title: Celecoxib inhibits osteoblast maturation by suppressing the expression of Wnt target genes.
abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to impair bone healing. We previously reported that in colon cancer cells, celecoxib, a COX-2-selective NSAID, inhibited the canonical Wnt/β-catenin signaling pathway. Since this pathway also plays an important role in osteoblast growth and differentiation, we examined the effect of celecoxib on maturation of osteoblast-like cell line MC3T3-E1. Celecoxib induced degradation of transcription factor 7-like 2, a key transcription factor of the canonical Wnt pathway. Subsequently, we analyzed the effect of celecoxib on two osteoblast differentiation markers; runt-related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP), both of which are the products of the canonical Wnt pathway target genes. Celecoxib inhibited the expression of both RUNX2 and ALP by suppressing their promoter activity. Consistent with these observations, celecoxib also strongly inhibited osteoblast-mediated mineralization. These results suggest that celecoxib inhibits osteoblast maturation by suppressing Wnt target genes, and this could be the mechanism that NSAIDs inhibit bone formation and fracture healing.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Periodontology Section, Division of Oral Rehabilitation, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nagano
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Arioka
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Global Medical Science Education Unit, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: yanaga@clipharm.med.kyushu-u.ac.jp.
authors.forename: Fumi
authors.initials: F
authors.lastname: Takahashi-Yanaga
authors.affiliation: Periodontology Section, Division of Oral Rehabilitation, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan; Section of Operative Dentistry and Endodontology, Department of Odontology, Fukuoka Dental College, Fukuoka, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Matsuzaki
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sasaguri
mesh_terms: D000469:Alkaline Phosphatase / Q000096:biosynthesis; D000818:Animals; D002113:Calcification, Physiologic / Q000187:drug effects; D000068579:Celecoxib / Q000009:adverse effects*; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000096:biosynthesis; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D000469:Alkaline Phosphatase; D000068579:Celecoxib
keywords: Celecoxib; Fracture healing; Mineralization; Osteoblast; Wnt/β-catenin signaling pathway