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Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Histone demethylase UTX counteracts glucocorticoid deregulation of osteogenesis by modulating histone-dependent and
Feng-Sheng Wang1,2,3, Wei-Shiung Lian1,2, Mel S Lee4
1Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung District, Kaohsiung, 83303, Taiwan.
Abstract:
Excess glucocorticoid administration impairs osteogenic activities, which raises the risk of osteoporotic disorders. Epigenetic methylation of DNA and histone regulates the lineage commitment of progenitor cells. This study was undertaken to delineate the actions of histone lysine demethylase 6a (UTX) with regard to the glucocorticoid impediment of osteogenic differentiation. Osteogenic progenitor cells responded to supraphysiological glucocorticoid by elevating CpG dinucleotide methylation proximal to transcription start sites within Runx2 and osterix promoters and Wnt inhibitor Dickkopf-1 (Dkk1) expression concomitant with low UTX expression. 5'-Aza-deoxycystidine demethylation of Runx2 and osterix promoters abolished the glucocorticoid inhibition of mineralized matrix accumulation. Gain of UTX function attenuated the glucocorticoid-induced loss of osteogenic differentiation, whereas UTX silencing escalated adipogenic gene expression and adipocyte formation. UTX sustained osteogenic gene transcription through maintaining its occupancy to Runx2 and osterix promoters. It also mitigated the trimethylation of histone 3 at lysine 27 (H3K27me3), which reduced H3K27me3 enrichment to Dkk1 promoter and thereby lowered Dkk1 transcription. Modulation of β-catenin and Dkk1 actions restored UTX signaling in glucocorticoid-stressed cells. In vivo, UTX inhibition by exogenous methylprednisolone and GSK-J4 administration, an effect that disturbed H3K27me3, β-catenin, Dkk1, Runx2, and osterix levels, exacerbated trabecular microarchitecture loss and marrow adiposity. Taken together, glucocorticoid reduction of UTX function hindered osteogenic differentiation. Epigenetic hypomethylation of osteogenic transcription factor promoters and H3K27 contributed to the UXT alleviation of Dkk1 transcription and osteogenesis in glucocorticoid-stressed osteogenic progenitor cells. Control of UTX action has an epigenetic perspective of curtailing glucocorticoid impairment of osteogenic differentiation and bone mass.
Key Messages:
UTX attenuates glucocorticoid deregulation of osteogenesis and adipogenesis. UTX reduces Runx2 promoter methylation and H3K27me3 enrichment in the Dkk1 promoter. β-catenin and Dkk1 modulate the glucocorticoid inhibition of UTX signaling. UTX inhibition exacerbates bone mass, trabecular microstructure and fatty marrow. UTX signaling is indispensable in fending off glucocorticoid-impaired osteogenesis.
Insights
Histone lysine demethylase 6a (UTX) protects against glucocorticoid-induced bone loss by maintaining osteogenic differentiation. Restoring UTX function preserves bone mass and reduces marrow adiposity, offering an epigenetic target for osteoporosis treatment.
Area of Science:
- Molecular Biology
- Epigenetics
- Bone Biology
Background:
- Excess glucocorticoids impair osteogenic differentiation, increasing osteoporosis risk.
- Epigenetic modifications, including DNA and histone methylation, regulate cell lineage commitment.
Purpose of the Study:
- To investigate the role of histone lysine demethylase 6a (UTX) in glucocorticoid-impaired osteogenic differentiation.
- To elucidate the epigenetic mechanisms by which UTX influences osteogenesis and adipogenesis.
Main Methods:
- Assessed effects of glucocorticoids on osteogenic progenitor cells, focusing on DNA methylation, UTX expression, and key gene promoters (Runx2, osterix, Dkk1).
- Utilized 5'-Aza-deoxycytidine to demethylate promoters and manipulated UTX function (gain-of-function and silencing).
- Evaluated in vivo effects of UTX inhibition on bone microarchitecture and marrow adiposity.
Main Results:
- Glucocorticoids increased DNA methylation in Runx2 and osterix promoters and elevated Dkk1 expression, correlating with reduced UTX levels.
- Demethylation of Runx2 and osterix promoters reversed glucocorticoid inhibition of matrix accumulation.
- UTX gain-of-function preserved osteogenic differentiation, while UTX silencing promoted adipogenesis.
- UTX maintained osteogenic gene transcription by occupying Runx2 and osterix promoters and reduced Dkk1 transcription by mitigating H3K27me3 enrichment.
- In vivo UTX inhibition exacerbated bone loss and marrow adiposity.
Conclusions:
- Glucocorticoid-induced reduction in UTX function impairs osteogenic differentiation.
- Epigenetic modifications, including promoter hypomethylation and histone methylation, are key mediators of UTX's protective effects.
- Modulating UTX activity offers a potential epigenetic strategy to counteract glucocorticoid-induced bone loss.
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