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.

骨骼衰老是一个复杂的过程，其特征是骨形成减少、骨髓脂肪增加和干细胞耗竭。 H3K9me3（一种异染色质标记）的缺失被认为与衰老有关。在此，我们报告间充质基质细胞 (MSC) 中 KDM4B 的缺失会减少骨形成并通过增加 H3K9me3 增加骨髓脂肪，从而加剧骨骼老化和骨质疏松。 KDM4B 通过去除抑制性 H3K9me3 来表观遗传协调 β-catenin/Smad1 介导的转录。重要的是，KDM4B 消融通过诱导衰老相关异染色质灶形成，损害 MSC 自我更新并促进 MSC 耗竭，为衰老过程中干细胞耗竭提供了机制解释。此外，虽然甲状旁腺激素介导的骨合成代谢需要 KDM4B，但 KDM4B 的消耗会加速高脂肪饮食引起的骨质流失和骨髓肥胖。我们的结果表明，表观遗传复兴和逆转骨脂失衡可能是通过激活 MSC 中的 KDM4B 来预防和治疗骨骼衰老和骨质疏松症的新策略。