Liu Sisi, Saloustros Emmanouil, Berthon Annabel, Starost Matthew F, Sahut-Barnola Isabelle, Salpea Paraskevi, Szarek Eva, Faucz Fabio R, Martinez Antoine, Stratakis Constantine A
Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development (NICHD), National Institutes of Health, 10 Center Drive, Building 10-Clinical Research Center, Room 1-3330, Bethesda, Maryland 20892, USAOffice of Research Services (ORS)Division of Veterinary Resources (DVR), Office of the Director (OD), National Institutes of Health, Bethesda, Maryland 20892, USACNRS UMR6247Génétique Reproduction et Développement, Clermont Université, Aubière, France.
Endocr Relat Cancer. 2016 Jan;23(1):15-25. doi: 10.1530/ERC-15-0472. Epub 2015 Oct 5.
Primary pigmented nodular adrenocortical disease (PPNAD), whether in the context of Carney complex (CNC) or isolated, leads to ACTH-independent Cushing's syndrome (CS). CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1α) of cAMP-dependent protein kinase (PKA). Mice lacking Prkar1a, specifically in the adrenal cortex (AdKO) developed CS caused by bilateral adrenal hyperplasia (BAH), which is formed from the abnormal proliferation of fetal-like adrenocortical cells. Celecoxib is a cyclooxygenase 2 (COX2) inhibitor. In bone, Prkar1a inhibition is associated with COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of bone stromal cells. We hypothesized that COX2 inhibition may have an effect in PPNAD. In vitro treatment of human cell lines, including one from a patient with PPNAD, with celecoxib resulted in decreased cell viability. We then treated AdKO and control mice with 1500 mg/kg celecoxib or vehicle. Celecoxib treatment led to decreased PGE2 and corticosterone levels, reduced proliferation and increased apoptosis of adrenocortical cells, and decreased steroidogenic gene expression. We conclude that, in vitro and in vivo, celecoxib led to decreased steroidogenesis. In a mouse model of PPNAD, celecoxib caused histological changes that, at least in part, reversed BAH and this was associated with a reduction of corticosterone levels.
原发性色素沉着性结节性肾上腺皮质疾病（PPNAD），无论处于卡尼综合征（CNC）背景下还是孤立存在，都会导致促肾上腺皮质激素（ACTH）非依赖性库欣综合征（CS）。CNC和PPNAD通常由PRKAR1A基因的失活突变引起，该基因编码环磷酸腺苷（cAMP）依赖性蛋白激酶（PKA）的1a型调节亚基（R1α）。特异性敲除肾上腺皮质Prkar1a基因的小鼠（AdKO）出现双侧肾上腺增生（BAH）导致的CS，BAH由胎儿样肾上腺皮质细胞异常增殖形成。塞来昔布是一种环氧化酶2（COX2）抑制剂。在骨骼中，Prkar1a抑制与COX2激活和前列腺素E2（PGE2）产生相关，进而激活骨基质细胞增殖。我们推测COX2抑制可能对PPNAD有作用。用塞来昔布对包括一名PPNAD患者的细胞系进行体外处理，导致细胞活力下降。然后我们用剂量为1500mg/kg的塞来昔布或赋形剂处理AdKO小鼠和对照小鼠。塞来昔布治疗导致PGE2和皮质酮水平降低，肾上腺皮质细胞增殖减少、凋亡增加，以及类固醇生成基因表达降低。我们得出结论，在体外和体内，塞来昔布均导致类固醇生成减少。在PPNAD小鼠模型中，塞来昔布引起组织学变化，至少部分逆转了BAH，这与皮质酮水平降低相关。
