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Iwata, J. Metabolism and Bone Diseases. Encyclopedia. Available online: (accessed on 11 December 2023).
Iwata J. Metabolism and Bone Diseases. Encyclopedia. Available at: Accessed December 11, 2023.
Iwata, Junichi. "Metabolism and Bone Diseases" Encyclopedia, (accessed December 11, 2023).
Iwata, J.(2020, December 29). Metabolism and Bone Diseases. In Encyclopedia.
Iwata, Junichi. "Metabolism and Bone Diseases." Encyclopedia. Web. 29 December, 2020.
Metabolism and Bone Diseases

Bone, a highly mineralized organ that serves as a skeleton of the body, is continuously depositing and resorbing bone matrix to maintain homeostasis. This highly coordinated event is regulated throughout life by bone cells such as osteoblasts, osteoclasts, and osteocytes, and requires synchronized activities from different metabolic pathways. The dysregulation of these metabolic pathways leads to bone disorders.

Bone Development Metabolism Osteoblasts Bone Diseases Osteoclasts Bone homeostasis Bone metabolism

1. Introduction

Bone (re)modeling is responsible for the growth and repair/regeneration of the bony structures by maintaining a balance between bone matrix deposition and resorption during development and homeostasis [1]. Osteoblasts and osteoclasts are the cells responsible for bone deposition/mineralization and resorption, respectively. The functions of bones include acting as a locomotorium coordinated with muscles, tendons, and joints, the support of posture, the protection of the brain and other organs, the storage of minerals, and hematopoiesis in the bone marrow. Because various metabolic networks act in bone tissues, the metabolic status of bone cells affects bone formation and homeostasis via multiple biological reactions. The metabolism comprises complex physical and biochemical processes that allow organisms to generate, maintain, and regenerate their structures as well as respond to environmental cues [2][3]. In recent years, it has been reported that an imbalance of cellular and systemic metabolism is associated with various bone diseases and developmental defects. For example, type I and type II diabetes mellitus, obesity, and dyslipidemia are associated with increased risk of osteoporosis and a delay in bone healing [4][5][6].

2. Cholesterol Metabolism

Cholesterol is crucial as a source of numerous biomolecules, including bile acids, steroid hormones, and oxysterols, and is a vital component of cellular membranes; therefore, dysregulation of cholesterol synthesis leads to cellular dysfunction and results in disease. Its synthesis is regulated by more than 30 biochemical reactions, which are catalyzed by 15 different enzymes [7]. Either upregulation or downregulation of intracellular cholesterol synthesis compromises osteogenesis and chondrogenesis. In addition, there is a positive feedback loop for the expression of genes regulating the sterol metabolic pathway (e.g., Cyp11a1, Cyp39a1, Cyp51, Lss, Dhcr7), which is turn is regulated by Runx2, a key transcription factor associated with osteoblast differentiation. Thus, cholesterol synthesis is directly linked to osteogenic differentiation.

3. Fatty Acid Metabolism

Fatty acid metabolism involves an enzymatic cascade that degrades fatty acids into bioactive substrates and synthesizes straight-chain fatty acids to be stored as triglycerides in adipose tissues. The catabolic pathway starts with the release of free fatty acids from glycerol, consumed in the diet or derived from triglycerides in adipose tissue through lipolysis, followed by transport to peripheral cells and the entire body, according to its needs. Mice with a deficiency of palmitoyl-protein thioesterase 1 (Ppt1; Ppt1−/− mice), acyl-CoA synthetase bubblegum family member 2 (Acsbg2; Acsbg2−/− mice), carnitine palmitoyltransferase 2 (Cpt2; Cpt+/− mice), Cd36, and Gpr40 display various defects in bone formation and/or homeostasis [8][9][10].

