Lysophosphatidic acid cooperates with 1alpha,25(OH)2D3 in stimulating human MG63 osteoblast maturation.
Osteoblast maturation is partly controlled by the interaction of 1alpha,25(OH)(2)D(3) (D3), an active metabolite of Vitamin D, with other growth factors. The first reports describing the in vitro effect of D3 on human osteoblast differentiation performed experiments in the presence of serum. One potentially exciting candidate that might help explain the D3 responses observed for osteoblasts cultured with serum is lysophosphatidic acid (LPA). Drawn to the possibility that D3 and serum borne LPA might interact to induce osteoblast maturation we co-treated human cells with D3 and serum in the presence of Ki16425, an LPA receptor antagonist. Ki16425 inhibited osteoblast maturation as determined by markedly reduced alkaline phosphatase (ALP) expression. We subsequently found that LPA and D3 acted synergistically in generating mature osteoblasts and that this differentiation response could be inhibited using pertussis toxin, implying an important role of Galphai signal transduction. Furthermore, we found evidence for a dependency on both mitogen activated protein kinase kinase (MEK) and Rho associated coiled kinase (ROCK) for LPA and D3 stimulated maturation.
Gidley
J
J
Department of Oral & Dental Science, University of Bristol Dental School, Lower Maudlin St., Bristol BS 2LY, UK.
Openshaw
S
S
Pring
E T
ET
Sale
S
S
Mansell
J P
JP
D000469:Alkaline Phosphatase / Q000096:biosynthesis; D002070:Butadienes / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D003599:Cytoskeleton / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007555:Isoxazoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects*; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation; D011422:Propionates / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D022502:Stress Fibers / Q000502:physiology; D054460:rho-Associated Kinases
C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D002070:Butadienes; D047908:Intracellular Signaling Peptides and Proteins; D007555:Isoxazoles; D008246:Lysophospholipids; D009570:Nitriles; D011422:Propionates; C113580:U 0126; D051546:Cyclooxygenase 2; D037342:Pertussis Toxin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D000469:Alkaline Phosphatase; D002117:Calcitriol; C032881:lysophosphatidic acid