Bone is an important tissue to provide biomechanical and structural supports to the body (Lee and Karsenty, 2008). Besides, it is a dynamic organ that undergoes bone formation and resorption. Bone is formed through two forms: endochondral and intramembranous ossification (Soltanoff et al., 2009), formation of which begins when mesenchymal cells adhere, and the osteogenesis can be made through the transformation of the pre-existing mesenchymal cells into bone tissue or sometimes by the replacement of the cartilage by bone (Zaidi, 2007). Then bone remodeling takes place after bone formation and development and continues during the whole lifetime (Kronenberg, 2003; Roberts et al., 2015; Serra-Vinardell et al., 2020). Development and lifelong remodeling of the bone involve some major bone-related cells, such as osteoblasts (Matsuo and Irie, 2008), osteoclast precursors, osteoclasts, osteocytes, bone lining cells, bone marrow stem cells (Lee et al., 2017), adipocytes, fibroblasts, immune cells (Arron and Choi, 2000; Pacifici, 2010, 2013; Rauner et al., 2013; Purdue et al., 2014; Pietschmann et al., 2016), and non-osteogenic cell populations by the blood supply. Their proliferation, differentiation, death, and dynamic balance determine the shape and function of bone. Besides, some other cellular systems, including cartilage, also play important roles. Among these cells, osteoblasts and osteoclasts play a critical role in bone remodeling. The maintenance of bone size, shape, integrity, and function of bone depends on the exquisite balance between osteoblasts and osteoclasts (Huang et al., 2007; Soltanoff et al., 2009; Matsuoka et al., 2014). Mainly osteoclasts are responsible for bone resorption, and osteoblasts are responsible for new bone formation. The imbalance can result in abnormal bone architecture or function; therefore, bone metabolism diseases will occur, such as osteoporosis and osteopetrosis (Zaidi, 2007). But osteoblasts and osteoclasts are closely connected through cytokine, cell-bone matrix contact, or direct cell-cell contact. Besides, the communication between osteoblasts and osteoclasts happens at various stages of bone remodeling (Matsuo and Irie, 2008). Lipid is an important nutrient of the body by offering energy, essential fatty acids (FAs), and other derivatives and influences many cell types, cell functions, and signaling pathways. Lipid could also be divided into eight categories, including fatty acyls, glycerolipid, glycerophospholipid, sphingolipid, sterol lipid, prenol lipid, saccharolipid, and polyketide. Each of them contains distinct classes and subclasses of molecules (Fahy et al., 2005; Liebisch et al., 2020). Lipid metabolism that is a complex process associated with biosynthesis and degradation controls the level of lipid. Lipid metabolism also involves the hydrolysis of lipid (Mu and Porsgaard, 2005) and then its hydrolysis product is absorbed, packaged, and transported to the rest of the cells or tissues.

Lipids play an important role in bone remodeling and bone disease. The study about the relationship between lipid metabolism and biomineralization was early in 1963 (Irving, 1963). The presence of lipid within a porous compartment of cortical bone restricts radial permeability, possibly influencing the metabolic functions of osteoblasts and osteocytes (Wen et al., 2010). Recently, a study found the obstruction of vascular invasion during bone healing tends to chondrogenic rather than osteogenic differentiation of skeletal progenitor cells, due to a decreased availability of extracellular lipids. Thus, lipid availability has been found to determine the fate of skeletal progenitor cells (van Gastel et al., 2020). It highlights that lipid plays a crucial role in a signal pathway, cell types, and functions in bone biology, and suggests its significance in bone pathology. Indeed, emerging data suggest the sphingolipid metabolism plays a critical role in skeletogenesis. Recent studies indicate the multifaceted influences of the sphingolipid on osteoblasts, osteoclasts, and the pivotal interaction underlying bone homeostasis-osteoblast and osteoclast crosstalk and highlight the multifaced roles of sphingolipid metabolism on bone remodeling. Hence, this review will focus on sphingolipid metabolism that regulates bone development and remodeling, involving the representative Sphingomyelin, Ceramide, and sphingosine 1-phosphate (Figure 1), teasing out their roles in the crosstalk of osteoblasts and osteoclasts.

Sphingolipids carry a long-chain sphingoid base with the 2-amino group amide-linked to a fatty acid, which forms ceramide, the core unit. Then different types of sphingolipids are formed by polar head groups added. The family of sphingolipids is defined by characters of the fatty acid, including carbon length, degree of unsaturation, and hydroxylation, along with other modifications of the LCBs and the polar head group (Hannun and Obeid, 2008; Teixeira and Costa, 2016). The sphingolipid metabolism shares a similar spatial organization which is highly conserved. It is governed by an integrated network of common synthetic and catabolic pathways that are modulated in response to different stimuli despite the diversity of sphingolipids (Hannun and Obeid, 2008; Teixeira and Costa, 2016).

