Tca Cycle Intermediates Improve Bone and Joint Disorders

Tricarboxylic acid (TCA) cycle is known to synthesize a plethora of intermediates by various key enzymes in mitochondrial compartment and is indispensable in producing energy to fuel cellular activity. TCA cycle intermediates, like citrate, also are important building blocks for mineralized extracellular matrix, iron homeostasis, and redox balance for bone and cartilage microstructures. TCA dysfunction is correlated with the development of human osteoporosis and osteoarthritis. Mice deficient in key TCA cycle enzymes specifically in mesenchymal stem cells or osteoblasts develop osteoporosis-like features, including low bone mass, sparse trabecular microarchitecture, and decreased biomechanical strength. Of TCA cycle intermediates, α-ketoglutarate (α-KG) plays an important role in succinate biosynthesis, glutamate metabolism, and redox capacity. In epigenetic pathways, α-KG is an indispensable co-factor of histone demethylases, which remove methylated groups of lysine and arginine in histones to reverse transcription repression. Osteoblast-specific histone lysine and arginine demethylase knockout mice exhibit severe osteoporosis phenotypes with visceral adiposis, fatty marrow, and decreased serum a-KG production. Gain of α-KG function and loss of succinate dehdrogenase activity shift energy metabolism from anaerobic glycoslysis to mitochondrial oxidative phosphorylation to preserve mineralized matrix biosynthesis in osteogenic cells from these gene knockout mice. Notably, decreased serum α-KG levels are correlated with human osteoporosis and knee osteoarthritis. α-KG supplementation improves age- and estrogen deficiency-induced bone loss and counteracts glycosaminoglycan underproduction and senescence in inflamed chondrocytes. This talk conveys productive insight into the canonical and non-canonical functions of TCA cycle intermediates to skeletal tissue metabolism and highlight their disease modifying potential of osteoporosis and osteoarthritis.