Essential role of the metabolite α-ketoglutarate in bone tissue and bone-related diseases

Abstract

Bone metabolism in bone tissue is constantly maintained in a state of dynamic equilibrium. The mass of bone and joint tissues is determined by both bone formation and bone resorption. It is hypothesized that disrupted metabolic balance leads to osteoporosis, osteoarthritis, rheumatoid arthritis, and bone tumors. Such disruptions often manifest as either a reduction or abnormality in bone mass and are frequently accompanied by pathological changes such as inflammation, fractures, and pain. α-Ketoglutarate (α-KG) serves as a pivotal intermediate in various metabolic pathways in mammals, significantly contributing to cellular energy metabolism, amino acid metabolism, and other physiological processes. α-KG may be a therapeutic target for a variety of bone-related diseases, such as osteoporosis, osteoarthritis, and rheumatoid arthritis, because of its role in maintaining the metabolic balance of bone. After the application of α-KG, bone loss and inflammation in bone tissue are alleviated. This review focuses on the regulatory effects of α-KG on various cells in bone and joint tissues. Owing to the regulatory effect of α-KG on the balance of bone metabolism, the application of α-KG in the treatment of osteoporosis, osteoarthritis, rheumatoid arthritis, bone tumors, and other bone tissue diseases has been clarified.

Keywords: bone metabolism; osteoarthritis; osteoporosis; periodontitis; rheumatoid arthritis; α-ketoglutarate.

Figure 1

Sources and metabolism of α-ketoglutarate Metabolic sources of α-ketoglutarate: TCA cycle production or the amino acid metabolic pathway. Metabolic pathways of α-KG: (1) Synthetic amino acid: combined deamination to produce glutamic acid glutamine (2) Energy supply for cyclic oxidation of TCAs. (3) Fat synthesis (acetyl coenzyme A forms fatty acids through the TCA cycle, or pyruvate is generated through gluconeogenesis, and pyruvate is converted into glycerol through glycolysis). (4) Synthetic sugars (through the TCA cycle, pyruvate is generated from oxaloacetic acid, and glucose is synthesized through gluconeogenesis)

Figure 2

Regulation of α-KG in osteoblasts, osteoclasts, and mesenchymal stem cells In osteoblasts, α-KG promotes the secretion of glutamate, proline and collagen. In addition, α-KG activates the JNK pathway and downstream of mTOR/S6K1/S6, promotes the expression of Runx2 and Osterix, and then promotes osteogenesis. The α-KG analogue DMAKG activates the BMP2 pathway and promotes osteoblast maturation and bone mineralization. Additionally, α-KG participates in the metabolism of glutamate and arginine through IDH, promotes the secretion of NO by osteoblasts, and increases the activity of osteoblasts. In osteoclasts, α-KG inhibits ROS accumulation in mitochondria through the glutathione pathway, alleviates oxidative stress, and inhibits osteoclast differentiation and maturation. In osteoblasts, α-KG is converted to glutamine, and arginine is subsequently produced to release NO, which inhibits osteoclast maturation through a paracrine mechanism. In IDH2-deficient individuals, the ATF4-NFATc1 pathway in osteoblasts is inhibited, resulting in insufficient secretion of RANKL, which subsequently affects osteoblasts to promote their differentiation and maturation. DMAKG promotes H3K27me3 demethylation inhibition and inhibits osteoclast maturation through the NFATc1 pathway. DMAKG promotes H3K9me3 demethylation, activates the expression of SLC7A11, produces GSH, clears ROS accumulated in mitochondria, and alleviates oxidative stress. Mesenchymal stem cells. (1) Increased glycolysis in stem cells inhibits the expression of superoxide dismutase 2 (SOD2) in cells with excessive accumulation of α-KG, leading to vacuolation of the nuclear cytoplasm and chromatin condensation of mesenchymal precursors, which inhibits the activity of stem cells. (2) DMAKG inhibits the adipogenic differentiation of mesenchymal stem cells and promotes the osteogenic differentiation of stem cells. 3. α-KG can inhibit the accumulation of H3K9me3 and H3K27me3, upregulate BMP signaling, and promote osteogenic differentiation and osteoblast maturation.

Figure 3

α-KG inhibits the inflammation of chondrocytes and synoviocytes and regulates their functional activity (Left) Chondrocytes. 1. α-KG can increase the synthesis of the extracellular matrix by increasing the expression of glutamine in chondrocytes and stimulating the secretion of collagen. 2. α-KG alleviates the morphological abnormalities of chondrocytes by stimulating the secretion of glutamine and hydroxyproline. 3. α-KG inhibits the p-JAK2/STAT3 pathway, reduces inflammation, and reduces the degeneration of nucleus pulposus cells. 4. The α-KG analogue DMOG promotes the expression and nuclear localization of hypoxia inducible factor-1 α-hydroxylase (HIF-1α) and promotes chondrocyte differentiation. 5. HIF-1α increases the content of α-KG through glutamine metabolism, enhances hydroxyproline secretion, and promotes chondrocyte differentiation and maturation. (Right) Synoviocyte. Under anaerobic conditions, TNF-α can promote the accumulation of inflammatory factors such as IL-1, IL-6, PGE and Cox through PI3K-Akt signaling pathway in glycolysis. During this process, the content of α-KG decreased but still participated in the function.

Figure 4

α-KG promotes osteogenic activity, inhibits bone resorption, and alleviates symptoms of osteoporosis α-KG increases the phosphorylation levels of JNK, mTOR, S6K1 and S6 and promotes the expression of Runx2 and Ostreix in osteoblasts. α-KG promotes the osteogenic differentiation of mesenchymal stem cells and increases the level of collagen secreted by osteoblasts. α-KG dimethyl ester (DMAKG) promotes the differentiation and mineralization of osteoblasts induced by BMP2. It can also alleviate the inflammatory response of macrophages stimulated by lipopolysaccharide (LPS) and protect against osteoblast differentiation. α-KG inhibits the activation of the Atf4-NFATc1-Rankl pathway and osteoclast activity through IDH2.

Figure 5

Regulatory role of α-KG in alleviating osteoarthritis and rheumatoid arthritis α-KG promotes the secretion of collagen in the bone and joint matrix through amino acid metabolism and alleviates bone loss in osteoarthritis. α-KG can relieve the accumulation of ammonia toxicity in chondrocytes and inhibit their apoptosis. Dexamethasone and other hormones inhibit the excessive accumulation of ROS in the mitochondria of chondrocytes and relieve oxidative stress injury in these cells. Inhibiting the expression of IL-1β in chondrocytes and inhibiting the degeneration and necrosis of inflammatory chondrocytes. α-KG inhibits the expression of TNF-α and the progression of inflammation. α-KG inhibits the energy supply in the glycolysis of dendritic cells (DCs), inhibits the expression of Th17 cells promoted by Tregs, and inhibits immune inflammation.

Figure 6

α-KG participates in macrophage polarization and bone metabolism in the periodontal environment α-KG promotes M2-type macrophage activation by inhibiting LPS, reduces alveolar bone absorption, and alleviates periodontal inflammation. DMAKG can inhibit the polarization of M1 macrophages in early periodontitis. α-KG around implants in alveolar bone can promote the proliferation, osteogenic differentiation and autophagy of bone marrow mesenchymal stem cells. α-KG can also promote the differentiation and maturation of osteoblasts and inhibit the differentiation and maturation of osteoclasts.