Sphingolipid biosynthesis de novo taking place in the endoplasmic reticulum (ER) involves a condensation reaction of serine and palmitoyl-CoA to produce 3-ketodihydrosphingosine catalyzed by serine palmitoyltransferase (SPT) (Merrill, 2002; Teixeira and Costa, 2016). 3-ketodihydrosphingosine generation is converted to the dihydroxyceramide (DHS) by ketodihydrosphingosine reductase (Kihara and Igarashi, 2004). DHS is acylated to dihydroceramides catalyzed by ceramide synthase (CERS1-6). Then dihydroceramide is catalyzed by dihydroceramide desaturases DES1 and DES2 to generate ceramide (Ternes et al., 2002). Ceramide serves as a substrate for enzymes that produce sphingolipids, sphingomyelin included. The ceramide is transported to the Golgi compartment by transfer protein CERT or vesicular, and then converted into sphingomyelin by sphingomyelin synthases (SMS). There are two isoforms of SMS, which is SMS1 and SMS2. SMS1 is only located in the Golgi apparatus while SMS2 is located in both the Golgi apparatus and the plasma membrane. These enzymes have been classified into three categories—acidic, alkaline, and neutral sphingomyelinases (Stoffel, 1999). The hydrolysis of ceramide generates sphingosine, which can generate sphingosine-1-phosphate (S1P) (Figure 2). The current review will discuss the role of some important sphingolipids in bone remodeling.

De novo sphingolipid biosynthesis begins at the endoplasmic reticulum (ER) with the condensation reaction of serine and palmitoyl-CoA forming 3-ketosphingosine. 3-ketodihydrosphingosine generation is converted to the dihydroxyceramide, and then acylated to dihydroceramides by ceramide synthase (CerS 1-6). Dihydroxyceramide is dehydrated between carbons 4 and 5 by dihydroceramide desaturase (DES) to form ceramide, and then be translocated to the Golgi. The action of SMS on ceramide results in the production of sphingomyelin (SM). Acid sphingomyelinase (SMase) is an enzyme converting sphingomyelin into ceramide. GSL can be transported intracellularly in the lysosome to generate ceramide. Ceramide can be generated through degradation of SM in the lysosome or at the plasma membrane by SMase. Then hydrolysis of ceramide by ceramidase generates sphingosine, which can be phosphorylated and generate sphingosine-1-phosphate (S1P).

Sphingomyelin exists in diverse species, from protozoa to mammals. It is the major component of the double membrane-bound sphingolipids, which is generated from ceramide and phosphatidylcholine by sphingomyelin synthase and is implicated in cell survival, proliferation, migration, and inflammation (Tafesse et al., 2006; Taniguchi and Okazaki, 2014). However, its bioactive function mainly relies on its hydrolysis and downstream lipids, including ceramide and S1P. SM is essential for bone formation and normal mineralization. The abnormity of SM could cause defective bone mineralization, including osteoporosis, severe short stature, neonatal fractures, osteogenesis imperfecta, spondylometaphyseal dysplasia, severe bone and tooth mineralization defects, and gross skeletal abnormalities.

(1) Sphingomyelin and bone formation

Sphingomyelin is essential for bone formation. The local SM catabolism is found to be essential for the mineralization process in healthy bones. Catalyzing SM hydrolysis forms phosphocholine and ceramide, which are highly expressed in bone and are required for normal mineralization (During et al., 2015). Mutations in the sphingomyelin synthase 2 gene (SGMS2) could cause defective bone mineralization (Pekkinen et al., 2019). Patients with skeletal phenotypes and osteoporosis were identified with mutations in the SGMS2 gene encoding for the SMS2, with some sharing the same nonsense variant to yield a catalytically inactive enzyme and presenting with childhood-onset osteoporosis. In addition, others had a missense variant to enhance the rate of sphingomyelin production by blocking the export of a functional enzyme from the endoplasmic reticulum, with severe short stature, neonatal fractures, and spondylometaphyseal dysplasia. A recent case reported a family with moderately severe bone fragility and multiple sclerotic skull lesions similar to the osteogenesis imperfecta mentioned above; however, no pathogenic variant was found in SGMS2 (Makitie et al., 2021). Knocking down the SMS2 suppressed TRAP-positive multinucleated cells’ formation through co-culture of bone marrow cells and osteoblasts, which indicated that knockdown of SMS2 inhibits osteoclastogenesis through decreasing RANKL expression in primary osteoblasts of mice (Yoshikawa et al., 2019). In addition, the recent study found that based on metabolomic analysis, giant cell tumor of bone (GCTB), SM was checked as the most dysregulated phospholipid in GCTB, with high expression of SMS1 and SMS2, and low expression of nSMase2 (Quiroz-Acosta et al., 2021).

