Prostacyclin regulates bone growth via the Epac/Rap1 pathway

Endocrinology. 2015 Feb;156(2):499-510. doi: 10.1210/en.2014-1348. Epub 2014 Nov 18.


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. We show 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 prostaglandin D2 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal
  • Bone Development*
  • Cattle
  • Celecoxib
  • Cells, Cultured
  • Chondrocytes / enzymology
  • Cyclooxygenase 2 / metabolism
  • Epoprostenol / metabolism
  • Female
  • Growth Plate / drug effects
  • Growth Plate / enzymology
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Iloprost
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Prostaglandins I / physiology*
  • Pyrazoles
  • Signal Transduction
  • Sulfonamides
  • rap1 GTP-Binding Proteins / metabolism*


  • Anti-Inflammatory Agents, Non-Steroidal
  • Epac protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Prostaglandins I
  • Pyrazoles
  • Sulfonamides
  • Insulin-Like Growth Factor I
  • Epoprostenol
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • rap1 GTP-Binding Proteins
  • Celecoxib
  • Iloprost