Lysophosphatidic acid induces interleukin-6 and CXCL15 secretion from MLO-Y4 cells through activation of the LPA1 receptor and PKCθ signaling pathway

Abstract Lysophosphatidic acid (LPA) is a multifunctional phospholipid. Osteocytes are the most abundant cells in bone and can orchestrate bone formation and resorption, in part by producing cytokines that regulate osteoblast and osteoclast differentiation and activity. Interleukin (IL)-6 and IL-8 are two important cytokines that have potent effects on bone fracture healing. Previous studies suggest that platelet-derived LPA may influence fracture healing by inducing osteocyte dendrite outgrowth. However, the biological mechanism through which LPA induces cytokine production in osteocytes is poorly understood. In this study, we report that LPA markedly enhanced IL-6 and CXCL15 (mouse homologue of human IL-8) production in MLO-Y4 cells and that this enhancement was suppressed by the LPA 1/3 -selective antagonist Ki16425, the G i/o protein inhibitor PTX or the protein kinase C (PKC) inhibitor sotrastaurin. We also observed that of all the PKC isoform targets of sotrastaurin, only PKCθ was activated by LPA in MLO-Y4 cells and that this activation was blocked by sotrastaurin, Ki16425 or PTX. Taken together, the results of the present study demonstrate that LPA may be a potent inducer of IL-6 and CXCL15 production in MLO-Y4 cells and that this induction is associated with the activation of LPA 1 , G i/o protein and the PKCθ pathway. These findings may help us better understand the mechanism of fracture healing and contribute to the treatment of bone damage.