Inhibition of KDM6B prevents osteoarthritis by blocking growth plate-like H3K27me3 loss in bivalent genes

Hao Du^#¹, Yao Zhang^#¹, Xi Yu^{1

2}, Xuanhe You¹, Diwei Wu¹, Ze Du¹, Yongrui Cai¹, Zhenyu Luo¹, Hanpeng Lu¹, Zhixin Liao¹, Bi-Sen Ding³, Ya Zhao^{4

5}, Yan Wang^{6

7}, Ke Xiao⁸, Fan Yang⁹, Fangji Gan¹⁰, Ning Ning¹, Jiancheng Zeng¹, Peiliang Shi¹¹, Zongke Zhou¹², Shishu Huang¹³

Affiliations

¹ Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China.
² Rehabilitation Medicine Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
³ Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
⁴ Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, China.
⁵ Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou, 225001, China.
⁶ College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China.
⁷ Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, China.
⁸ Department of Lower Limb Surgery of Sichuan Province Orthopedic Hospital, Central Laboratory of Sichuan Province Orthopedic Hospital, Chengdu, 610000, China.
⁹ Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518000, China.
¹⁰ School of Mechanical Engineering, Sichuan University, Chengdu, 610065, China.
¹¹ GemPharmatech (Chengdu) Co., Ltd., Chengdu, 610000, China.
¹² Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China. zongke@126.com.
¹³ Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China. h0794062@scu.edu.cn.

^# Contributed equally.

PMID: 39969745
DOI: 10.1007/s11427-024-2676-y

Inhibition of KDM6B prevents osteoarthritis by blocking growth plate-like H3K27me3 loss in bivalent genes

Hao Du et al. Sci China Life Sci. 2025 May.

. 2025 May;68(5):1423-1436.

doi: 10.1007/s11427-024-2676-y. Epub 2025 Feb 17.

Authors

Affiliations

¹ Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China.
² Rehabilitation Medicine Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
³ Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
⁴ Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, China.
⁵ Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou, 225001, China.
⁶ College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China.
⁷ Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, China.
⁸ Department of Lower Limb Surgery of Sichuan Province Orthopedic Hospital, Central Laboratory of Sichuan Province Orthopedic Hospital, Chengdu, 610000, China.
⁹ Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518000, China.
¹⁰ School of Mechanical Engineering, Sichuan University, Chengdu, 610065, China.
¹¹ GemPharmatech (Chengdu) Co., Ltd., Chengdu, 610000, China.
¹² Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China. zongke@126.com.
¹³ Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China. h0794062@scu.edu.cn.

^# Contributed equally.

PMID: 39969745
DOI: 10.1007/s11427-024-2676-y

Abstract

Osteoarthritis (OA) is the most prevalent joint disorder occurring with articular cartilage degradation. It includes a switch from an articular to a growth plate chondrocyte phenotype. Here, we investigated the histone modification profiles and found significant H3K27me3 loss in OA, which led to disease-associated gene expression. Surprisingly, these genes were occupied by both H3K27me3 and H3K4me3 in normal chondrocytes, showing a poised bivalent state. Furthermore, we observed the derepression of similar bivalent genes in growth plate chondrocytes. Finally, a KDM6B inhibitor GSK-J4 prevented the H3K27me3 loss and cartilage damage in the rat OA model. Our results reveal an inherited bivalent epigenetic signature on developmental genes that makes articular chondrocytes prone to hypertrophy and contributes to a promising epigenetic therapy for OA.

Keywords: H3K27me3; bivalency; growth plate; histone modifications; osteoarthritis.

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Conflict of interest statement

Compliance and ethics. The authors declare that they have no conflict of interest. The authors state that they conformed with the Helsinki Declaration of 1975 (as revised in 2008) concerning Human and Animal Rights and that they followed the policy concerning Informed Consent as shown on Springer.com . Experiments involving human subjects were performed according to the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University. Informed consent was obtained from patients. Experiments involving animal subjects were performed in accordance with the Institutional Animal Care and Use Committee of the Sichuan University-approved protocols.

References

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Inhibition of KDM6B prevents osteoarthritis by blocking growth plate-like H3K27me3 loss in bivalent genes

Affiliations

Inhibition of KDM6B prevents osteoarthritis by blocking growth plate-like H3K27me3 loss in bivalent genes

Authors

Affiliations

Abstract

Conflict of interest statement

References

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Full Text Sources

Medical