Fig. 2.

Simplified illustration of the effects of S1P and its receptors on osteoblasts, osteoclasts, their respective precursors, and the role of S1P in osteoblast-osteoclast coupling. The involvement of the 3 major S1P receptor subtypes (red: S1P₁, green: S1P₂, orange: S1P₃) in particular responses is indicated by different arrow shapes. Briefly, osteoclast and osteoblast precursor migration is influenced by S1P₁-mediated chemoattraction and S1P₂-mediated chemorepulsion in response to the the S1P concentration gradient (larger quantities of S1P are generated in serum mainly by red blood cells and endothelial cells, while lower S1P concentrations predominate in tissue compartments, such as bone). S1P, produced locally by osteoclasts or osteoclast precursors (20, 69, 80), directly stimulates the proliferation of osteoblast precursors and their differentiation into mature osteoblasts, while increasing RANKL mRNA in osteoblasts, indirectly stimulating osteoclast precursor differentiation via RANK. The RANKL/RANK signalling pathway also upregulates SK in osteoclast precursors.