Introduction

Bone is a vital organ that is constantly remodeled throughout the lifetime1. Bone consists of cortical bone that surrounds a central bone marrow cavity and trabecular bone that traverses a bone marrow cavity. Bone includes various components, including bone cells such as osteoclasts, osteoblasts, and osteocytes, along with the extracellular matrix. Bone matrix is composed of organic and inorganic components. The breakdown of bone by osteoclasts releases ions, organic acids, and proteases and provides metabolic substrates to fuel metabolic anabolism in bone resident cells, including stem cells, immune cells, and bone cells. Liberated phosphate, magnesium, and calcium play a critical role in cellular metabolism by providing co-factors for metabolic enzymes and modifying metabolites.

Bone plays a central role in providing structural support to the body, protecting organs, and facilitating locomotion and sensory perception1. On the other hand, bone also serves additional functions2. Bone acts as storage for vital minerals and other essential ions2,3. Additionally, bone is a source of stem cells and bone marrow provides an ideal environment for the process of hematopoiesis. Hematopoiesis takes place at “niches” situated inside the bone marrow, within the central cavity of bones4. Importantly, bone is also considered to be an endocrine organ as bone releases various proteins, hormones, and growth factors into the circulation and affects other cells’ function and energy homeostasis5,6. However, these diverse functions of bone have been overlooked.

The bone microenvironment is constantly changing due to multiple factors such as aging, lifestyle, health conditions, nutritional status, and pathological conditions. Bone cells constantly undergo metabolic adaptation to counter these changes. Bone is affected by the metabolic status of individuals. However, the mechanisms behind this process and the bioenergetic characteristics of bone cells are not yet fully understood. It is crucial to comprehend the metabolic needs of various bone cells to gain a deeper understanding of bone diseases and create cell-specific treatments for bone cells. In this review, we aim to present an overview of the current knowledge on metabolic reprogramming in certain bone cells.

Bone cells

Bone is continuously being maintained through bone remodeling, a delicate process balanced between osteoclastic bone resorption and osteoblastic bone formation7. Osteoclasts, osteoblasts, and osteocytes are key cells involved in bone remodeling (Fig. 1). Old and/or damaged bone is constantly replaced with newly formed bone by the coordinated actions of bone cells. Bone remodeling plays a crucial role in maintaining and modifying bone structure, repairing micro-cracks and fractures, and maintaining blood calcium homeostasis. The process of bone remodeling is tightly regulated and is affected by numerous factors, such as metabolic hormones and the availability of nutrients. A disruption in this balance can lead to poor bone health and diseases.

Fig. 1: Bone remodeling.
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Bone remodeling is a fundamental process to maintain bone throughout life. It involves the removal of old bone tissue by osteoclasts and subsequent formation of new bone formation by osteoblasts. Maintaining a balance between these two types of cells is tightly regulated and essential for healthy bone homeostasis. Osteoclasts are multinucleated cells that originate from myeloid lineage cells. Osteoclasts are multinucleated cells that originate from hematopoietic stem cells. Osteoclast precursor cells fuse with each other to form these multinucleated cells. The formation of osteoclasts is activated by RANKL. On the other hand, mesenchymal stem cells differentiate into osteochodroprogenitors. Osteochondroprogenitor cells further differentiate into preosteoblasts that eventually mature into osteoblasts. A subpopulation of osteoblasts undergoes terminal differentiation to osteocytes which are embedded within the bone tissue. Osteocytes play a crucial role in controlling both osteoblasts and osteoclasts.

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Osteoclasts

Osteoclasts are multinucleated cells responsible for bone resorption and are derived from precursor cells in a myeloid cell origin8,9,10. Osteoclasts were traditionally considered terminally differentiated cells. However, recent studies have discovered that they are long-lived, constantly renewed by circulating precursors11, and recycled by fusion and fission of osteomorphs12. High energy is required for cell-cell fusion during osteoclast differentiation and bone resorption. Osteoclasts not only resorb bone but also play a role in regulating additional functions, including hematopoiesis, stem cell mobilization, and specific immune functions13. Dysregulated osteoclast formation and activity are linked to various bone diseases such as osteoporosis, osteopetrosis, rheumatoid arthritis, bone metastasis, and periodontitis. M-CSF (macrophage colony-stimulating factor) and RANKL (receptor activator of nuclear factor kB ligand) are key factors for osteoclast differentiation and function. M-CSF is an essential growth factor for the differentiation and survival of myeloid cells14. RANKL is a key driver of osteoclast differentiation and has been used as a therapeutic target for bone loss. Denosumab, an anti-human RANKL monoclonal antibody, is an FDA-approved anti-resorptive drug for osteoporosis and pathological bone loss by competitively inhibiting the RANKL-RANK interaction15,16. However, in certain pathological conditions, such as inflammatory arthritis, RANKL-independent osteoclastogenesis has been observed (reviewed in ref. 17).

