Prostacyclin regulates bone growth via the Epac/Rap1 pathway

Area of Science:

• Biochemistry
• Cell Biology
• Developmental Biology

Background:

• Prostaglandins influence adult bone and joint health, but their role in growth plate cartilage and bone growth remains unclear.
• Cyclooxygenase (COX)-2 mRNA expression differs between articular and growth plate cartilage, with higher expression in growth plate chondrocytes, further stimulated by IGF-I.

Purpose of the Study:

• To investigate the role of prostaglandins, specifically prostacyclin, in growth plate cartilage development and bone growth.
• To elucidate the molecular mechanisms by which nonsteroidal anti-inflammatory drugs (NSAIDs) affect chondrocyte proliferation and signaling pathways.

Main Methods:

• Examined COX-2 mRNA expression in growth plate and articular cartilage.
• Inhibited COX activity in bovine chondrocytes, ATDC5 cells, and human metatarsal explants using NSAIDs.
• Administered NSAIDs to young mice to assess effects on bone growth.
• Investigated the reversal of NSAID-induced inhibition using various signaling molecules and analogs.

Main Results:

• NSAID inhibition of COX activity reduced chondrocyte proliferation and ERK activation by IGF-I, an effect reversed by prostaglandin E2 and prostacyclin (PGI2).
• NSAID treatment in young mice led to dwarfism.
• In growth plate chondrocytes, NSAID-induced inhibition was reversed by forskolin, 8-bromoadenosine, 3',5'-cAMP, and the prostacyclin analog iloprost.
• Celecoxib inhibition was reversed by an Epac activator, suggesting involvement of the Rap1 pathway.

Conclusions:

• Prostacyclin signaling is essential for normal growth plate development and bone elongation.
• NSAIDs interfere with growth plate chondrocyte function and bone growth, likely by inhibiting prostacyclin pathways.