Celecoxib treatment of fibrous dysplasia (FD) in a human FD cell line and FD-like lesions in mice with protein kinase A (PKA) defects.
Celecoxib treatment of fibrous dysplasia (FD) in a human FD cell line and FD-like lesions in mice with protein kinase A (PKA) defects.
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DOI：
10.1016/j.mce.2016.08.004
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发表时间：
2017-01-05
影响因子：
4.1
通讯作者：
Stratakis, Constantine A.
中科院分区：
文献类型：
--
作者：
Saloustros, Emmanouil;Liu, Sisi;Mertz, Edward L.;Bhattacharyya, Nisan;Starost, Matthew F.;Salpea, Paraskevi;Nesterova, Maria;Collins, Michael;Leikin, Sergey;Stratakis, Constantine A.
关键词：
小鼠卡尼复合体 (CNC) 和纤维发育不良 (FD) 样病变 (FDLL) 背景下的骨软骨粘液瘤 (OMX) 以及人类孤立的粘液瘤可能是由 PRKAR1A 失活引起的，PRKAR1A 是编码 cAMP 依赖性蛋白激酶 (PKA) 1a 型调节亚基 (R1α) 的基因。缺乏 Prkar1a 的小鼠中的 OMX 和 FDLL 来自成体骨基质细胞 (aBSC) 的异常增殖。 Prkar1a 和 Prkaca（编码 Cα）单倍体不足导致 COX2 激活和前列腺素 E2 (PGE2) 产生，进而激活 aBSC 增殖。 Celecoxib 是一种环氧合酶 2 (COX2) 抑制剂。我们假设 COX-2 抑制可能对 FD 和 FDLL 有影响。用塞来昔布对 FD 患者制备的人类细胞系进行体外治疗，结果导致 PGE2 和细胞增殖减少。用 1,500 mg/kg 塞来昔布治疗 R1α 和 Cα 单倍体不足的小鼠，导致 PGE2 和增殖减少，细胞凋亡增加，并产生相应的基因表达谱，从而导致肿瘤生长急剧减少。此外，治疗还改善了肿瘤附近皮质骨的组织。我们的结论是，在体外和体内，塞来昔布分别对 FD 细胞增殖和小鼠 FDLL 结构具有抑制作用。我们推测，COX-2 抑制剂为 OMX 和 FD 等良性肿瘤的当前治疗提供了一种有吸引力的替代方案，除了抑制肿瘤外，还可以机械稳定受影响的骨骼。
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 lead 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 1,500 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.
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