Osteoblasts

Osteoblasts promote mineralization and bone formation by synthesizing osteoid and secreting bone matrix. The skeletal lineage cells are involved in osteogenesis and undergo three distinct differentiation stages: osteoprogenitor, preosteoblasts, and osteoblasts18. During bone remodeling, osteoblasts require ATP to increase collagen biosynthesis and mineralization.

Mesenchymal stem cells (MSCs) can differentiate into multiple cells in the skeletal system, including osteoblasts, osteocytes, chondrocytes, fibroblasts, adipocytes, stromal cells, and myoblasts19. Osteoblasts can be derived from multicomponent MSCs and skeletal stem cells (SSCs)20. Various stem cell-specific markers have been identified, and recent studies suggest that osteoblasts in different bones may have originated from site-specific stem cells. Osteochondroprogenitor cells originate from precursors that express SOX9 and can differentiate into chondrocyte and osteoblast-lineage cells21. After the synthesis of type I collagen, the main component of bone matrix, the Runt-related transcription factor 2 (Runx2) is expressed in preosteoblasts. Runx2 is a key determinant of osteoblast differentiation22. Runx2 is required for the commitment of preosteoblasts to osteogenic lineage and induces the expression of major bone matrix genes, leading to the formation of immature bone22. During the maturation of preosteoblasts, osterix (OSX, also known as Sp7), which is induced by the WNT-β catenine signaling, directs the differentiation of preosteoblasts to osteoblasts23. Mature osteoblasts differentiate into lining cells or osteocytes or undergo apoptosis.

Osteocytes

Osteocytes, which are derived from a subset of osteoblasts, are terminally differentiated cells embedded within the mineralized bone matrix24,25. Osteocytes are the most abundant cells in bone and are a master regulator of bone remodeling. Osteocytes respond to hormonal and mechanical signals and orchestrate bone homeostasis by controlling osteoblasts and osteoclasts. Mature osteocytes selectively secrete molecules such as Dickkopf-related protein 1 (DKK1), osteoprotegerin (OPG), and sclerostin. Osteocytes are a mechanosensory cell, and the mechanical loading regulates the lifespan and the gene expression of osteocytes26. There are several mechanosensors in osteocytes, including the osteocyte cytoskeleton, dendritic processes, integrin-based focal adhesions, connexin/pannexin channels, primary cilium, ion channels, and extracellular matrix27. During the mechanotransduction process, osteocytes decrease the expression of sclerostin, leading to increased bone formation through the activation of WNT signaling in osteoblasts.

Bone cells and energy metabolism

Bone cells use various metabolic pathways, such as carbohydrate metabolism, energy metabolism, lipid metabolism, nucleotide metabolism, and amino acid metabolism, to obtain energy for their survival, differentiation, and function (Fig. 2).

Fig. 2: Energy metabolism.
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In bone cells, energy is generated by interconnected metabolic pathways, including glycolysis, the tricarboxylic acid cycle (TCA cycle), glutaminolysis, and oxidative phosphorylation (OXPHOS). Glucose is the primary energy and carbon source for bone growth and development. The transportation of glucose by glucose transporter (GLUT) proteins occurs spontaneously along a concentration gradient, without the need for energy. Once inside the cell, glucose is converted to glucose-6-phosphate (G6P) by hexokinase, which can then be used to generate glycogen or enter the glycolytic pathway to generate pyruvate. Glycolysis coupled with lactic acid fermentation and oxidative phosphorylation in the mitochondria produces adenosine triphosphate (ATP), the most important high-energy chemical in the body. Lactate dehydrogenase (LDH) can also convert glucose to lactate independently of oxygen through aerobic glycolysis. The glucose 6-phosphate, produced early in glycolysis, can be directed towards the pentose phosphate pathway, leading to nucleotide synthesis, or it can contribute to the serine synthesis pathway, which is important for amino acid production. The serine biosynthetic pathway, which generates methyl groups for DNA and histone methylation, is also vital for one-carbon metabolism. OXPHOS occurs in the mitochondria and is the final metabolic pathway for all oxidative steps in carbohydrates, amino acids, and fatty acid catabolism. The electron carriers NAD+ and NADP+ drive the ETC for oxidative phosphorylation, resulting in the production of ATP. The Krebs cycle, also known as the tricarboxylic acid cycle (TCA), is the primary metabolic pathway that produces energy in cells and provides reduced co-factors and metabolic intermediates. Acetyl CoA, derived from pyruvate, is also supplied by the TCA cycle and acts as a central hub to promote intracellular lipid synthesis. Parallel to these processes, glutamine is metabolized through glutaminolysis, contributing to the pool of substrates necessary for energy production and biosynthesis in bone cells. TCA cycle tricarboxylic acid cycle, Acetyl CoA acetyl coenzyme A, NAD+ nicotinamide adenine dinucleotide, NADP+ nicotinamide adenine dinucleotide phosphate, ETC electron transport chain, ATP adenosine triphosphate.

