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.
Song
Hae Young
HY
Medical Research Center for Ischemic Tissue Regeneration, the Medical Research Institute, School of Medicine, Pusan National University, Busan, Republic of Korea.
Lee
Mi Jeong
MJ
Kim
Min Young
MY
Kim
Kyung Hye
KH
Lee
Il Hwan
IH
Shin
Sang Hun
SH
Lee
Jung Sub
JS
Kim
Jae Ho
JH
D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D013582:Synovial Fluid / Q000737:chemistry* / Q000378:metabolism
D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C032881:lysophosphatidic acid