LPA induces osteoblast differentiation through interplay of two receptors: LPA1 and LPA4.
The bioactive phospholipid, lysophosphatidic acid (LPA), acting through at least five distinct receptors LPA1-LPA5, plays important roles in numerous biological processes. Here we report that LPA induces osteoblastic differentiation of human mesenchymal stem cells hMSC-TERT. We find that hMSC-TERT mostly express two LPA receptors, LPA1 and LPA4, and undergo osteoblastic differentiation in serum-containing medium. Inhibition of LPA1 with Ki16425 completely abrogates osteogenesis, indicating that this process is mediated by LPA in the serum through activation of LPA1. In contrast to LPA1, down-regulation of LPA4 expression with shRNA significantly increases osteogenesis, suggesting that this receptor normally exerts negative effects on differentiation. Mechanistically, we find that in hMSC-TERT, LPA induces a rise in both cAMP and Ca(2+). The rise in Ca(2+) is completely abolished by Ki16425, whereas LPA-mediated cAMP increase is not sensitive to Ki16425. To test if LPA signaling pathways controlling osteogenesis in vitro translate into animal physiology, we evaluated the bones of LPA4-deficient mice. Consistent with the ability of LPA4 to inhibit osteoblastic differentiation of stem cells, LPA4-deficient mice have increased trabecular bone volume, number, and thickness.
Liu
Yao-Bin
YB
Tissue Repair, Pfizer, Inc., Collegeville, Pennsylvania 19426, USA.
Kharode
Yogendra
Y
Bodine
Peter V N
PV
Yaworsky
Paul J
PJ
Robinson
John A
JA
Billiard
Julia
J
D000818:Animals; D001842:Bone and Bones; D002118:Calcium / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000032:analysis; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D010012:Osteogenesis; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D011983:Receptors, Purinergic / Q000378:metabolism*; D018048:Receptors, Purinergic P2
C082320:LPAR4 protein, human; D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D011983:Receptors, Purinergic; D018048:Receptors, Purinergic P2; D000242:Cyclic AMP; C032881:lysophosphatidic acid; D002118:Calcium