Background: Little is known presently about the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the longitudinal bone growth occurring in the growth plate. We have examined the effects of administration of different types of NSAIDs on the longitudinal growth of the growth plate using a fetal rat metatarsal bone culture model.
Methods: Cultured fetal rat metatarsal bones were used to study the effect of nonselective (indomethacin) and selective cyclooxygenase-2 (COX-2, celecoxib) NSAIDs on longitudinal bone growth. The effect of NSAIDs on proliferation and apoptosis of growth plate chondrocytes were analyzed by BrdU incorporation and a TUNEL assay. Prostaglandin E2 (PGE2) production was measured by an ELISA kit. We also examined the effect of exogenous PGE2 on the growth plate.
Results: NSAIDs caused a dose-dependent growth retardation of cultured metatarsal bones. Both nonselective and COX-2 selective NSAIDs inhibit longitudinal bone growth. We found that NSAIDs suppressed the proliferation of chondrocytes and production of PGE2, and increased the apoptosis of chondrocytes. Supplemental PGE2 could not reverse the effects of NSAIDs on the growth plate.
Conclusions: Our data show that NSAIDs induce a dose-dependent growth retardation of cultured rat metatarsal bones. A detailed analysis revealed decreased proliferation and increased apoptosis of chondrocytes in the growth plate, indicating that COX-2 is responsible for PGE2 production in growth plate chondrocytes.
Clinical relevance: The data from the present study suggest that deleterious effects on the growth plate by chronic NSAIDs use should be considered for children who have chronic inflammatory diseases, such as juvenile rheumatoid arthritis.