Growth hormone stimulates osteoprotegerin expression and secretion in human osteoblast-like cells.
It is presently thought that osteoprotegerin (OPG) is a cytokine involved in the regulation of osteoblast/osteoclast crosstalk and maintenance of bone mass. Recent studies showed that GH replacement therapy in GH-deficient patients was able to induce a significant increase of OPG in the plasma, as well as in the cortical and the trabecular bone. In order to determine whether GH could directly modulate OPG secretion, the effect of GH on human osteoblast-like cells (hOB) in primary culture was studied. After detecting the presence of the mRNA for the GH receptor (GHR) by RT-PCR, hOB were exposed to increasing concentrations of GH, from 0.1 to 25 ng/ml, for 24 h. The results showed that GH exposure was able to stimulate OPG secretion in a concentration-dependent manner. In addition, the OPG mRNA levels were increased, indicating that the hormone has a stimulatory effect on gene expression. The stimulatory effect on OPG expression and production was prevented by exposing the cells to tyrphostin AG490 (10 muM), an inhibitor of Janus kinase 2, which is one of the kinases involved in the intracellular pathway activated by the binding of GH to its receptor. Similar results were obtained when the cells were exposed to a receptor antagonist of GH, pegvisomant at 50 nM. GH exposure neither induced an increase in IGF-I expression nor secretion in hOB. These results suggest that the stimulation of OPG production induced by GH in hOB is specific and receptor mediated and further support the view that GH is able to modulate bone remodeling by directly influencing osteoblast-osteoclast crosstalk.
Mrak
E
E
Bone Metabolic Unit, Scientific Institute San Raffaele, Via Olgettina, 60, 20132 Milano, Italy.
Villa
I
I
Lanzi
R
R
Losa
M
M
Guidobono
F
F
Rubinacci
A
A
D000704:Analysis of Variance; D002478:Cells, Cultured; D013006:Growth Hormone / Q000494:pharmacology*; D019382:Human Growth Hormone / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000032:analysis; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020032:Tyrphostins / Q000494:pharmacology
D053244:Osteoprotegerin; D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D019382:Human Growth Hormone; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; C406545:pegvisomant