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Glycolysis

Osteoclasts and glycolysis

Osteoclast formation requires both glycolytic and oxidative metabolism to meet high-energy requirements. Glycolysis is crucial for osteoclast activity, especially when resorbing the bone matrix28,29,30,31. During osteoclastogenesis, RANKL stimulation induces the expression of glycolytic genes and glucose uptake. Mature osteoclasts consume glucose as their primary source of nutrients17. Immunostaining experiments reveal that several key glycolytic enzymes are located in the actin ring of polarized mature osteoclasts that adhere to the bone surface32. Osteoclast precursor cells express glucose transporters, including GLUT1 and GLUT3, while GLUT1 is upregulated in mature osteoclasts29. GLUT1 deficiency in LysM Cre suppresses in vitro osteoclastogenesis while exhibiting an osteopetrotic bone phenotype only in female mice33, supporting the independent role of aerobic glycolysis in osteoclast differentiation. However, the mechanism for female-biased phenotype is not clear. Increased glycolysis leads to the accumulation of glycolytic intermediates that regulate osteoclastogenesis. High concentrations of fructose 1,6-bisphosphate, one of glycolytic intermediates, have been shown to inhibit RANKL-induced osteoclastogenesis and TRAP activity by inhibiting the NF-kB/NFATc1 pathway in mouse bone marrow (BM)-derived osteoclasts in vitro34. During osteoclastogenesis, glycolysis-derived lactate progressively increases and supports bone resorption28. The expression of lactate dehydrogenase (LDH), which catalyzes the conversion of pyruvate to lactate, is elevated in mature osteoclasts. Deletion of LDHA or LDHB subunits suppresses both glycolysis and mitochondrial respiration, leading to impaired fusion of osteoclast precursor cells35. Inhibition of glycolysis with 2-deoxy-glucose (2DG) suppresses osteoclastogenesis and bone resorption, whereas the addition of lactate and pyruvate restores impaired osteoclastogenesis. Additionally, individual glycolytic intermediates can be further utilized in other metabolic pathways36. Coactivator-associated arginine methyltransferase 1 (CARM1) mediates arginine methylation of PPP1CA and reprograms glucose metabolism in osteoclasts and osteoblasts by switching from oxidative phosphorylation to aerobic glycolysis, resulting in enhanced osteogenic differentiation and impaired osteoclast differentiation37.

As oxygen tension is very low in bone38, bone tissue exhibits a hypoxic nature. While there is conflicting evidence on the impact of hypoxia on osteoclasts, most studies indicate that hypoxia increases both osteoclast formation and activity and leads to an increase in the glycolytic flux in osteoclasts39. Hypoxia-inducible factor (HIF)-1 is a key regulator of cellular response to hypoxia and is stabilized in hypoxic microenvironments. When osteoclasts are formed under hypoxia, they exhibit increased expression of HIF-1 and glycolytic enzymes. Blocking glycolytic enzymes reduces acid secretion from hypoxic osteoclasts, and chemical inhibition of phosphofructokinase E1 (PFK1) and LDHA significantly reduces hypoxia-induced osteoclast formation40. Osteoclasts under hypoxic conditions increase ATP production by consuming more oxygen and using HIF-1α-dependent glucose uptake41. However, the role of HIF-1 proteins in osteoclasts remains controversial42. While knockdown of HIF-1α inhibits bone resorption by mature osteoclasts, studies show that osteoclast differentiation is not affected by the deficiency of HIF-1α29,43. Another study shows that hypoxia suppresses the copper metabolic domain containing 1 (COMMD1), which then leads to an increased expression of E2F1, a transcription factor that primarily controls the cell cycle in non-proliferating human osteoclast precursor cells (OCPs) in response to RANKL44. E2F1 increases the expression of genes in glycolysis. A recent study shows that RANKL-induced LSD1 stabilizes the HIF-1α protein in OCPs, leading to increased glycolysis in conjunction with E2F1, which is also upregulated by LSD145. These observations indicate that increased glucose metabolism fuels bone resorption, contributing to osteoclast-mediated pathologies.

