Table 1.

Summary table outlining the effects of S1P on the different stages of bone remodelling and their potential as therapeutic targets in catabolic bone disorders.

Cell Type, Function	Effect of S1P Signalling	Therapeutic Application in Catabolic Bone Disorders	Ref
Osteoblast migration	S1PR1 and S1PR3 mediate chemoattraction to S1P—supports migration of precursors to the bone surface. S1PR2 has dual actions: low concentrations promote migration towards S1P. High concentrations cause chemo-repulsion.	Direct targeting of receptors is contraindicated due to expected off-target effects on osteoclasts. Targeting of downstream signalling could prove effective.	[43,44]
Osteoblast proliferation	Exogenous application of S1P increases proliferation. Inhibition of S1PR2 enhances proliferation but not differentiation.	Inhibition of S1PR2 enhances total osteoblast number but not their maturation. Unlikely to be effective therapeutically.	[41,52]
Osteoblast differentiation	S1P increases osteoblast differentiation. S1PR2 is required for osteoblast differentiation and maturation. Inhibition reduces differentiation. S1P signalling via S1PR3 is required for bone formation and maintenance.	S1PR3 is an interesting potential therapeutic target as (unlike, e.g., S1PR2) it has no alternative effects on osteoclasts. S1PR3 agonists likely to increase osteoblast differentiation and increase bone formation.	[29,41,47,50,51,53]
Osteoclast migration	S1PR1 is required for chemoattraction to S1P, maintaining osteoclast precursors within the circulation. S1PR2 is required for chemorepulsion towards S1P, promoting osteoclast precursors migration to tissue.	Inhibition of S1PR2 via antagonists (e.g., JTE013), may lower the number of osteoclasts present within bone tissue, reducing resorption.	[36,37,39,40]
Monocyte fusion	S1PR2 is required for monocyte fusion into osteoclasts, via regulation of podosome-adhesive proteins.	Inhibition of S1PR2 via antagonists (e.g., JTE013) prevents osteoclast formation, reducing resorption.	[40]
Osteoclast differentiation	SPHK1 is required for negative regulation of RANKL-mediated differentiation, through suppression of p38 signalling. The impact of exogenous S1P on osteoclast differentiation is unknown (incomplete data available).	Therapeutics that upregulate SPHK1 function or suppress p38 signalling may reduce mature osteoclasts.	[24,48]
RANKL production	Activation of S1PR1/3 on osteoblasts induces RANKL release, via activation of ERK/p38.	Reduction of RANKL-mediated osteoclast differentiation could be achieved through inhibition of osteoblast S1PR1/S1PR3 receptors or targeting the downstream signalling pathways.	[23]
OPG Production	Activation of S1PR2 on osteoblasts induces OPG release via GSK3β and β-catenin.	S1PR2 agonists or targeting of β-catenin-mediated secretion of OPG may reduce osteoclast numbers to prevent bone resorption.	[23,35,54]