title: Acidic fibroblast growth factor autocrine system as a mediator of calcium-regulated parathyroid cell growth.
abstract: Both parathyroid hormone secretion and cell growth are negatively regulated by extracellular calcium in parathyroid cells. The mechanism of growth regulation by calcium has been unknown. Previously, we reported that clonal parathyroid cells (PT-r cells) bear two high affinity receptors for acidic fibroblast growth factor (aFGF) and that at least a subpopulation of the receptors with a higher molecular mass carries heparan sulfate (HS) glycosaminoglycan chains which give the receptor higher affinity (Sakaguchi, K., Yanagishita, M., Takeuchi, Y., and Aurbach, G. D. (1991) J. Biol. Chem. 266, 7270-7278). Here, I have found that the parathyroid cells expressed aFGF and that aFGF receptors with lower affinity apparently translocated in response to changing extracellular calcium concentrations. Expression of both aFGF mRNA and peptide was suppressed by calcium. Cells had more ligand-accessible receptors on the cell surface at lower calcium concentrations. This apparent translocation was temperature-dependent but independent of de novo protein synthesis. Heparin or HS glycosaminoglycans are a prerequisite for the FGF receptor encoded by flg gene to bind basic FGF (Yayon, A., Klagsbrun, M., Esko, J. D., Leder, P., and Ornitz, D. M. (1991) Cell 64, 841-848). In PT-r cells, major cellular HS proteoglycans redistribute between intracellular and extracellular compartments with more HS proteoglycans expressed on the cell surface at lower calcium concentrations (Takeuchi, Y., Sakaguchi, K., Yanagishita, M., Aurbach, G. D., and Hascall, V. C. (1990) J. Biol. Chem. 265, 13661-13668). However, this redistribution of HS proteoglycans cannot explain the difference in bindability of radiolabeled aFGF to its receptors in different calcium concentrations, since addition of heparin did not change the binding of radiolabeled aFGF to the receptors either at high or low calcium conditions. In concordance with the apparent translocation of aFGF receptors, thymidine incorporation was stimulated by decreasing extracellular calcium concentrations with further stimulation by added aFGF. Anti-aFGF antibody inhibited thymidine incorporation by more than 32% in the cells exposed to 0.05 mM Ca2+ shortly before adding [3H]thymidine, whereas the incorporation was not significantly affected by the antibody at 0.7 mM Ca2+. Cell growth was also stimulated by low calcium. Anti-aFGF antibody inhibited cell growth significantly only at low calcium concentrations. From these observations, an aFGF autocrine system including the apparent translocation of aFGF receptors may explain, if not entirely, the mechanism by which calcium regulates parathyroid cell growth.
mesh_terms: D000818:Animals; D000906:Antibodies; D015152:Blotting, Northern; D015153:Blotting, Western; D002118:Calcium / Q000494:pharmacology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects*; D002999:Clone Cells; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D010280:Parathyroid Glands / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011061:Poly A / Q000235:genetics / Q000302:isolation & purification; D011133:Polysaccharide-Lyases / Q000494:pharmacology; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D013431:Sulfates / Q000378:metabolism; D013462:Sulfur Radioisotopes; D013936:Thymidine / Q000378:metabolism
chemical_list: D000906:Antibodies; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D013431:Sulfates; D013462:Sulfur Radioisotopes; D016220:Fibroblast Growth Factor 1; D011061:Poly A; D012313:RNA; D004247:DNA; D003513:Cycloheximide; D011133:Polysaccharide-Lyases; C021349:heparitinsulfate lyase; D002118:Calcium; D013936:Thymidine