Osteoblasts and glucose metabolism

Glucose is an essential nutrient for osteoblast differentiation and bone formation, as demonstrated in early studies showing the rapid consumption of glucose by bone explants and isolated osteoblasts46,47,48. Glucose provides energy and a carbon source for bone-building block molecules. Studies using radiolabeled glucose analogs confirm significant uptake of glucose by mouse bones49,50. It is estimated that approximately 40% of ATP in immature osteoblasts and nearly 80% of ATP in mature osteoblasts are produced through glycolysis51,52,53. Osteoblasts express GLUT1, GLUT3, and GLUT4, which show distinct expression patterns and functions for osteoblast proliferation and differentiation49,54,55,56. GLUT1 is essential for osteoblast differentiation, and genetic studies in mice demonstrate that it is required for the osteoanabolic activity of WNT7b49,57. In addition, GLUT1 helps regulate RUNX2 protein expression by maintaining ATP levels to limit AMPK activation and preventing the proteasomal degradation of RUNX245. However, glucose flux is not able to initiate bone formation when RUNX2 is not present, suggesting the feed-forward requirement between RUNX2 and GLUT1 for increased glucose uptake and matrix production in osteoblasts. However, the impact of GLUT1-mediated glucose uptake on osteoblast differentiation varies by differentiation stages and may be transient. GLUT1 deletion with Prx1 Cre shows severe limb shortening and impaired chondrocyte proliferation and hypertrophy52. GLUT1 deficiency with osteocalcin (OCN) Cre exhibits diminished bone mass, while GLUT deficiency with Col1 Cre displays a high bone mass49. GLUT4 regulates insulin-stimulated glucose uptake and in vitro osteoblast differentiation. GLUT4 deficiency with OCN Cre exhibits an increase in peripheral fat in association with hyperinsulinemia, β-cell islet hypertrophy, and reduced insulin sensitivity but shows normal bone architecture55, suggesting the redundant and transient role of GLUT proteins in osteoblast differentiation.

Lactate is a major byproduct of glycolysis in osteoblasts regardless of the presence of oxygen. Lactate production increases in primary osteoblasts during differentiation58,59. The Warburg effect (aerobic glycolysis) is observed in in vitro cultures of osteoblasts. Metabolic tracing with labeled glucose confirms that lactate is the predominant product of glycolysis in the cortical bone of mouse long bone in vivo60. Lactate promotes osteoblast differentiation by several mechanisms, including stabilizing HIF-1, enhancing the effect of PTH and acetylation of p300, and limiting the generation of reactive oxygen species (ROS) and oxidative stress. Moreover, lactate serves as a major carbon source of histone lactylation that is involved in promoting osteoblast differentiation61. Glycolysis in osteoblast lineage cells is known to be directly stimulated by various bone anabolic signals. Parathyroid hormone (PTH) stimulates both bone formation and bone resorption. PTH stimulates glucose consumption and lactate production during bone explants48,62,63 and in osteoblasts54,63,64,65,66,67. In a study using MC3T3-E1 cells, PTH was found to stimulate aerobic glycolysis through the activation of insulin-like growth factor (IGF) signaling67. Conversely, reducing aerobic glycolysis with dichloroacetic acid (DCA) markedly suppressed PTH-mediated bone anabolism, supporting a functional link between glycolysis and bone formation67. Other signals, including the wingless/int-1 (Wnt) pathway, the myokine irisin, and nitric oxide (NO), also regulate glycolysis in osteoblasts68,69. MiR-34a targets the expression of glycolytic enzymes, thereby impeding osteoblast differentiation in human MSCs70. Therefore, the activation of aerobic glycolysis is a crucial mechanism underlying the osteoanabolic effects of PTH and is regulated by various signals that are important for bone formation.

Bone cells and oxidative phosphorylation

Osteoclasts and oxidative phosphorylation

Oxidative phosphorylation (OXPHOS) is one of the preferred bioenergetic pathways for supporting osteoclast differentiation. Inhibiting OXPHOS suppresses osteoclastogenesis71. Osteoclast differentiation is accompanied by an increase in the number of mitochondria72, an increased expression of enzymes involved in metabolic pathways, increased metabolites73, and increased OXPHOS71. Peroxisome proliferator–activated receptor-gamma coactivator 1β (PGC1β), mitochondrial DNA, or mitochondrial transcription factor (Tfam) can stimulate the mitochondrial biogenesis during osteoclastogenesis74,75. There is controversy regarding the prerequisite of mitochondrial biogenesis for osteoclast differentiation, as there are conflicting results regarding the bone phenotype of myeloid-specific PGC1β-deficient mice76,77. OXPHOS generates ATP for osteoclast differentiation while RANKL-induced OXPHOS is diminished in mature osteoclasts71. The MYC-ERRa axis serves as an upstream regulator of OXPHOS without regulating mitochondrial biogenesis, while MYC also activates NFATc1 and the osteoclastogenic program71. The electron transport chain (ETC) complexes in mitochondria produce mitochondrial reactive oxygen species (ROS) and intermediate metabolites that regulate a variety of cellular functions. Inhibiting the ETC complexes or the mitochondrial network also suppresses osteoclastogenesis, supporting the significance of OXPHOS in osteoclast differentiation (reviewed in refs. 17,78). Several studies suggest that alternative metabolic pathways, such as fatty acid oxidation or amino acid metabolism, may be necessary for OXPHOS in osteoclasts. L-arginine suppresses TNFα-mediated osteoclast formation and protects against inflammatory bone loss by perturbing energy metabolism from glycolysis to oxidative phosphorylation79. Although lactate-producing glycolysis occurs independent of OXPHOS in osteoclasts33, knockdown of LDHA or LDHB suppresses osteoclastogenesis and mitochondrial respiration35, suggesting the significant but uncharacterized role of the crosstalk between glycolysis and OXPHOS in osteoclasts.

Osteoblasts and oxidative phosphorylation

Although glycolysis is the primary mode of energy metabolism in osteoblasts, there is an increase in OXPHOS along with the expansion of the mitochondrial network during osteoblast differentiation58,80,81. However, the use of OXPHOS-driven ATP generation in osteoblasts varies based on cell differentiation stages or cell sources. In bone marrow stromal cells (BMSCs), oxidative phosphorylation provides ATP at the early stage of osteoblast differentiation but glycolysis plays a significant role in energy production in mature osteoblasts53,58. A recent study analyzes cellular metabolism in MC3T3-e1 cells at the single-cell level using two-photon microscopy and shows that osteoblasts undergoing mineralization may use OXPHOS as an energy souce82. During osteogenic differentiation, human mesenchymal stem cells (MSCs) activate OXPHOS while undifferentiated human MSCs are more dependent on glycolysis83. Misra et al. show that BMSCs use OXPHOS for ATP generation in the early stage of differentiation, while mature osteoblasts depend on glycolysis53. Altering OXPHOS affects osteoblast differentiation and function. The deletion of Evolutionarily Conserved Signaling Intermediate in Toll pathways (ECSIT) in skeletal progenitors results in impaired OXPHOS, skeletal deformity, defects in the bone marrow niche and spontaneous fractures84, supporting the potential link between OXPHOS and osteoblast differentiation. Similarly, reducing OXPHOS by targeting the nuclear receptor PPARδ inhibits osteoblast differentiation in vitro and bone formation in vivo85. On the other hand, forced stimulation of OXPHOS leads to the activation and acetylation of β-catenin and promotes osteoblast differentiation86. Mitochondrial dysfunction impacts osteoblast formation and is linked with accelerated bone loss87. Lee et al. showed that mitochondrial malic enzyme sustains aerobic glycolysis, suggesting a functional coupling between the mitochondria and aerobic glycolysis in osteoblasts60. PTH treatment of primary calvarial cells or MC3T3E1 cells stimulates both aerobic glycolysis and oxidative phosphorylation88. A recent study shows that PTH regulates the function of the ETC through induction of mitochondrial complex I and II activity, while PTH acutely induces glycolysis in the presence of exogenous glucose89. When glycolysis is inhibited, osteoblasts increase OXPHOS to generate ATP, indicating the dynamic regulation between glycolysis and OXPHOS for the metabolic adaptation of osteoblasts.

Bone cells and lipid metabolism

Lipids affect the function and differentiation of bone cells90. Lipid species such as cholesterols and fatty acids are circulating and are present in the bone marrow sera91. The oxidation of dietary lipids is a critical source of ATP for many cells and fuels bone remodeling. Cholesterols are delivered to the tissues by LDL through LDL receptor-mediated endocytosis92. The levels of LDL-cholesterol in the circulation have a strong inverse correlation with bone mineral density (BMD)93. Skeletal fatty acid utilization contributes to whole-body lipid homeostasis (Fig. 3). Dyslipidemia, a condition characterized by abnormal levels of lipids in the blood, can lead to an excessive accumulation of fat and adversely affect the skeletal system. Additionally, dyslipidemia indirectly affects bone loss by increasing parathyroid hormone, homocysteine, and lipid oxidation products, or by affecting estrogen, vitamin D, and K levels94. Among fatty acids, short-chain fatty acids (SCFAs) are produced in the gut by microbial fermentation of dietary fiber and provide a beneficial effect on bone homeostasis95,96,97. It is important to note that bone marrow is an important site for fat storage98, and marrow adipose tissues occupy over 70% of bone marrow space. Bone mass shows an inverse correlation with marrow fat99. Emerging evidence indicates the contribution of lipid species from membrane phospholipids, including sphingosine-1-phosphate, to skeletal health. Further studies are required to understand the local action of lipids in the bone environment and the underlying mechanism of lipid-mediated regulation of bone cells.

