Sphingosine 1-phosphate signaling in bone remodeling: multifaceted roles and therapeutic potential

Abstract

Sphingolipids belong to a complex class of lipid molecules that are crucially involved in the regulation of important biological processes including proliferation, migration and apoptosis. Given the significant progress made in understanding the sphingolipid pathobiology of several diseases, sphingolipid-related checkpoints emerge as attractive targets. Recent data indicate the multifaceted contribution of the sphingolipid machinery to osteoclast - osteoblast crosstalk, representing one of the pivotal interactions underlying bone homeostasis. Imbalances in the interplay of osteoblasts and osteoclasts might lead to bone-related diseases such as osteoporosis, rheumatoid arthritis, and bone metastases. Areas covered: We summarize and analyze the progress made in bone research in the context of the current knowledge of sphingolipid-related mechanisms regulating bone remodeling. Particular emphasis was given to bioactive sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs). Moreover, the mechanisms of how dysregulations of this machinery cause bone diseases, are covered. Expert opinion: In the context of bone diseases, pharmacological interference with sphingolipid machinery may lead to novel directions in therapeutic strategies. Implementation of knowledge derived from in vivo animal models and in vitro studies using pharmacological agents to manipulate the S1P/S1PRs axes suggests S1PR2 and S1PR3 as potential drug targets, particularly in conjunction with technology for local drug delivery.

Keywords: Bone biology; bone diseases; coupling factor; osteoclast – osteoblast crosstalk; osteoporosis; osteotropic therapies; sphingolipid-related checkpoints; sphingosine 1-phosphate; sphingosine 1-phosphate receptor antagonist/agonist.

Figure 1.

A partly hypothetical model of the role of S1P as a coupling factor in bone homeostasis. Under physiological conditions, normal bone remodeling is maintained by the balance between bone formation and bone resorption; an imbalance causes aberrant bone metabolism and leads to pathological disorders such as osteoporosis; the respective trabecular microstructures assessed by µ-computed tomography are shown. BM, bone marrow; RANKL, Receptor activator of nuclear factor-kappa B ligand; OPG, osteoprotegerin; S1P, sphingosine 1-phosphate; FTY720, the S1PRs modulator.

Figure 2.

Interconnected processes of (i) S1P synthesis and degradation within the sphingomyelin/salvage pathway, (ii) S1P export and (iii) signaling through binding to five specific G-protein-coupled receptors, S1PR1-5. S1P can function as an autocrine, intracrine, paracrine, or endocrine bioactive mediator. Both osteoblasts and osteoclasts are among the cells which are able to produce, secrete, and respond to S1P. S1P, sphingosine 1-phosphate; S1PR, sphingosine 1-phosphate receptor; SPHK, sphingosine kinase; SPP, sphingosine-1-phosphate phosphatase; LPP, lipid phosphate phosphatase; SPL,sphingosine-1-phosphate lyase; SPNS2, spinster homolog 2; HDL, high-density lipoprotein; PLC, phospholipase C; PI3K, phosphoinositide 3-kinase; Ras, rat sarcoma; Rho, ras homolog; ERK,extracellular-signal regulated kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase.

Figure 3.

Expression pattern of S1PRs on bone cells and their downstream cellular responses. This illustration summarizes the current knowledge derived from studies/cells of mouse, rat and human origin. Osteoblast precursors and osteoclast precursors express S1PR1 and S1PR2; osteoblasts and osteoclasts express S1PR1-4. Which S1PRs underlie the pro-survival and proliferative effects, however, was not yet evaluated. Implementation of knowledge allows to consider S1PR2 and S1PR3 as potential drug targets in bone pathobiology.