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.
Highlights
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
Osteoporosis is the systemic loss of bone mass and exhibits significant degradation in mechanical properties, which subsequently leads to an increased risk of bone fracture[2]
MicroCT analyses showed that vertebral bone volume (BV/TV) of both female and male animals were elevated after αKG administration
Summary
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. As for the treatment of age-associated osteoporosis, FDA/Europe-approved treatments represented by bisphosphonates[5] and recombinant human parathyroid hormone exert their therapeutic effects via either anabolic or anti-resorptive function[6]. Their uses in long-term treatment are limited due to their adverse effects such as osteosarcoma, osteonecrosis of jaw, and atypical femur fractures[6,7]. Recent studies reveal a pivotal role of αKG in maintaining the pluripotency of embryonic stem cells (ESCs)[21] and in anti-aging therapy[22]. Its influence on the agerelated osteoporosis remains to be investigated
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