State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, 90095, USA.
Nat Commun. 2020 Nov 5;11(1):5596. doi: 10.1038/s41467-020-19360-1.
Age-related osteoporosis is characterized by the deterioration in bone volume and strength, partly due to the dysfunction of bone marrow mesenchymal stromal/stem cells (MSCs) during aging. Alpha-ketoglutarate (αKG) is an essential intermediate in the tricarboxylic acid (TCA) cycle. Studies have revealed that αKG extends the lifespan of worms and maintains the pluripotency of embryonic stem cells (ESCs). Here, we show that the administration of αKG increases the bone mass of aged mice, attenuates age-related bone loss, and accelerates bone regeneration of aged rodents. αKG ameliorates the senescence-associated (SA) phenotypes of bone marrow MSCs derived from aged mice, as well as promoting their proliferation, colony formation, migration, and osteogenic potential. Mechanistically, αKG decreases the accumulations of H3K9me3 and H3K27me3, and subsequently upregulates BMP signaling and Nanog expression. Collectively, our findings illuminate the role of αKG in rejuvenating MSCs and ameliorating age-related osteoporosis, with a promising therapeutic potential in age-related diseases.
年龄相关性骨质疏松症的特征是骨量和骨强度的恶化，部分原因是骨髓间充质基质/干细胞（MSCs）在衰老过程中的功能障碍。α-酮戊二酸（αKG）是三羧酸（TCA）循环中的必需中间产物。研究表明，αKG 延长了蠕虫的寿命，并维持了胚胎干细胞（ESCs）的多能性。在这里，我们表明 αKG 可增加老年小鼠的骨量，减轻与年龄相关的骨质流失，并加速老年啮齿动物的骨再生。αKG 改善了来源于老年小鼠的骨髓 MSCs 的衰老相关（SA）表型，并促进其增殖、集落形成、迁移和成骨潜能。在机制上，αKG 减少了 H3K9me3 和 H3K27me3 的积累，随后上调了 BMP 信号和 Nanog 表达。总之，我们的研究结果阐明了 αKG 在恢复 MSCs 和改善与年龄相关的骨质疏松症中的作用，为与年龄相关的疾病提供了有前途的治疗潜力。