4. Glycolysis and Gluconeogenesis

Glycogen, a long, branched polymer of glucose residues, is a readily mobilized storage form of glucose that is mainly present in the liver and skeletal muscles; when the body needs energy, glycogen is broken down into glucose. Excessive glucose addition inhibits cell proliferation and osteogenic differentiation in a dose-dependent manner in human bone marrow mesenchymal stem cells and osteoblast cell lines. Glucose is uptaken through glucose transporters SLC2A1-4 (solute carrier family 2, member 1-4; a.k.a. GLUT1-4). Among them, SLC2A1 is expressed in osteoclasts, osteoblasts, and hypertrophic chondrocytes. The deletion of Slc2a1 in these cells causes  osteoclastogenesis deficiency [11], bone mineralization defects [12][13], and growth plate disorganization [14]. Thus, glucose uptake and the consequent aerobic glycolysis play crucial roles in bone formation and remodeling. Gluconeogenesis is the opposite pathway of glycolysis, where glucose-6-phosphatase (G6PC) catalyzes D-glucose-6- phosphate to D-glucose. Mice with deficient for G6pc exhibit cartilage dysplasia and delaying ossification [15] through suppression of the growth hormone-mediated insulin-like growth factor 1 pathway [16][17].

5. Glycogenolysis and Glycogenesis

Glycogenolysis initiates with the breakdown of uptaken glycogen into glucose-1- phosphate (G1P) by amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase (AGL), and glycogen phosphorylase [18]. AGL has two enzymatic activities—glucosyltransferase and glucosidase—and breaks down (debranches) glycogen into G1P, together with glycogen phosphorylase [19]. In humans, mutations in AGL are associated with glycogen storage disease type III (GSD-III), an autosomal recessive metabolic disorder caused by the accumulation of glycogen in the liver and skeletal muscles, resulting in organ dysfunction. GSD-III is further characterized into two subtypes: 1) GSD-IIIa, which affects only the liver; and 2) GSD-IIIb, which involves both the liver and skeletal muscles. Unlike patients with GSD-IIIa, patients with GSD-IIIb exhibit low bone mineral density [20][21]. In addition, Agl knockout mice (Agl−/− mice) exhibit kyphosis [22].

6. TCA Cycle

The TCA cycle (a.k.a. the citric acid cycle or the Krebs cycle) is an essential metabolic cycle present in the mitochondria of all aerobic organisms. Through glycolysis, pyruvic acid and fatty acyl-CoA are converted into acetyl-CoA, with subsequent synthesis of guanosine triphosphate (GTP)/ATP, NADH, and amino acids. Studies in mice have shown that a deficiency of Idh1 (isocitrate dehydrogenase 1, cytosolic) and Sdhc (succinate dehydrogenase complex subunit C) in the TCA cycle pathway induces defects in bone formation and/or homeostasis. In addition, exogenous supplementation of D-2-hydroxyglutarate inhibits osteoblast differentiation and bone formation [23].

7. Phospholipid Metabolism

Phospholipids are synthesized in the endoplasmic reticulum and include a hydrophobic fatty acid tail and a hydrophilic head that form the lipid bilayer in the eukaryotic plasma membrane. The metabolites of phospholipids serve as second messengers in signal transduction [e.g., phosphatidic acid (PA), phosphatidylinositol-(4,5)-bisphosphate (PIP2), diacylglycerol (DAG), and prostaglandins]. Phosphatidylserine receptors such as TIM4, BAI1, and STAB2 are expressed in mature osteoclasts; blocking these receptors or reducing extracellular phosphatidylserine inhibits fusion of pre-osteoclasts without affecting osteoclastogenesis [24][25]. In the phospholipid metabolic pathway, mice with a deficiency of either choline O-acetyltransferase (Chat), choline kinase beta (Chkb), phosphoethanolamine/phosphocholine phosphatase (Phospho1), phospholipase A2 group VI (Pla2g6), membrane-bound O-acyltransferase domain containing 7 (Mboat7), 1-acylglycerol-3-phosphate O-acyltransferase 3 (Agpat3), or 1-acylglycerol-3-phosphate O-acyltransferase 4 (Agpat4) exhibit defects in bone formation and/or homeostasis [26][27][28][29][30][31][32].

8. Summary

There are a variety of metabolic pathways that may affect bone development and homeostasis. While there is significant evidence showing a possible link between bone diseases and metabolic disorders, the specific players and molecular interactions in these metabolic networks remain to be determined.


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