title: Inhibition of cyclooxygenase-2 impacts chondrocyte hypertrophic differentiation during endochondral ossification.
abstract: 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. We show that COX-2 activity fulfils an important regulatory function in chondrocyte hypertrophic differentiation. Our data reveal essential cross-talk between COX-2 and bone morphogenic protein-2 (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 by NSAIDs (e.g., Celecoxib) decreases hypertrophic differentiation in various chondrogenic models in vitro and in vivo, while leaving early chondrogenic development unaltered. Our findings demonstrate that COX-2 activity is a novel factor partaking in chondrocyte hypertrophy in the context of endochondral ossification and 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.
authors.affiliation: Department of Orthopaedic Surgery, CAPHRI School for Public Health and Primary Care, Maastricht University Medical Center, Maastricht, The Netherlands. t.welting@maastrichtuniversity.nl
authors.forename: T J M
authors.initials: TJ
authors.lastname: Welting
authors.forename: M M J
authors.initials: MM
authors.lastname: Caron
authors.forename: P J
authors.initials: PJ
authors.lastname: Emans
authors.forename: M P F
authors.initials: MP
authors.lastname: Janssen
authors.forename: K
authors.initials: K
authors.lastname: Sanen
authors.forename: M M E
authors.initials: MM
authors.lastname: Coolsen
authors.forename: L
authors.initials: L
authors.lastname: Voss
authors.forename: D A M
authors.initials: DA
authors.lastname: Surtel
authors.forename: A
authors.initials: A
authors.lastname: Cremers
authors.forename: J W
authors.initials: JW
authors.lastname: Voncken
authors.forename: L W
authors.initials: LW
authors.lastname: van Rhijn
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology / Q000502:physiology; D000068579:Celecoxib; D002454:Cell Differentiation; D049108:Cell Enlargement; D002460:Cell Line; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015870:Gene Expression; D006132:Growth Plate / Q000166:cytology / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000943:Antigens, Differentiation; D055396:Bone Morphogenetic Protein 2; C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D024121:Collagen Type X; D050659:Core Binding Factor Alpha 1 Subunit; D052246:Cyclooxygenase 2 Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; C493716:Runx2 protein, mouse; D013449:Sulfonamides; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D000469:Alkaline Phosphatase; D000068579:Celecoxib