Modulatory Role of Cyclooxygenase-2 Derived Prostaglandins on Anabolic Skeletal Hormone Actions

Date of Completion

January 2011

Keywords

Biology, Molecular|Biology, Cell|Biology, Endocrinology

Degree

Ph.D.

Abstract

Prostaglandins (PG), particularly of the E class (PGE2), are abundantly produced by bone in response to many stimuli, which increase the local synthesis of PGs by stimulating the expression of cyclooxygenase-2 (COX-2). COX-2 dependent PGs are both anabolic, by increasing bone formation by osteoblasts, and catabolic, by increasing hone resorption by ostcoclasts, however the mechanism by which they stimulate the net formation or net loss of bone is not known. ^ We have previously shown that the osteogenic response to BMP-2 is decreased in the absence of COX-2 dependent PGs. Others have used PGs and PG receptor agonists to augment the formation of bone by BMP-2. While BMP-2 is typically described as an anabolic factor, it has also been described to increase osteoclast formation in a number of systems, which may limit the net bone formed. Because PGE2 increases bone resorption by stimulating osteoclast differentiation, we hypothesized that the combination of BMP-2 and PGE2 may increase osteoclast differentiation greater than individual treatments. Using in vitro models of osteoclast differentiation from bone marrow precursors, BMP-2 alone did not stimulate osteoclastogcnsis, but enhanced PGE2-stimulated osteoclast formation via osteoblasts by increasing expression of the osteoclastogenic factor receptor activator of NF-κB (RANKL) and decreasing expression of the decoy ligand osteoprotegerin (OPG). Thus, PGE2 may have complex effects on BMP-2 stimulated bone formation in vivo.^ On the other hand, while we have similarly shown that PGE2 enhances PTH stimulated ostcoclast formation, it also inhibits the anabolic and osteogenic responses. To better study the effects of PGE2 on the osteoeenic and ostcoclastogenie responses to PTH, we used cultured primary calvarial osteoblasts for the long-term differentiation response and the early responses. We found that endogenous PGs attenuated the anabolic response to PTH, such that PTH had a greater osteogenic response in cells from COX-2 KO mice or with pharmacological inhibition of COX-2. Additionally, while PTH and PGE2 tended to stimulate similar early response gene expression, Pill increased IGF-1 mRNA where as PGE2, stimulated phosphorylation of the mitogen-activated kinases Erk1/2. These factors may underlie the subtle differences in response to PTH and PGE2. ^

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