Loss of KDM4B Exacerbates Bone-fat Imbalance and Mesenchymal Stromal Cell Exhaustion in Skeletal Aging

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 Feb 11

PMID 33571444

Citations 76

Authors

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

Affiliations

Soon will be listed here.

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.

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