Histone H3K27 demethylase UTX compromises articular chondrocyte anabolism and aggravates osteoarthritic degeneration
Abstract Epigenome alteration in chondrocytes correlates with osteoarthritis (OA) development. H3K27me3 demethylase UTX regulates tissue homeostasis and deterioration, while its role was not yet studied in articulating joint tissue in situ. We now uncovered that increased UTX and H3K27me3 expression...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04985-5 |
| _version_ | 1828732798836408320 |
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| author | Wei-Shiung Lian Re-Wen Wu Jih-Yang Ko Yu-Shan Chen Shao-Yu Wang Chun-Ping Yu Holger Jahr Feng-Sheng Wang |
| author_facet | Wei-Shiung Lian Re-Wen Wu Jih-Yang Ko Yu-Shan Chen Shao-Yu Wang Chun-Ping Yu Holger Jahr Feng-Sheng Wang |
| author_sort | Wei-Shiung Lian |
| collection | DOAJ |
| description | Abstract Epigenome alteration in chondrocytes correlates with osteoarthritis (OA) development. H3K27me3 demethylase UTX regulates tissue homeostasis and deterioration, while its role was not yet studied in articulating joint tissue in situ. We now uncovered that increased UTX and H3K27me3 expression in articular chondrocytes positively correlated with human knee OA. Forced UTX expression upregulated the H3K27me3 enrichment at transcription factor Sox9 promoter, inhibiting key extracellular matrix molecules collagen II, aggrecan, and glycosaminoglycan in articular chondrocytes. Utx overexpression in knee joints aggravated the signs of OA, including articular cartilage damage, synovitis, osteophyte formation, and subchondral bone loss in mice. Chondrocyte-specific Utx knockout mice developed thicker articular cartilage than wild-type mice and showed few gonarthrotic symptoms during destabilized medial meniscus- and collagenase-induced joint injury. In vitro, Utx loss changed H3K27me3-binding epigenomic landscapes, which contributed to mitochondrial activity, cellular senescence, and cartilage development. Insulin-like growth factor 2 (Igf2) and polycomb repressive complex 2 (PRC2) core components Eed and Suz12 were, among others, functional target genes of Utx. Specifically, Utx deletion promoted Tfam transcription, mitochondrial respiration, ATP production and Igf2 transcription but inhibited Eed and Suz12 expression. Igf2 blockade or forced Eed or Suz12 expression increased H3K27 trimethylation and H3K27me3 enrichment at Sox9 promoter, compromising Utx loss-induced extracellular matrix overproduction. Taken together, UTX repressed articular chondrocytic activity, accelerating cartilage loss during OA. Utx loss promoted cartilage integrity through epigenetic stimulation of mitochondrial biogenesis and Igf2 transcription. This study highlighted a novel noncanonical role of Utx, in concert with PRC2 core components, in controlling H3K27 trimethylation and articular chondrocyte anabolism and OA development. |
| first_indexed | 2024-04-12T18:07:21Z |
| format | Article |
| id | doaj.art-6fb744a909a24bbd9777401b0e528866 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T18:07:21Z |
| publishDate | 2022-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-6fb744a909a24bbd9777401b0e5288662022-12-22T03:21:57ZengNature Publishing GroupCell Death and Disease2041-48892022-06-0113611110.1038/s41419-022-04985-5Histone H3K27 demethylase UTX compromises articular chondrocyte anabolism and aggravates osteoarthritic degenerationWei-Shiung Lian0Re-Wen Wu1Jih-Yang Ko2Yu-Shan Chen3Shao-Yu Wang4Chun-Ping Yu5Holger Jahr6Feng-Sheng Wang7Core Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineDepartment of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineDepartment of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineCore Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineCore Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineBiodiversity Research Center, Academia SinicaDepartment of Anatomy and Cell Biology, University Hospital RWTH AachenCore Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineAbstract Epigenome alteration in chondrocytes correlates with osteoarthritis (OA) development. H3K27me3 demethylase UTX regulates tissue homeostasis and deterioration, while its role was not yet studied in articulating joint tissue in situ. We now uncovered that increased UTX and H3K27me3 expression in articular chondrocytes positively correlated with human knee OA. Forced UTX expression upregulated the H3K27me3 enrichment at transcription factor Sox9 promoter, inhibiting key extracellular matrix molecules collagen II, aggrecan, and glycosaminoglycan in articular chondrocytes. Utx overexpression in knee joints aggravated the signs of OA, including articular cartilage damage, synovitis, osteophyte formation, and subchondral bone loss in mice. Chondrocyte-specific Utx knockout mice developed thicker articular cartilage than wild-type mice and showed few gonarthrotic symptoms during destabilized medial meniscus- and collagenase-induced joint injury. In vitro, Utx loss changed H3K27me3-binding epigenomic landscapes, which contributed to mitochondrial activity, cellular senescence, and cartilage development. Insulin-like growth factor 2 (Igf2) and polycomb repressive complex 2 (PRC2) core components Eed and Suz12 were, among others, functional target genes of Utx. Specifically, Utx deletion promoted Tfam transcription, mitochondrial respiration, ATP production and Igf2 transcription but inhibited Eed and Suz12 expression. Igf2 blockade or forced Eed or Suz12 expression increased H3K27 trimethylation and H3K27me3 enrichment at Sox9 promoter, compromising Utx loss-induced extracellular matrix overproduction. Taken together, UTX repressed articular chondrocytic activity, accelerating cartilage loss during OA. Utx loss promoted cartilage integrity through epigenetic stimulation of mitochondrial biogenesis and Igf2 transcription. This study highlighted a novel noncanonical role of Utx, in concert with PRC2 core components, in controlling H3K27 trimethylation and articular chondrocyte anabolism and OA development.https://doi.org/10.1038/s41419-022-04985-5 |
| spellingShingle | Wei-Shiung Lian Re-Wen Wu Jih-Yang Ko Yu-Shan Chen Shao-Yu Wang Chun-Ping Yu Holger Jahr Feng-Sheng Wang Histone H3K27 demethylase UTX compromises articular chondrocyte anabolism and aggravates osteoarthritic degeneration Cell Death and Disease |
| title | Histone H3K27 demethylase UTX compromises articular chondrocyte anabolism and aggravates osteoarthritic degeneration |
| title_full | Histone H3K27 demethylase UTX compromises articular chondrocyte anabolism and aggravates osteoarthritic degeneration |
| title_fullStr | Histone H3K27 demethylase UTX compromises articular chondrocyte anabolism and aggravates osteoarthritic degeneration |
| title_full_unstemmed | Histone H3K27 demethylase UTX compromises articular chondrocyte anabolism and aggravates osteoarthritic degeneration |
| title_short | Histone H3K27 demethylase UTX compromises articular chondrocyte anabolism and aggravates osteoarthritic degeneration |
| title_sort | histone h3k27 demethylase utx compromises articular chondrocyte anabolism and aggravates osteoarthritic degeneration |
| url | https://doi.org/10.1038/s41419-022-04985-5 |
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