(2) Sphingomyelin and bone resorption

The excessive accumulation or catabolism of SM seemed to be linked to bone resorption. SMPD3 encodes neutral sphingomyelinase 2, the expression of which is restricted to the cartilage, bone, and brain (Khavandgar et al., 2011). Currently, there are two established SMPD3-deficient mouse models fro/fro model and SMPD3-/- model (Aubin et al., 2005; Stoffel et al., 2005). Both the two SMPD3-deficient mouse models show severe bone and tooth mineralization defects, and gross skeletal abnormalities. The fro mutation completely abolishes the enzymatic activity without affecting the location of SMPD3, thus reduction of nSMase activity in skeletal tissues marked by abnormal bone mineralization defects with high expression of SMPD3 is found in fro/fro mice (Khavandgar et al., 2011). Fro/fro mice also showed delayed mantle dentin mineralization and a consequent delay in enamel formation, but these tooth abnormalities progressively improved with time (Khavandgar et al., 2013). So far, no abnormalities of bone in mice lacking SMPD1 or SMPD2 activity have been reported. All of these revealed the excessive accumulation of SM properly could be tightly associated with bone defects. On the other side, although there is an increase of SM in bone marrow while there is a significant reduction of SM in the mineralized tissue part of OVX rat femurs (During et al., 2020), which suggested that excessive catabolism of SM could be associated with bone resorption. But more investigations will be needed regarding the potential role of SM in bone and the underlying mechanism.

Ceramide can arise from the endoplasmic reticulum by de novo synthesis (Hirschberg et al., 1993) and it can also be generated from the hydrolysis of SM by sphingomyelinases either at the plasma membrane or in endosomes or lysosomes. Ceramide is a bioactive lipid that serves as a second messenger in the regulation of cell death pathways and metabolism in response to stress, apoptotic triggers, and chemotherapy (Ryland et al., 2011; Kurek et al., 2013), involving extrinsic mechanism by mimicking the cytotoxicity of TNF (Hannun, 1994), and an intrinsic mechanism by modifying enzymes to regulate the level of ceramide (Morales et al., 2007), further leading to signal cascade and cell death by the downstream of Bcl2. However, S1P opposes the proapoptotic function of ceramide (Rutherford et al., 2013) and the ratio of S1P and ceramide is described as a rheostat of sphingolipid which is involved in the pathogenesis of certain cancers and this rheostat is one of the targets of anticancer drugs (Dyatlovitskaya et al., 2001). Ceramide plays an important role in bone metabolism. The abnormity of ceramide could cause osteoblast metabolic disorder and dysfunction, and thus influence the bone formation, and some special ceramides (C16:0, C18:0, C18:1, and C24:1) are correlated with bone resorption markers.

(1) Ceramide and bone formation

The alteration in the intracellular levels of ceramide could play a vital role in bone formation. C2-ceramide is reported to promote osteoblast viability, while high concentration (≥2 × 10^–6M) reduces osteoblast viability. Increasing intracellular levels of ceramide also increase osteoblast apoptosis, determined by nuclear appearance and DNA fragmentation (Hill and Tumber, 2010). Endogenous cellular ceramide concentrations increase after TNF-α treatment, while the apoptosis of osteoblasts is triggered by TNF-α-generated ceramide by activating NF-κB signaling pathway. In addition, reducing the production of ceramide by dexamethasone inhibits TNF-α-induced activation of NF-κB and apoptosis in osteoblasts (Chae et al., 2000). Some external or internal stimuli impair the viability or physiological function of osteoblast through ceramide accumulation. Sodium nitroprusside enhances the release of intracellular ceramides C22 and C24 to decrease osteoblast viability (Olivier et al., 2005). Elevated palmitic acid intake significantly increases C16 ceramide accumulation and thus reduces osteoblast function in vitro and bone formation markers in vivo (Alsahli et al., 2016). In obese mice with palmitic acid or oleic acid-enriched high fat diet, ceramide accumulation in osteoblasts and suppresses bone formation (Alsahli et al., 2016). The influence of ceramide on osteoblast is in a dose- and time-dependent manner, and increasing levels of intracellular ceramide with either an inhibitor of ceramide metabolism or sphingomyelinase increased osteoblast apoptosis (Hill and Tumber, 2010).

