Abstract
Purpose: Skeletogenesis and bone fracture healing involve endochondral ossification, a process during which cartilaginous primordia are gradually replaced by bone tissue. In line with a role for cyclooxygenase-2 (COX-2) in the endochondral ossification process, non-steroidal anti-inflammatory drugs (NSAIDs) were reported to negatively affect bone fracture healing due to impaired osteogenesis. However, a role for COX-2 activity in the chondrogenic phase of endochondral ossification has not been addressed before. Methods: The role of COX-2 was studied during chondrogenic differentiation of ATDC5 cells and rabbit periosteal explants. BMP-2 was used to increase hypertrophic differentiation and the NSAIDs NS398 and Celecoxib were applied to specifically inhibit COX-2 activity. Chondrogenic outcome was measured by gene- and protein expression analysis, and (immuno) histochemical stainings. For in vivo evidence skeletally immature NZW rabbits were treated with Celecoxib (10mg/kg) for 21 days. Growth plate development was analyzed by histochemistry. Results: Our data reveal essential cross-talk between COX-2 and BMP-2 during chondrocyte hypertrophic differentiation. BMP-2 mediated chondrocyte hypertrophy is associated with increased COX-2 expression and pharmacological inhibition of COX-2 activity decreased BMP-2 induced hypertrophic differentiation in independent chondrogenic models in vitro and ex vivo, while leaving chondrogenesis unaltered. Importantly, systemic inhibition of COX-2 activity in vivo resulted in significantly decreased growth plate thickness, which could be attributed to impaired chondrocyte hypertrophic differentiation. Conclusions: Our findings demonstrate that COX-2 is an important executing factor of BMP-2-induced chondrocyte hypertrophy in the context of endochondral ossification. These observations provide a novel etiological perspective on the adverse effects of NSAIDs on bone fracture healing and have important implications for the use of NSAIDs during endochondral skeletal development. In addition, our data provides a novel strategy to improve the outcome of cartilage regenerative medicine by decreasing the level of unwanted chondrocyte hypertrophy and ossification.
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