Lysophosphatidic acid mediates migration of human mesenchymal stem cells stimulated by synovial fluid of patients with rheumatoid arthritis

Migration of mesenchymal stem cells plays a key role in regeneration of injured tissues. Rheumatoid arthritis (RA) is a chronic inflammatory disease and synovial fluid (SF) reportedly contains a variety of chemotactic factors. This study was undertaken to investigate the role of SF in migration of human bone marrow-derived mesenchymal stem cells (hBMSCs) and the molecular mechanism of SF-induced cell migration. SF from RA patients greatly stimulated migration of hBMSCs and the SF-induced migration was completely abrogated by pretreatment of the cells with the lysophosphatidic acid (LPA) receptor antagonist Ki16425 and by small interfering RNA- or lentiviral small hairpin RNA-mediated silencing of endogenous LPA(1)/Edg2. Moreover, SF from RA patients contains higher concentrations of LPA and an LPA-producing enzyme autotoxin than normal SF. In addition, SF from RA patients increased the intracellular concentration of calcium through a Ki16425-sensitive mechanism and pretreatment of the cells with the calmodulin inhibitor W7 or calmodulin-dependent protein kinase II inhibitor KN93 abrogated the SF-induced cell migration. These results suggest that LPA-LPA(1) plays a key role in the migration of hBMSCs induced by SF from RA patients through LPA(1)-dependent activation of calmodulin-dependent protein kinase II.