated epigenome related to fatty acid metabolism and the forkhead box P1 (Foxp1) pathway, which occupied the PPARγ2 promoter to modulate glucocorticoid-induced adipocytic activity. In vivo, BRD4 inhibitor JQ-1 treatment mitigated methylprednisolone-induced suppression of bone mass, trabecular microstructure, mineral acquisition, and osteogenic differentiation. Foxp1 signaling, marrow fat, and adipocyte formation in glucocorticoid-treated skeleton were reversed upon JQ-1 treatment. Taken together, glucocorticoid-induced H3K9 hypoacetylation augmented BRD4 action to Foxp1, which steered mesenchymal progenitor cells toward adipocytes at the cost of osteogenic differentiation in osteoporotic skeletons. BRD4 inhibition slowed bone mass loss and marrow adiposity. Collective investigations convey a new epigenetic insight into acetyl histone reader BRD4 control of osteogenesis and adipogenesis in skeleton, and highlight the remedial effects of the BRD4 inhibitor on glucocorticoid-induced osteoporosis.

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Erratum: Telomerized presenescent osteoblasts prevent bone mass loss in vivo

Gene Therapy ◽

10.1038/sj.gt.3302730 ◽

2006 ◽

Vol 13 (4) ◽

pp. 375-375

Author(s):

K Yudoh ◽

K Nishioka

Keyword(s):

Bone Mass ◽

Mass Loss ◽

Bone Mass Loss

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Telomerized presenescent osteoblasts prevent bone mass loss in vivo

Gene Therapy ◽

10.1038/sj.gt.3302234 ◽

2004 ◽

Vol 11 (11) ◽

pp. 909-915 ◽

Cited By ~ 25

Author(s):

K Yudoh ◽

K Nishioka

Keyword(s):

Bone Mass ◽

Mass Loss ◽

Bone Mass Loss

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Impaired autophagy triggered by HDAC9 in mesenchymal stem cells accelerates bone mass loss

10.21203/rs.3.rs-20744/v1 ◽

2020 ◽

Author(s):

Liqiang Zhang ◽

Meng Qi ◽

Ji Chen ◽

Jiangdong Zhao ◽

Liya Li ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Mass ◽

Mass Loss ◽

Adipogenic Differentiation ◽

Marrow Fat ◽

P53 Expression ◽

Bone Mass Loss ◽

Lineage Differentiation ◽

Age Related

Abstract 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 signalling 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 the 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 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 is thus, a potential target of age-related bone loss treatment.

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Impaired autophagy triggered by HDAC9 in mesenchymal stem cells accelerates bone mass loss

10.21203/rs.3.rs-20744/v2 ◽

2020 ◽

Author(s):

Liqiang Zhang ◽

Meng Qi ◽

Ji Chen ◽

Jiangdong Zhao ◽

Liya Li ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Mass ◽

Mass Loss ◽

Adipogenic Differentiation ◽

Marrow Fat ◽

P53 Expression ◽

Bone Mass Loss ◽

Lineage Differentiation ◽

Age Related

Abstract 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.

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Zoledronic acid modulates osteoclast apoptosis through activation of the NF-κB signaling pathway in ovariectomized rats

Experimental Biology and Medicine ◽

10.1177/15353702211011052 ◽

2021 ◽

pp. 153537022110110

Author(s):

Yu-Ting Cheng ◽

Jian Liao ◽

Qian Zhou ◽

Hua Huo ◽

Lucas Zellmer ◽

...

Keyword(s):

Zoledronic Acid ◽

Bone Mass ◽

Mass Loss ◽

Ovariectomized Rats ◽

Therapeutic Effects ◽

Bone Mass Loss ◽

Cellular Effects ◽

Protein Levels ◽

Adverse Factor ◽

Osteoclast Apoptosis

Bone mass loss (osteoporosis) seen in postmenopausal women is an adverse factor for implant denture. Using an ovariectomized rat model, we studied the mechanism of estrogen-deficiency-caused bone loss and the therapeutic effect of Zoledronic acid. We observed that ovariectomized-caused resorption of bone tissue in the mandible was evident at four weeks and had not fully recovered by 12 weeks post-ovariectomized compared with the sham-operated controls. Further evaluation with a TUNEL assay showed ovariectomized enhanced apoptosis of osteoblasts but inhibited apoptosis of osteoclasts in the mandible. Zoledronic acid given subcutaneously as a single low dose was shown to counteract both of these ovariectomized effects. Immunohistochemical staining showed that ovariectomized induced the protein levels of RANKL and the 65-kD subunit of the NF-κB complex mainly in osteoclasts, as confirmed by staining for TRAP, a marker for osteoclasts, whereas zoledronic acid inhibited these inductions. Western blotting showed that the levels of RANKL, p65, as well as the phosphorylated form of p65, and IκB-α were all higher in the ovariectomized group than in the sham and ovariectomized + zoledronic acid groups at both the 4th- and 12th-week time points in the mandible. These data collectively suggest that ovariectomized causes bone mass loss by enhancing apoptosis of osteoblasts and inhibiting apoptosis of osteoclasts. In osteoclasts, these cellular effects may be achieved by activating RANKL-NF-κB signalling. Moreover, zoledronic acid elicits its therapeutic effects in the mandible by counteracting these cellular and molecular consequences of ovariectomized.

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