Fig. 3: Fatty Acids regulate bone cells.
figure 3

Fatty acids are classified according to the presence and number of double bonds in their carbon chain: saturated fatty acids (SFA) contain no double bonds, monounsaturated fatty acids (MUFA) contain one, and polyunsaturated fatty acids (PUFA) contain more than one double bond. There are numerous types of SFA according to the length of their chain (containing 4–16 carbon atoms). PUFAs, such as alpha-linolenic acid (an omega-3 fatty acid) and linoleic acid (an omega-6 fatty acid), are called essential fatty acids because they are precursors to vitamins, cofactors, and derivatives, but our body cannot synthesize them. Fatty acids have both positive and negative effects on the regulation of osteoclasts (green cells and lines) and osteoblasts (orange cells and lines).

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Osteoclasts and lipid metabolism

It is well-documented that lipids play a critical role in the survival, formation, and activity of osteoclasts90. Cholesterol can be obtained through both delivery and biosynthesis processes in osteoclasts. Increased cholesterol delivery via LDL significantly increases osteoclast viability100. Depleting cholesterol uptake in osteoclast via HDL or cyclodextrin treatment dose-dependently induced apoptosis101. The depletion of LDL suppresses osteoclast formation, and resupplying oxidized LDLs reverses the impaired osteoclastogenesis in the LDL-depleted serum102. Osteoclast lineage cells express genes involved in the cholesterol biosynthesis pathways, such as HMG-CoA reductase. Osteoclasts have lower expression of HMGCR compared to liver cells, and its expression level is not upregulated upon depletion of cholesterol from the plasma membrane101, suggesting the lack of feedback regulation of the cholesterol biosynthesis pathway during osteoclastogenesis. Statins are FDA-approved drugs targeting the cholesterol biosynthesis pathway and lowering cholesterols103. Clinical and animal studies show that statins increase BMD and prevent pathological bone loss and fractures90,104. These data suggest that both cholesterol uptake and de novo biosynthesis contribute to osteoclast differentiation, and reducing cholesterol levels may have a positive impact on bone health.

Different types of fatty acids (FA) have differential effects on osteoclast formation (Fig. 3). Common saturated fatty acids (SFAs), such as lauric acid and palmitic acid, are reported to enhance osteoclastic action by enhancing osteoclast survival105 or inducing osteoclast differentiation106,107. Palmitoleic acid inhibits RANKL-induced osteoclast differentiation from RAW264.7 through suppression of MAPK and NF-kB signaling108. Oleic acids, a mono-unsaturated FA, both positively and negatively regulate osteoclastogenesis106,109. Other unsaturated fatty acids (UFAs) inhibit human osteoclastogenesis by activating peroxisome proliferator-activated receptors (PPARs) through the inhibition of the RANKL signaling pathway110 or by reducing key signaling transduction pathways111. SCFAs are known to suppress osteoclastogenesis95,96. Although acetate does not protect mice from OVX-induced bone loss, feeding other SCFAs to ovariectomized mice, collagen-induced arthritic mice, or K/BxN serum transfer-induced arthritic mice protects mice from bone loss95,112. Medium-chain fatty acids such as capric acid also suppress osteoclastogenesis113. It is likely that different species of fatty acids have varying effects on osteoclastogenesis.

Recently, the importance of mitochondrial fatty acid β-oxidation (FAO) in osteoclast differentiation has been recognized. FAO converts long-chain FA to acetyl-CoA and plays a key role in the production of ATP and mitochondrial NADPH. Mature osteoclasts significantly increase FAO. Blocking FAO by deleting key enzymes of FAO, such as carnitine palmitoyltransferase 1a (Cpt1a) or Cpt2, in osteoclast progenitors suppresses in vitro osteoclastogenesis in both males and females. Interestingly, this negative impact of blocking FAO on in vivo osteoclastic bone resorption is observed only in female mice109,114, suggesting that FAO is differentially utilized by female-specific factors. Taken together, since diets and microbiomes have a significant contribution to the supply and processing of fatty acids, manipulating fatty acid metabolism can be a potential therapeutic strategy for bone diseases.

