Up-regulation of the alpha2-macroglobulin signaling receptor on rheumatoid synovial fibroblasts.
In the present study, we demonstrate that the alpha2-macroglobulin (alpha2M) signaling receptor is up-regulated on rheumatoid synovial fibroblasts. In rheumatoid cells, 125I-alpha2M-methylamine bound to two sites; namely, one of high affinity (Kd approximately 52 pM) and the second of lower affinity (Kd approximately 9.7 nM). In normal synovial fibroblasts only one site for 125I-alpha2M-methylamine (Kd approximately 5.36 nM) was present. Receptor-associated protein did not inhibit the binding of alpha2M-methylamine to the high affinity binding sites, but it caused a 70-80% reduction in its binding to low affinity binding sites establishing its identity as the low density lipoprotein receptor-related protein/alpha2M receptor. Binding of alpha2M-methylamine to rheumatoid but not normal synovial fibroblasts caused a rapid rise in inositol 1,4,5-trisphosphate synthesis with a peak reached within 10 s of ligand exposure. Concomitantly, rheumatoid but not normal cells showed a rise in intracellular Ca2+. Pretreatment of rheumatoid cells with Receptor-associated protein or pertussis toxin did not affect the alpha2M-methylamine-induced increase in intracellular Ca2+. These are characteristic properties of ligation by alpha2M-methylamine of the alpha2M signaling receptor but not the lipoprotein receptor-related protein/alpha2M receptor. Binding of alpha2M-methylamine to rheumatoid synovial fibroblasts significantly increased the synthesis of DNA compared with normal synovial fibroblasts treated similarly.
Misra
U K
UK
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Gonzalez-Gronow
M
M
Gawdi
G
G
Pizzo
S V
SV
D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010972:Platelet Activating Factor / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction; D013583:Synovial Membrane / Q000378:metabolism*; D015854:Up-Regulation; D000511:alpha-Macroglobulins / Q000378:metabolism*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010972:Platelet Activating Factor; D011971:Receptors, Immunologic; D000511:alpha-Macroglobulins; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium