The Role of S1PR1 in Osteoclast Differentiation Under Compressive Stress

Objectives: Differentiation of osteoclast precursors is important for the initiation of tooth movement and the efficiency of orthodontic treatment. The Sphingosine-1-phosphate receptor 1 (S1PR1) regulates cellular processes by interactions with the bioactive sphingolipid S1P. In this study, the role of S1PR1 in regulating osteoclast differentiation under compressive stress and its possible mechanism were investigated.
Methods: Orthodontic nickel-titanium springs were applied to the left maxillary first molars of rats to induce OTM. The rats were sacrificed at 3, 7, 14, or 28 d after forces loaded. osteoclastic activity, SPHK1 /S1PR1 and RANKL expression was investigated with immunohistochemistry staining. Meanwhile, the effect of S1PR1 on osteoclast differentiation and the downstream signaling pathway under compressive stress was investigated by cell culture model with compressive force application in vitro.
Results: It was found that the number of S1PR1-positive osteoclasts was lower and osteoclast differentiation activated on the compressive side of rat periodontium with orthodontic force applications for 7d. Under the compressive force, the mouse monocytes macrophages cell line Raw264.7 showed a downregulated S1PR1 expression, and an upregulated expression of microphthalmia-associated transcription factor (MITF). Treatment with S1P agonist, SEW2871, decreased MITF expression, while treatment with S1PR1 antagonist, W146, increased MITF expression. Furthermore, compressive force inhibited extracellular signal-regulated kinase (ERK) activation within 30 min. Treatment with W146 decreased ERK activation, whereas ERK inhibitor U0126 resulted in increased MITF expression in the Raw264.7 cell line.
Conclusions: The findings suggest that compressive stress down-regulates S1PR1 expression and facilitates osteoclast differentiation through increased MITF expression and inhibition of ERK activity.