Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging

Peng Deng; Quan Yuan; Yingduan Cheng; Jiong Li; Zhenqing Liu; Yan Liu; Ye Li; Trent Su; Jing Wang; Mari Ekimyan Salvo; Weiguang Wang; Guoping Fan; Karen Lyons; Bo Yu; Cun-Yu Wang

doi:10.1016/j.stem.2021.01.010

Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging

Cell Stem Cell. 2021 Jun 3;28(6):1057-1073.e7. doi: 10.1016/j.stem.2021.01.010. Epub 2021 Feb 10.

Authors

Peng Deng¹, Quan Yuan², Yingduan Cheng², Jiong Li², Zhenqing Liu¹, Yan Liu², Ye Li², Trent Su³, Jing Wang⁴, Mari Ekimyan Salvo¹, Weiguang Wang⁵, Guoping Fan⁴, Karen Lyons⁵, Bo Yu⁶, Cun-Yu Wang⁷

Affiliations

¹ Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.
² Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, UCLA, Los Angeles, CA 90095, USA.
³ Institute for Quantitative and Computational Biology and Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA.
⁴ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles Young Drive South, Los Angeles, CA 90095, USA.
⁵ Department of Orthopaedic Surgery, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.
⁶ Division of Constitutive and Regenerative Science, School of Dentistry, UCLA, Los Angeles, CA 90095, USA.
⁷ Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, UCLA, Los Angeles, CA 90095, USA. Electronic address: cwang@dentistry.ucla.edu.

Abstract

Skeletal aging is a complex process, characterized by a decrease in bone formation, an increase in marrow fat, and stem cell exhaustion. Loss of H3K9me3, a heterochromatin mark, has been proposed to be associated with aging. Here, we report that loss of KDM4B in mesenchymal stromal cells (MSCs) exacerbated skeletal aging and osteoporosis by reducing bone formation and increasing marrow adiposity via increasing H3K9me3. KDM4B epigenetically coordinated β-catenin/Smad1-mediated transcription by removing repressive H3K9me3. Importantly, KDM4B ablation impaired MSC self-renewal and promoted MSC exhaustion by inducing senescence-associated heterochromatin foci formation, providing a mechanistic explanation for stem cell exhaustion with aging. Moreover, while KDM4B was required for parathyroid hormone-mediated bone anabolism, KDM4B depletion accelerated bone loss and marrow adiposity induced by a high-fat diet. Our results suggest that the epigenetic rejuvenation and reversing bone-fat imbalance might be new strategies for preventing and treating skeletal aging and osteoporosis by activating KDM4B in MSCs.

Keywords: bone marrow adiposity; bone metabolism; mesenchymal stem cells; mesenchymal stromal cells; osteoporosis; parathyroid hormone; senescence-associated heterochromatin foci; skeletal aging; stem cell self-renewal.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Bone Marrow
Bone Marrow Cells
Cell Differentiation
Mesenchymal Stem Cells*
Osteogenesis

Abstract

Publication types

MeSH terms

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