Thyroid hormone activates fibroblast growth factor receptor-1 in bone.
Thyroid hormone activates fibroblast growth factor receptor-1 in bone.
复制标题
甲状腺激素激活骨骼中的成纤维细胞生长因子受体 1。
作者：
D. Stevens;C. Harvey;A. J. Scott;P. O’Shea;Joanna C. Barnard;Allan J. Williams;G. Brady;J. Samarut;O. Chassande;G. Williams
甲状腺激素（T3）和T3受体（TR）α基因对骨骼发育至关重要，而成人甲状腺功能亢进症会增加骨质疏松性骨折的风险。我们分离成纤维细胞生长因子受体-1（FGFR 1）作为T3靶基因在成骨细胞中的减法杂交。在用T3处理6-48 h的成骨细胞中，FGFR 1 mRNA被诱导2- 3倍，FGFR 1蛋白被刺激2- 4倍。FGFR 1的诱导是独立的mRNA半衰期和废除放线菌素D和放线菌酮，表明中间蛋白的参与。成纤维细胞生长因子2（FGF 2）刺激成骨细胞中的MAPK，T3预处理6小时诱导了对FGF的更快速反应，其幅度增加了2至3倍。类似地，T3增强了FGF 2激活的FGFR 1的自磷酸化，但不改变FGF 2诱导的对接蛋白FRS 2的磷酸化。FGFR选择性抑制剂PD 166866和PD 161570消除了这些作用。原位杂交分析TR α基因敲除小鼠的骨化和骨骼矿化受损，发现成骨细胞和骨细胞中FGFR 1 mRNA表达减少，而T3未能刺激FGFR 1 mRNA或增强TR α基因敲除小鼠成骨细胞中FGF 2激活的MAPK信号传导。这些发现暗示FGFR 1信号在T3依赖性骨发育和甲状腺疾病引起的骨骼疾病的发病机制。
Thyroid hormone (T3) and the T3 receptor (TR) alpha gene are essential for bone development whereas adult hyperthyroidism increases the risk of osteoporotic fracture. We isolated fibroblast growth factor receptor-1 (FGFR1) as a T3-target gene in osteoblasts by subtraction hybridization. FGFR1 mRNA was induced 2- to 3-fold in osteoblasts treated with T3 for 6-48 h, and FGFR1 protein was stimulated 2- to 4-fold. Induction of FGFR1 was independent of mRNA half-life and abolished by actinomycin D and cycloheximide, indicating the involvement of an intermediary protein. Fibroblast growth factor 2 (FGF2) stimulated MAPK in osteoblasts, and pretreatment with T3 for 6 h induced a more rapid response to FGF that was increased in magnitude by 2- to 3-fold. Similarly, T3 enhanced FGF2-activated autophosphorylation of FGFR1, but did not modify FGF2-induced phosphorylation of the docking protein FRS2. These effects were abolished by the FGFR-selective inhibitors PD166866 and PD161570. In situ hybridization analyses of TRalpha-knockout mice, which have impaired ossification and skeletal mineralization, revealed reduced FGFR1 mRNA expression in osteoblasts and osteocytes, whereas T3 failed to stimulate FGFR1 mRNA or enhance FGF2-activated MAPK signaling in TRalpha-null osteoblasts. These findings implicate FGFR1 signaling in T3-dependent bone development and the pathogenesis of skeletal disorders resulting from thyroid disease.
登录
查看更多内容
影响因子：
158.5
作者：
Cummings, SR;Browner, WS;Ettinger, B
通讯作者：
Ettinger, B
影响因子：
10.5
作者：
Sahni, M;Ambrosetti, DC;Basilico, C
通讯作者：
Basilico, C
甲状腺激素对生长的影响。
DOI：
10.1016/s0889-8529(05)70349-2
发表时间：
1996
期刊：
Endocrinology and metabolism clinics of North America.
影响因子：
--
作者：
Weiss,RE;Refetoff,S
通讯作者：
Refetoff,S
影响因子：
10.5
作者：
Göthe, S;Wang, ZD;Forrest, D
通讯作者：
Forrest, D
影响因子：
6
作者：
Greenwald, JA;Mehrara, BJ;Longaker, MT
通讯作者：
Longaker, MT