Effect of dexamethasone on proliferating osteoblasts: inhibition of prostaglandin E2 synthesis, DNA synthesis, and alterations in actin cytoskeleton.
Elevated levels of glucocorticoids caused by disease (Cushing's syndrome) or therapeutic treatment of asthma are known to cause osteoporosis. Space flight, an environmental condition, is known to cause a rise in endogenous cortisols accompanied by a significant loss of bone and calcium. Long-term space inhabitants have lost up to 18% of weight bearing bone during long-term flight. This study demonstrates that elevated concentrations of glucocorticoids lower the endogenous production of PGE2 and interfere with osteoblast proliferation. Osteoblasts grown with dexamethasone had significantly lower DNA synthesis and endogenous synthesis of PGE2. Addition of exogenous dmPGE2 to the dexamethasone growth-inhibited cells stimulated DNA synthesis over twofold. In synchronous control cultures, we found that endogenous prostaglandin synthesis increased in late G1, preceding S-phase DNA synthesis by several hours. The addition of exogenous dexamethasone to synchronous cultures resulted in a significant decrease in the prostaglandin synthesis followed by a significant decrease in DNA synthesis in parallel cultures. Further, dexamethasone caused the actin cytoskeleton to collapse and the cell morphology to become rounded and spindle shaped. Addition of exogenous PGE2 to the dexamethasone-treated osteoblasts caused recovery of the actin architecture and phenotype. These data support the hypothesis that the glucocorticoid-mediated decrease in prostaglandin synthesis may be a contributing factor in the reduced bone quality and trabecular bone formation seen in glucocorticoid-induced osteoporosis.
Hughes-Fulford
M
M
Research Services, Veterans Administration Medical Center, San Francisco, California.
Appel
R
R
Kumegawa
M
M
Schmidt
J
J
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004247:DNA / Q000096:biosynthesis* / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007700:Kinetics; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014176:Protein Biosynthesis; D013997:Time Factors
D000199:Actins; D003907:Dexamethasone; D004247:DNA; D015232:Dinoprostone