Osteoblasts and lipid metabolism

Osteoblast differentiation is primarily dependent on glycolysis (see “Bone Cells and Glycolysis” section). Emerging evidence shows that lipid metabolism is also important for osteoblast function, although its mechanism has not been clearly defined yet115. Cholesterol and its derivatives regulate osteoblast differentiation and their cellular functions116,117. However, the relationship between cholesterols and bone formation is quite complex. A series of studies have shown that exogenous cholesterol can inhibit in vitro osteoblast differentiation and the expression of osteoblastic genes118. In contrast, cholesterol treatment on mouse MSCs has been found to increase cell number and alkaline phosphatase (ALP) activity, along with an increase in gene expression of bone morphogenetic protein-1 (BMP1), Runx2, and Bglap2. Additionally, inhibiting acyl-CoA: cholesterol acyltransferase (ACAT) has been shown to attenuate osteogenesis, suggesting the essential role of cholesterol esters in osteoblast differentiation116. Oxidized LDLs inhibit osteoblast survival and mineralization119. Specific oxysterols, a product of cholesterol oxidation, show a pro-osteogenic effect on pluripotent mesenchymal cells120. Recent studies also show the dual role of cholesterol in bone formation. In ST2 bone marrow stromal cell lines, exogenous cholesterol treatment decreased the expression of osteoblast marker genes and ALP activity, while the physiological levels of endogenous cholesterol are critical for osteogenic response to Purmo121.

SFAs inhibit osteoblast differentiation and induce lipotoxicity and cell death. However, a recent study shows that endogenous FAs stored in lipid droplets can be utilized during osteoblast maturation122. Long-chain PUFAs such as EPA and DHA positively regulate osteoblast survival and differentiation. FAO increases in mature osteoblasts, and the Wnt-Lrp5 signaling pathway induces genes related to FAO. Mice lacking Lrp5 in osteoblasts and osteocytes exhibit a decrease in bone mass with increased body fat123. Cpt2 deletion with OCN-CRE impairs in vitro osteoblast differentiation and results in increased lactate production. However, FAO affects postnatal bone acquisition dominantly in female mice124. Further research is needed to discover factors that are specific to females and related to FAO. While the promoting effect of SCFAs on bone mass is evident, the direct role of SCFAs on bone formation is still controversial. Butyrate promotes bone formation. Acetate, one of the SCFAs, increases bone mass by enhancing bone formation in a T cell-dependent manner97. However, other studies show a minimal effect of SCFAs on osteoblasts. Taken together, lipid metabolism plays a key role in osteoblast function, although the source of fatty acids and the dual role of cholesterols need to be clarified. Furthermore, there is an increasing appreciation of the critical role of SCFAs in bone metabolism and inflammation, as well as the therapeutic potential of dietary fatty acids (FAs) in bone diseases.

Nutrition and bone health

Nutrition plays a critical role in maintaining the health of our bones and metabolism in our bodies125. A well-balanced diet and sufficient intake of essential nutrients are crucial for optimal bone health. Adequate nutrition plays a significant role in postnatal bone formation, and metabolic disturbances can affect it.

The current research supports the idea that the consumption, digestion, and storage of fats play a crucial role in bone health. Obesity is characterized by an abnormal accumulation of excessive fat in the body, which is defined by a body mass index (BMI) over 30. A World Health Organization (WHO) report revealed that the prevalence of obesity in the European region has reached epidemic proportions with 59% of adults and nearly 1 in 3 children affected by overweight or obesity126. Obesity is a complex disorder associated with a wide range of complications and is a condition with a low-grade, systemic inflammatory state via the release of pro-inflammatory cytokines, such as leptin, TNF-alpha, and IL-6127. Obesity leads to other diseases, including diabetes, characterized by insulin insensitivity, cardiovascular diseases, and musculoskeletal disorders. There is an increased risk of fractures and bone fragility among obese individuals compared to normal-weight individuals128. However, the impact of obesity on bones is still controversial. Multiple population studies report a positive correlation between BMI and bone mass density (BMD) in both weight-bearing and non-weight-bearing bones for men and women129,130,131, suggesting that obesity is associated with increased bone mass in humans. The positive correlation between obesity and bone can be explained by multiple factors, such as an increase in load-bearing activity, increased estrogens released by adipose tissue, and/or an increase in mesenchymal progenitor cells that can differentiate into either osteoblasts or adipocytes132. In contrast, other studies report that obese subjects have a site-specific increase in BMD or have normal or slightly low BMD compared to non-obese subjects133. Romagnoli et al. show that the TBS (trabecular bone score) is inversely related to BMI134. A recent study demonstrates that obese postmenopausal women have higher bone resorption markers and lower bone formation markers than non-obese control subjects135, suggesting a reduction in trabecular bone and altered bone turnover markers may be related to an increased fracture risk in obese people. In addition, an inverse correlation between BMD and obesity has been documented in sarcopenic obesity and high-fat-fed animal mice136,137. Developing children and adults who are fed high-fat diets (aka Ketogenic diets) also observe a decrease in total BMD138,139. The mechanism underlying an increased risk of fracture in individuals with obesity and the interplay between metabolism-associated environment and bone cells are not fully characterized yet.

