title: Celecoxib treatment of fibrous dysplasia (FD) in a human FD cell line and FD-like lesions in mice with protein kinase A (PKA) defects.
abstract: Osteochondromyxomas (OMX) in the context of Carney complex (CNC) and fibrous dysplasia (FD)-like lesions (FDLL) in mice, as well as isolated myxomas in humans may be caused by inactivation of PRKAR1A, the gene coding for the type 1a regulatory subunit (R1α) of cAMP-dependent protein kinase (PKA). OMXs and FDLL in mice lacking Prkar1a grow from abnormal proliferation of adult bone stromal cells (aBSCs). Prkar1a and Prkaca (coding for Cα) haploinsufficiency leads to COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of aBSCs. Celecoxib is a cyclooxygenase-2 (COX2) inhibitor. We hypothesized that COX-2 inhibition may have an effect in FD and FDLL. In vitro treatment of a human cell line prepared from a FD patient with Celecoxib resulted in decreased PGE2 and cell proliferation. Treatment of mice haploinsufficient for R1α and Cα with 1500 mg/kg Celecoxib led to decreased PGE2 and proliferation and increased apoptosis, with a corresponding gene expression profile, resulting in dramatic reduction of tumor growth. Furthermore, the treatment improved the organization of cortical bone that was adjacent to the tumor. We conclude that, in vitro and in vivo, Celecoxib had an inhibitory effect on FD cell proliferation and in mouse FDLL structure, respectively. We speculate that COX-2 inhibitors offer an attractive alternative to current treatments for benign tumors such as OMX and FD that, apart from tumor suppression, may mechanically stabilize affected bones.
authors: Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors: Emmanouil
authors: E
authors: Saloustros
authors: Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors: Sisi
authors: S
authors: Liu
authors: Section on Physical Biochemistry, Office of the Scientific Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors: Edward L
authors: EL
authors: Mertz
authors: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, MD 20892, USA.
authors: Nisan
authors: N
authors: Bhattacharyya
authors: Office of Research Services (ORS), Division of Veterinary Resources (DVR), Office of the Director (OD), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors: Matthew F
authors: MF
authors: Starost
authors: Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors: Paraskevi
authors: P
authors: Salpea
authors: Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors: Maria
authors: M
authors: Nesterova
authors: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, MD 20892, USA.
authors: Michael
authors: M
authors: Collins
authors: Section on Physical Biochemistry, Office of the Scientific Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors: Sergey
authors: S
authors: Leikin
authors: Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA. Electronic address: stratakc@mail.nih.gov.
authors: Constantine A
authors: CA
authors: Stratakis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D000068579:Celecoxib / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000172:deficiency / Q000378:metabolism*; D005357:Fibrous Dysplasia of Bone / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D008024:Ligands; D051379:Mice; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D058847:Inflammasomes; D008024:Ligands; D000068579:Celecoxib
keywords: Bone tumors; Carney complex; Cyclic AMP; Cyclooxygenase-2 (COX-2); McCune-Albright syndrome; Prostaglandin E2