The Ying and Yang of Sphingosine-1-Phosphate Signalling within the Bone

Abstract

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.

The Species Effect: Differential Sphingosine-1-Phosphate Responses in the Bone in Human Versus Mouse

“…S1P has been reported to contribute to the migration of bone progenitor cells, bone homeostasis, and cross-talk between osteoblasts and osteoclasts to regulate bone remodelling [3]. We report for the first time that S1P signalling within bone cells shows species differences-whereby S1P is catabolic in murine cells, reducing osteoblastogenesis and increasing osteoclast activity.…”

“…It is well known that both intracellular and extracellular S1P can have differing impacts on cell activity [3]. Therefore, we explored the impact of extracellular S1P on the protein expression of sphingosine kinases in osteoclasts, specifically focusing on those where we observed detectable protein at baseline.…”

“…By contrast, S1P tended to decrease hSPHK1 expression, although this was not statistically significant (Figure 7L), but could potentially indicate a change in intracellular S1P within the human osteoclasts. It is well known that both intracellular and extracellular S1P can have differing impacts on cell activity [3]. Therefore, we explored the impact of extracellular S1P on the protein expression of sphingosine kinases in osteoclasts, specifically focusing on those where we observed detectable protein at baseline.…”

“…Bone remodelling is an intricate, tightly regulated process that is accomplished by two major bone cell types: osteoblasts are responsible for forming new bone, whilst osteoclasts are tasked with resorbing and removing old or damaged bone tissue [2]. Sphingosine-1-phosphate (S1P) is a known regulator of bone homeostasis and has been implicated in driving the onset and/or progression of numerous bone diseases (e.g., as reviewed by [3]). Despite this, there remains conflicting evidence surrounding the functional responsiveness of osteoblasts and osteoclasts to S1P, making interpretation of the available data and translation of S1P related therapies in the bone disease arena fraught with difficulty.…”

Therapeutic avenues in bone repair: Harnessing an anabolic osteopeptide, PEPITEM, to boost bone growth and prevent bone loss

“…Osteoblasts and osteocytes release both positive (RANKL, M-CSF) and negative (osteoprotegerin [OPG]) regulators of osteoclastogenesis to control the rate of bone resorption. 8 Conversely, osteoclasts and osteocytes produce anabolic stimuli that include sphingosine 1-phosphate, 9 Wnt/β-catenin proteins, and bone morphogenic proteins 10 that induce osteoblast precursor recruitment, differentiation, and survival. The highly conserved and ubiquitously expressed seven isoforms of the human 14-3-3 family act as adaptor proteins influencing the function of other proteins, and thus a multitude of signaling pathways, to regulate cellular responses (reviewed by Obsilova and Obsil 11 ).…”