sphingosine-1-phosphate and Osteoporosis

Bone remodelling is a highly active and dynamic process that involves the tight regulation of osteoblasts, osteoclasts, and their progenitors to allow for a balance of bone resorption and formation to be maintained. Ageing and inflammation are risk factors for the dysregulation of bone remodelling. Once the balance between bone formation and resorption is lost, bone mass becomes compromised, resulting in disorders such as osteoporosis and Paget's disease. Key molecules in the sphingosine-1-phosphate signalling pathway have been identified for their role in regulating bone remodelling, in addition to its more recognised role in inflammatory responses. This review discusses the accumulating evidence for the different, and, in certain circumstances, opposing, roles of S1P in bone homeostasis and disease, including osteoporosis, Paget's disease, and inflammatory bone loss. Specifically, we describe the current, often conflicting, evidence surrounding S1P function in osteoblasts, osteoclasts, and their precursors in health and disease, concluding that S1P may be an effective biomarker of bone disease and also an attractive therapeutic target for disease.

Topics: Bone and Bones; Bone Resorption; Humans; Osteoblasts; Osteoclasts; Osteoporosis; Sphingosine

There are a large number of people worldwide who suffer from osteoporosis, which imposes a huge economic burden, so it is necessary to explore the underlying mechanisms to achieve better supportive and curative care outcomes. Sphingosine kinase (SphK) is an enzyme that plays a crucial role in the synthesis of sphingosine-1-phosphate (S1P). S1P with paracrine and autocrine activities that act through its cell surface S1P receptors (S1PRs) and intracellular signals. In osteoporosis, S1P is indispensable for both normal and disease conditions. S1P has complicated roles in regulating osteoblast and osteoclast, respectively, and there have been exciting developments in understanding how SphK/S1P/S1PR signaling regulates these processes in response to osteoporosis therapy. Here, we review the proliferation, differentiation, apoptosis, and functions of S1P, specifically detailing the roles of S1P and S1PRs in osteoblasts and osteoclasts. Finally, we focus on the S1P-based therapeutic approaches in bone metabolism, which may provide valuable insights into potential therapeutic strategies for osteoporosis.

Topics: Humans; Osteoporosis; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors

Sphingosine 1-phosphate (S1P) regulates many cellular functions, such as differentiation, proliferation, migration, morphogenesis, cytoskeletal organization, adhesion, tight junction assembly, apoptosis and the localization of different cell types. S1P also controls the migration of osteoclast precursors between the blood and bone, and it keeps osteoclast precursors away from bone surfaces to reduce bone degradation, thus preventing bone decay. Osteoporosis is a systemic bone disease that predisposes patients to bone fracture due to decreased bone density and quality, disrupted bone microarchitecture, and increased bone fragility. As the global elderly population increases, the incidence of osteoporosis will greatly increase, and the associated adverse consequences will become more serious. S1P plays an important role in homeostasis, and disruption of the balance between osteoblasts and osteoclasts may induce osteoporosis. A high frequency of osteoporotic fracture is associated with increased plasma S1P levels. Studies have shown that S1P is an important therapeutic target in osteoporosis because it controls the migration of osteoclast precursors, vigorously maintains the bone mineralization process, and is a critical regulator of osteoclastogenesis. Improved understanding of the functional roles and molecular mechanisms of S1P in bone turnover could facilitate the discovery of novel targets for the treatment of osteoporosis. This review provides a critical discussion of the role of S1P in osteoporosis and treatments.

Topics: Aged; Humans; Lysophospholipids; Osteoclasts; Osteoporosis; Sphingosine

Sphingosine-1-phosphate (S1P) is a natural bioactive lipid molecule and a common first or second messenger in the cardiovascular and immune systems. By binding with its receptors, S1P can serve as mediator of signalling during cell migration, differentiation, proliferation and apoptosis. Although the predominant role of S1P in bone regeneration has been noted in many studies, this role is not as well-known as its roles in the cardiovascular and immune systems. In this review, we summarize previous research on the role of S1P receptors (S1PRs) in osteoblasts and osteoclasts. In addition, S1P is regarded as a bridge between bone resorption and formation, which brings hope to patients with bone-related diseases. Finally, we discuss S1P and its receptors as therapeutic targets for treating osteoporosis, inflammatory osteolysis and bone metastasis based on the biological effects of S1P in osteoclastic/osteoblastic cells, immune cells and tumour cells.

Topics: Bone Neoplasms; Bone Resorption; Humans; Lysophospholipids; Neoplasm Metastasis; Osteoblasts; Osteoclasts; Osteolysis; Osteoporosis; Sphingosine; Sphingosine-1-Phosphate Receptors

The measurement of bone turnover markers is useful for the clinical investigation of patients with osteoporosis. Among the available biochemical markers, the measurements of serum procollagen type I N-terminal propeptide (PINP) and the crosslinked C-terminal telopeptide (serum CTX) have been recommended as reference markers of bone formation and bone resorption, respectively. The important sources of preanalytical and analytical variability have been identified for both markers, and precise measurement can now be obtained. Reference interval data for PINP and CTX have been generated across different geographical locations, which allows optimum clinical interpretation. However, conventional protein-based markers have some limitations, including a lack of specificity for bone tissue, and their inability to reflect osteocyte activity or periosteal metabolism. Thus, novel markers such as periostin, sclerostin and, sphingosine 1-phosphate have been developed to address some of these shortcomings. Recent studies suggest that the measurements of circulating microRNAs, a new class of marker, may represent early biological markers in osteoporosis. Bone markers have been shown to be a useful adjunct to bone mineral density for identifying postmenopausal women at high risk for fracture. Because levels of bone markers respond rapidly to both anabolic and anticatabolic drugs, they are very useful for investigating the mechanism of action of new therapies and, potentially, for predicting their efficacy to reduce fracture risk.

