TY - JOUR
T1 - Prostacyclin Regulates Bone Growth via the Epac/Rap1 Pathway
AU - Hutchison, Michele R.
AU - White, Perrin C.
N1 - Publisher Copyright:
Copyright © 2015 by the Endocrine Society.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - Prostaglandins, particularly PGE2, are important to adult bone and joint health, but how prostaglandins act on growth plate cartilage to affect bone growth is unclear.Weshow that growth plate cartilage is distinct from articular cartilage with respect to cyclooxygenase (COX)-2 mRNA expression; although articular chondrocytes express very little COX-2, COX-2 expression is high in growth plate chondrocytes and is increased by IGF-I. In bovine primary growth plate chondrocytes, ATDC5 cells, and human metatarsal explants, inhibition of COX activity with nonsteroidal antiinflammatory drugs (NSAIDs) inhibits chondrocyte proliferation and ERK activation by IGF-I. This inhibition is reversed by prostaglandin E2 and prostacyclin (PGI2) but not by prostaglandinD2 or thromboxane B2. Inhibition of COX activity in young mice by ip injections of NSAIDs causes dwarfism. In growth plate chondrocytes, inhibition of proliferation and ERK activation by NSAIDs is reversed by forskolin, 8-bromoadenosine, 3,5-cAMP and a prostacyclin analog, iloprost. The inhibition of proliferation and ERK activation by celecoxib is also reversed by 8CPT-2Me-cAMP, an activator of Epac, implicating the small G protein Rap1 in the pathway activated by iloprost. These results imply that prostacyclin is required for proper growth plate development and bone growth..
AB - Prostaglandins, particularly PGE2, are important to adult bone and joint health, but how prostaglandins act on growth plate cartilage to affect bone growth is unclear.Weshow that growth plate cartilage is distinct from articular cartilage with respect to cyclooxygenase (COX)-2 mRNA expression; although articular chondrocytes express very little COX-2, COX-2 expression is high in growth plate chondrocytes and is increased by IGF-I. In bovine primary growth plate chondrocytes, ATDC5 cells, and human metatarsal explants, inhibition of COX activity with nonsteroidal antiinflammatory drugs (NSAIDs) inhibits chondrocyte proliferation and ERK activation by IGF-I. This inhibition is reversed by prostaglandin E2 and prostacyclin (PGI2) but not by prostaglandinD2 or thromboxane B2. Inhibition of COX activity in young mice by ip injections of NSAIDs causes dwarfism. In growth plate chondrocytes, inhibition of proliferation and ERK activation by NSAIDs is reversed by forskolin, 8-bromoadenosine, 3,5-cAMP and a prostacyclin analog, iloprost. The inhibition of proliferation and ERK activation by celecoxib is also reversed by 8CPT-2Me-cAMP, an activator of Epac, implicating the small G protein Rap1 in the pathway activated by iloprost. These results imply that prostacyclin is required for proper growth plate development and bone growth..
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U2 - 10.1210/en.2014-1348
DO - 10.1210/en.2014-1348
M3 - Article
C2 - 25406016
AN - SCOPUS:84921669804
SN - 0013-7227
VL - 156
SP - 499
EP - 510
JO - Endocrinology
JF - Endocrinology
IS - 2
ER -