(2) Ceramide and bone resorption

The role of ceramide in apoptosis is studied extensively, and recently ceramide is reported to be involved in bone cell survival, cell death, and bone resorption. However, at present, few experimental data directly link it with the mineralization of skeletal tissue. DES1 is one of the enzymes that form ceramide through the de novo pathway. The DES1 null mice show a normal skeletal structure, although they have multiple physiologic anomalies such as weight loss and growth impairment (Holland et al., 2007). The C24:1 ceramide in serum extracellular vesicles increases with age and could induce senescence in human bone marrow stromal cells (BMSCs) (Khayrullin et al., 2019). In patients 65 years or older with hip surgery, age was correlated with circulating levels of C16:0, C18:0, and C24:1 ceramide positively. Higher levels of C16:0, C18:0, C18:1, and C24:1 ceramide were positively related to bone resorption markers in both blood and bone marrow samples. C18:0 and C24:1 ceramide directly increased osteoclastogenesis in vitro (Kim et al., 2019). In support, the Postmenopausal Osteoporosis Mouse model found a significant reduction of three to five SM species and increased six metabolites, of which five were ceramide species (Zhao et al., 2018).

Sphingosine-1-phosphate (S1P) is a natural lipid molecule that is formed by the phosphorylation of sphingosine and is derived from cell membrane sphingolipid (Spiegel and Milstien, 2002, 2003) as the product of sphingosine kinase(SK)1 and/or 2-mediated phosphorylation of sphingosine. In addition, S1P can either be converted back to sphingosine by specific S1P phosphatases or degraded by S1P lyase to form hexadecenal and phosphoethanolamine (Pebay et al., 2007). S1P is a common first or second messenger and serves as a mediator in regulating cell migration, death (Olivera and Spiegel, 1993), proliferation (Zhang et al., 1991; Cuvillier et al., 1996), and apoptosis (Cuvillier et al., 1996). Furthermore, it is involved in cell adhesion, cell motility, smooth muscle contraction, and platelet aggregation (Takuwa, 2002). It has been acquired in extensive study in cardiovascular, nervous, and immune systems, and its role in promoting angiogenesis is well-established (Alvarez et al., 2007). S1P acts either directly on intracellular targets or combines its known surface G-protein-coupled receptors S1P_1–5 as a common second messenger. The binding of S1P to these receptors induces differential signaling pathway, and sometimes overlapping. S1P and its S1P_1–5 receptors are expressed in variable systems, including vascular, immune, nervous, and reproductive systems (Hla, 2004). In recent years, S1P is implicated in osteogenesis-related processes, such as cell recruitment, cell differentiation, osteoblast survival, and coupling with osteoclasts.

S1P is important for osteoblast survival and the migration of osteoblasts and osteoclasts. The abnormity of S1P could cause osteopenia, reduced bone formation, and rheumatoid arthritis.

The appropriate level of sphingomyelin without excessive anabolism or catabolism plays an essential role in bone remodeling and prevents bone diseases. Adjusting the level of sphingomyelin in bone is the targeting treatment by activating the SMS or SMase. Sphingomyelin performed its function by its hydrolysis. While it lacks adequate studies of Ceramide, more research about S1P on bone disease is needed, thus introducing some possible treatments about S1P on bone diseases.

Although the published studies have displayed the critical role of sphingomyelin metabolism in osteoblasts, osteoclasts, and bone remodeling, the studies on the mechanism are still few. The sphingomyelin is essential in bone formation, but the excessive accumulation or catabolism of SM properly could be tightly associated with bone resorption. At present, limited direct evidence is available on the roles of sphingomyelin in osteoblasts and osteoclasts, and further, the enzymes of sphingomyelin are little studied in the bone tissue. As for Ceramide, despite the pro-apoptosis function in osteoblasts, the links of the differentiation of osteoblasts to ceramide are still unknown. In addition, recently, osteoclast can be mediated by ceramide. The comparatively sufficient studies of S1P on bone remodeling allow us to further study the treatment of associated bone diseases, although the role of S1P is complicated and depending on the different receptors of S1P_1–5.

TW and LL conceived of the presented idea. TQ finished the article. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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