Topics: Adaptor Proteins, Signal Transducing; Biomarkers; Bone Density; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Bone Resorption; Cell Adhesion Molecules; Collagen Type I; Disease Management; Female; Genetic Markers; Humans; Lysophospholipids; MicroRNAs; Osteoporosis; Peptide Fragments; Peptides; Postmenopause; Procollagen; Prognosis; Sphingosine

Osteoclasts play critical roles not only in normal bone homeostasis ('remodeling') , but also in the pathogenesis of bone destructive disorders such as osteoporosis, rheumatoid arthritis, and bone metastasis. However, it has not been known how osteoclast precursor monocytes migrate into the bone surface and what controls their migratory behaviors. To reveal these systems, we have recently established a new system for visualizing intact bone tissues and bone marrow cavities in live animals by using an advanced imaging technique with intravital two-photon microscopy. By means of the system we have revealed that sphingosine-1-phosphate (S1P) , a lipid mediator, dynamically regulates migration and localization of osteoclasts and their precursors in vivo . Here we show the latest data and the detailed methodology of intravital imaging of bone tissues, and also discuss its further application.

Topics: Animals; Arthritis, Rheumatoid; Bone and Bones; Bone Remodeling; Cell Movement; Chemokines; Humans; Lysophospholipids; Mice; Microscopy, Fluorescence, Multiphoton; Osteoclasts; Osteoporosis; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors

Sphingosine-1-phosphate (S1P) signaling influences bone metabolism, but its therapeutic potential in bone disorders has remained unexplored. We show that raising S1P levels in adult mice through conditionally deleting or pharmacologically inhibiting S1P lyase, the sole enzyme responsible for irreversibly degrading S1P, markedly increased bone formation, mass and strength and substantially decreased white adipose tissue. S1P signaling through S1P

Topics: Adipocytes; Adipose Tissue; Aldehyde-Lyases; Anabolic Agents; Animals; Bone Resorption; Cell Differentiation; Cell Line; Femur; Gene Deletion; Lysophospholipids; Mice, Knockout; Molecular Targeted Therapy; Obesity; Organ Size; Osteoblasts; Osteoclasts; Osteoporosis; Osteoprotegerin; PPAR gamma; Signal Transduction; Sp7 Transcription Factor; Sphingosine; X-Ray Microtomography

The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.

Topics: Alleles; Animals; Bone and Bones; Calcitonin; Collagenases; Crosses, Genetic; Female; Lysophospholipids; Mice; Mice, Inbred C57BL; Mice, Transgenic; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Phenotype; Porosity; Receptors, Calcitonin; Signal Transduction; Sphingosine

Osteoclasts are the only somatic cells with bone-resorbing capacity and, as such, they have a critical role not only in normal bone homeostasis (called 'bone remodelling') but also in the pathogenesis of bone destructive disorders such as rheumatoid arthritis and osteoporosis. A major focus of research in the field has been on gene regulation by osteoclastogenic cytokines such as receptor activator of NF-kappaB-ligand (RANKL, also known as TNFSF11) and TNF-alpha, both of which have been well documented to contribute to osteoclast terminal differentiation. A crucial process that has been less well studied is the trafficking of osteoclast precursors to and from the bone surface, where they undergo cell fusion to form the fully differentiated multinucleated cells that mediate bone resorption. Here we report that sphingosine-1-phosphate (S1P), a lipid mediator enriched in blood, induces chemotaxis and regulates the migration of osteoclast precursors not only in culture but also in vivo, contributing to the dynamic control of bone mineral homeostasis. Cells with the properties of osteoclast precursors express functional S1P(1) receptors and exhibit positive chemotaxis along an S1P gradient in vitro. Intravital two-photon imaging of bone tissues showed that a potent S1P(1) agonist, SEW2871, stimulated motility of osteoclast precursor-containing monocytoid populations in vivo. Osteoclast/monocyte (CD11b, also known as ITGAM) lineage-specific conditional S1P(1) knockout mice showed osteoporotic changes due to increased osteoclast attachment to the bone surface. Furthermore, treatment with the S1P(1) agonist FTY720 relieved ovariectomy-induced osteoporosis in mice by reducing the number of mature osteoclasts attached to the bone surface. Together, these data provide evidence that S1P controls the migratory behaviour of osteoclast precursors, dynamically regulating bone mineral homeostasis, and identifies a critical control point in osteoclastogenesis that may have potential as a therapeutic target.

Topics: Animals; Bone and Bones; Bone Density; Bone Resorption; Cell Line; Cell Lineage; Chemotaxis; Female; Fingolimod Hydrochloride; Homeostasis; Lysophospholipids; Mice; Mice, Inbred C57BL; Monocytes; Osteoclasts; Osteoporosis; Ovariectomy; Propylene Glycols; Receptors, Lysosphingolipid; Sphingosine