Inhibition of Phosphodiesterase 5 Promotes the Aromatase-Mediated Estrogen Biosynthesis in Osteoblastic Cells by Activation of cGMP/PKG/SHP2 Pathway.
Inhibition of Phosphodiesterase 5 Promotes the Aromatase-Mediated Estrogen Biosynthesis in Osteoblastic Cells by Activation of cGMP/PKG/SHP2 Pathway.
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DOI：
10.3389/fendo.2021.636784
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发表时间：
2021
影响因子：
5.2
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Wisanwattana W;Wongkrajang K;Cao DY;Shi XK;Zhang ZH;Zhou ZY;Li F;Mei QG;Wang C;Suksamrarn A;Zhang GL;Wang F
机械刺激通过成骨细胞中的次要信使环鸟苷3‘，5’-单磷酸(CGMP)诱导骨生长和改建。然而，cGMP在调节雌激素生物合成中的作用尚不清楚，而雌激素缺乏是导致骨质疏松症的主要原因。在此，我们发现用淫羊藿苷类似物合成的3-O-甲氧甲基-7-O-苄基淫羊藿苷(13)、7-O-苄基淫羊藿苷(14)和4‘-O-甲基-8-异戊基山奈酚(15)这些苯基化的黄酮类化合物能促进成骨细胞UMR106细胞雌激素的生物合成，计算的EC50值分别为1.53、3.45和10.57微米。14和15提高了成骨细胞中骨特异性启动子I.4驱动的芳香酶的表达水平，该酶是唯一一种以雄激素为底物催化雌激素形成的酶。14抑制磷酸二酯酶5(PDE5)，刺激细胞内cGMP水平，促进成骨细胞分化。抑制cGMP依赖的蛋白激酶G(PKG)可阻断14对雌激素生物合成和成骨细胞分化的刺激作用。此外，14激活PKG可刺激SHP2(含Src同源结构域的酪氨酸磷酸酶2)的活性，从而激活成骨细胞中的Src和ERK(细胞外信号调节激酶)信号，并增加ERK依赖的芳香化酶的表达。我们的发现揭示了以前未知的cGMP在调节骨骼中雌激素生物合成中的作用。这些结果支持了14作为PKG激活药物的进一步发展，以模拟骨机械刺激在治疗骨质疏松症中的合成代谢效应。
Mechanical stimulation induces bone growth and remodeling by the secondary messenger, cyclic guanosine 3’, 5’-monophosphate (cGMP), in osteoblasts. However, the role of cGMP in the regulation of estrogen biosynthesis, whose deficiency is a major cause of osteoporosis, remains unclear. Here, we found that the prenylated flavonoids, 3-O-methoxymethyl-7-O-benzylicaritin (13), 7-O-benzylicaritin (14), and 4'-O-methyl-8-isopentylkaempferol (15), which were synthesized using icariin analogs, promoted estrogen biosynthesis in osteoblastic UMR106 cells, with calculated EC50 values of 1.53, 3.45, and 10.57 µM, respectively. 14 and 15 increased the expression level of the bone specific promoter I.4-driven aromatase, the only enzyme that catalyzes estrogen formation by using androgens as substrates, in osteoblastic cells. 14 inhibited phosphodiesterase 5 (PDE5), stimulated intracellular cGMP level and promoted osteoblast cell differentiation. Inhibition of cGMP dependent-protein kinase G (PKG) abolished the stimulatory effect of 14 on estrogen biosynthesis and osteoblast cell differentiation. Further, PKG activation by 14 stimulated the activity of SHP2 (Src homology 2 domain-containing tyrosine phosphatase 2), thereby activating Src and ERK (extracellular signal-regulated kinase) signaling and increasing ERK-dependent aromatase expression in osteoblasts. Our findings reveal a previously unknown role of cGMP in the regulation of estrogen biosynthesis in the bone. These results support the further development of 14 as a PKG-activating drug to mimic the anabolic effects of mechanical stimulation of bone in the treatment of osteoporosis.
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