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Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations.

Nature communications (2020-11-07)
Yuan Wang, Peng Deng, Yuting Liu, Yunshu Wu, Yaqian Chen, Yuchen Guo, Shiwen Zhang, Xiaofei Zheng, Liyan Zhou, Weiqing Liu, Qiwen Li, Weimin Lin, Xingying Qi, Guomin Ou, Cunyu Wang, Quan Yuan
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Fast Blue B Salt, Dye content ~95 %
Sigma-Aldrich
Naphthol AS-BI phosphate, Technical grade
Sigma-Aldrich
α-Ketoglutaric acid, BioReagent, suitable for cell culture, suitable for insect cell culture
Sigma-Aldrich
EZ-Zyme Chromatin Prep Kit, Contains proprietary reagents optimized for the enzymatic shearing of chromatin from mammalian cells at higher resolution than sonication for use in chromatin immunoprecipitation (ChIP) assays.