title: Prostaglandin dependent control of an endogenous estrogen receptor agonist by osteoblasts.
abstract: Estrogen receptor (ER) activation has complex effects on bone cells, and loss of circulating estradiol adversely affects skeletal status in women. Hormone replacement therapy effectively circumvents bone loss after menopause, but enhances disease risk in other tissues. Here we show that prostaglandin E2 (PGE2) augments the activity of an osteoblast-derived selective ER modulator, ObSERM. The stimulatory effect of PGE2 is replicated in part by either the PG receptor EP3 agonist 17-phenyl trinor PGE2 or by the PG receptor FP agonist PGF2α⋅ Whereas activation of the various PG receptors induces multiple downstream signals, the response to PGE2 was mimicked by activators of protein kinase C, and suppressed by inhibition of protein kinase C but not by inhibition of protein kinase A. Moreover, inhibition of nitric oxide synthesis and activation of the PTH and Wnt pathways increases ObSERM activity. Our studies therefore reveal that ObSERM activity is controlled in distinct ways and revise our understanding of ER activation within bone by agents or events associated with PG expression. They also predict ways to sustain or improve bone formation, fracture repair, and surgical healing without adding the risk of disease in other tissues where ER activation also has important biological functions.
authors.affiliation: Departments of Pathology and Surgery, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: McCarthy
authors.forename: Michael
authors.initials: M
authors.lastname: Centrella
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D011982:Receptors, Prostaglandin; D020845:Selective Estrogen Receptor Modulators; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D015232:Dinoprostone