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.

Keywords: S1P; bone; bone mineral density; osteoblast; osteoclast; osteoporosis.

Figure 1

Sphingosine metabolic pathway. Ceramide, sphingosine, and sphingosine-1-phosphate can be metabolised into each other via various enzymes. Ceramide is converted into sphingosine through a reversible reaction by ceramidase (CDase) and ceramide synthase (CerS) [18]. Sphingosine frequently converted to sphingosine-1-phosphate via the two sphingosine kinases (SPHK1/2) [19]. S1P is metabolised back to sphingosine via sphingosine phosphate phosphatases (SPPase) or by an irreversible reaction by S1P lyase [19]. S1P is then exported out of the cell via spinster 2 (SPNS2). Created in Biorender.com.

Figure 2

S1PR function in osteogenic cells. Schematic representation of the downstream signalling from S1PRs in osteoclast precursors (OCPs), osteoclasts (OCs), osteoblast precursors (OBPs), and osteoblasts (OBs). S1PRs are G-protein coupled receptors that activate various pathways and are present at different stages of OB and OC differentiation [17]. Within OCPs, S1PR1 and S1PR2 alter OC maturation via activation of Rho and Rac signalling pathways [24]. S1P can increase OCPs differentiation via Cox2, although the mechanism is not fully understood [24]. Although S1PR1-4 are expressed in OCs, the role of S1PR3 and S1PR4 are not currently understood [30]. S1PR1/2 can alter OC migration but the mechanisms underpinning this remain unclear. S1PR2 appears to be essential for OC activation. Within OBs, S1PR1 mediates OB differentiation via PI3K/AKT signalling and regulates migration via JAK/STAT signalling [31], resulting in chemoattraction in response to S1P [31], whereas S1PR2 increases OB differentiation via RhoA/ROCK/Smad signalling [30] and can also act through FAK/PI3K/AKT signalling to promote chemorepulsion. In OBs, S1PR1 increases OB proliferation [32] and survival via MAPK and PI3K signalling. S1PR1-3 are involved in mediating OB maturation through as of yet unknown signalling pathways. Activation of SphK1 in OBs promotes osteoblast maturation via autocrine S1P signalling through S1PR3 [23]. The function of S1PR4 in OBs is currently unknown. Created in Biorender.com.

Figure 3

Osteoblast–Osteoclast Communication via S1P. S1P can act directly on osteoblasts via S1PR1/3 receptors to enhance osteoblast maturation and mineralisation [47]. S1PR1/3 also activates the ERK/p38 signalling pathway to enhance COX2 production [24,27]. COX2 then elicits the release of RANKL from osteoblasts to enhance osteoclastogenesis via p38-cfos-NFATc1 signalling [24]. RANK activation of osteoclasts by RANKL also upregulates SPHK1 expression and production, resulting in increased intracellular S1P, which inhibits p38. Inhibition of p38 causes a reduction in osteoclastogenesis, acting as a negative regulator of osteoclast maturation [24]. S1P released from osteoclasts increases extracellular S1P, which may act as a break on osteoclastogenesis through the S1PR2 receptor on osteoblasts, as S1PR2 acts to enhance the secretion of the RANKL decoy receptor osteoprotegerin (OPG) [40]. OPG acts to reduce further RANKL-mediated osteoclastogenesis through binding to RANKL. Created in Biorender.com.

Figure 4

Osteoclast precursor migration is increased in osteoporosis due to increased plasma S1P. During typical homeostatic remodelling, it has been suggested that the S1P gradient allows for regulated migration of osteoclast precursors into the bone tissue via S1PR2 [35,36]. This is regulated via S1PR1, which opposes S1PR2, keeping some cells within circulation. Osteoporotic patients express increased plasma S1P [64,65,66]. This is thought to result in internalisation of the regulator receptor, S1PR1, causing increased migration of cells due to reduced opposition to S1PR2. Due to increased S1PR2 activity on osteoclast precursors, there are more migrating precursors that are thought to result in an increase in osteoclast numbers within the tissue, resulting in increased bone resorption. Created in Biorender.com.