The uptake of key nutrients of bone, including vitamin D and calcium, affects bone mass140. Vitamin D is a steroid hormone that plays a vital role in maintaining calcium and phosphate homeostasis and calcium absorption. Vitamin D affects bone metabolism and metabolic diseases such as obesity, diabetes, and NAFLD. While vitamin D3 (cholecalciferol) is mainly produced from the skin by sunlight exposure, the synthesis of vitamin D3 varies by various factors such as age and season. Vitamin D also regulates non-skeletal tissues such as adipocytes, and adipocytes are a main vitamin D storage site. Individuals with obesity have lower levels of vitamin D in the circulation due to increased clearance of vitamin D141. Vitamin D deficiency leads to decreased calcium absorption, secondary hyperparathyroidism, high bone turnover, bone loss, bone fractures, and mineralization defects. Severe vitamin D deficiency causes osteomalacia in adults and rickets in children. However, the effect of vitamin D supplementation on BMD is still inconclusive and the optimal levels of vitamin D may differ by disease status or the levels of obesity of individuals. There are many other nutrient factors affecting bone and energy metabolism (reviewed in ref. 142), which are not discussed in this review.

Prospects

Research over the past decades has established metabolism as a fundamental requirement underlying bone cell function in health and disease. However, we are just beginning to understand the effects of metabolic signaling on bone cell activation and how metabolic coordination works during bone cell differentiation. This review discusses the current understanding of the role of glycolysis, lipid metabolism, and OXPHOS in bone cell differentiation and function. However, other metabolic pathways, such as glutamine and amino acid metabolism (reviewed in ref. 143), also play an essential role in the differentiation and activity of bone cells.

Bone functions as an endocrine organ. Critical regulators of the skeleton, such as WNT, RANKL, osteoprotegerin (OPG), and sex hormones, are significantly affected by the nutrition and metabolic status of the body144. Moreover, the other direction from bone cells to the body has been revealed. Bone cells produce bioactive proteins which circulate through blood and target other organs, affecting their energy homeostasis145. One of the examples is osteocalcin146. Osteocalcin promotes glucose uptake, controls insulin sensitivity outside bone, and contributes to energy metabolism in the whole body. However, many questions still remain in the field. Our knowledge about the bioenergetics of osteocytes is currently very limited147. However, it is hard to isolate functional mitochondria or test metabolic analysis in osteocytes from mineralized tissue. Since these cells play a crucial role in the process of bone repair and regeneration, it is essential to understand how their metabolic changes affect their functions. The next question is how environmental cues associated with metabolism further shape bone remodeling. Extensive communication among bone cells plays a significant role in bone remodeling. However, we don’t fully understand how metabolism contributes to the complicate networks of bone cells. Moreover, multiple signaling pathways are activated or deactivated during the differentiation and function of bone cells. However, we still need to uncover how various metabolic pathways contribute to key signaling transduction pathways in bone cells. Energy metabolism generates metabolic intermediates used as substrates and co-factors for epigenetic enzymes, which shape the epigenetic landscape and regulate gene expression and cell fate decision148. However, the reciprocal regulation between cellular metabolism and gene expression in bone cells is still not extensively studied yet. Since transcriptomics and metabolomics of bone cells have already been studied, integrating the analysis of those pathways promises to reveal new biology and disease therapies. As many ways to target metabolic pathways have been developed, a better understanding of bone metabolism may lead to more personalized treatment protocols for bone diseases.

Taken together, the bioenergetic of bone cells plays a crucial role in maintaining healthy bones, promoting bone development and function, as well as the pathogenesis of bone diseases. The significance of bone in systemic bioenergetics highlights the need for future research on bone metabolism. This will help identify potential targets for pharmacological intervention, leading to improved management of not just bone diseases, but also systemic metabolic diseases.