Motohashi Kanon, Soejima Yoshiaki, Yamamoto Koichiro, Iwata Nahoko, Suyama Atsuhito, Nakano Yasuhiro, Otsuka Fumio
Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
Int J Mol Sci. 2025 Sep 18;26(18):9127. doi: 10.3390/ijms26189127.
Thyroid hormones are fundamental regulators of cellular differentiation, development, and metabolism. Their receptors are expressed in reproductive tissues, including the ovary, and dysregulation of thyroid hormone homeostasis has been associated with menstrual disturbances, infertility, and adverse pregnancy outcomes. Bone morphogenetic protein (BMP) ligands and their receptors are functionally involved in gonadotropin-induced ovarian steroidogenesis in an autocrine or paracrine manner. In this study, we examined the effects of thyroid hormones on steroidogenesis and their interplay with BMP signaling by using human granulosa-like KGN cells and primary rat granulosa cells (GCs). In KGN cells, triiodothyronine (T3) enhanced forskolin-induced expression of key steroidogenic enzymes involved in both estradiol biosynthesis and progesterone synthesis/metabolism, whereas thyroxine (T4) exerted minimal effects. In rat GCs, T3 treatment increased follicle-stimulating hormone (FSH)-stimulated estradiol production without altering progesterone output. T3 pretreatment attenuated BMP-6-induced phosphorylation of Smad1/5/9 in KGN cells, accompanied by upregulation of inhibitory Smad6 and downregulation of the BMP type II receptor. Conversely, BMP-6 stimulation elevated thyroid hormone receptor β expression, indicating reciprocal regulatory interactions between thyroid hormone and BMP pathways. Collectively, these findings suggest that thyroid hormones modulate steroidogenesis, at least in part, through suppression of endogenous BMP-6 signaling in granulosa cells.
甲状腺激素是细胞分化、发育和代谢的基本调节因子。它们的受体在包括卵巢在内的生殖组织中表达，甲状腺激素稳态失调与月经紊乱、不孕和不良妊娠结局有关。骨形态发生蛋白（BMP）配体及其受体以自分泌或旁分泌方式在促性腺激素诱导的卵巢类固醇生成中发挥功能作用。在本研究中，我们使用人颗粒细胞样KGN细胞和原代大鼠颗粒细胞（GCs）研究了甲状腺激素对类固醇生成的影响及其与BMP信号的相互作用。在KGN细胞中，三碘甲状腺原氨酸（T3）增强了福斯可林诱导的参与雌二醇生物合成和孕酮合成/代谢的关键类固醇生成酶的表达，而甲状腺素（T4）的作用最小。在大鼠GCs中，T3处理增加了促卵泡激素（FSH）刺激的雌二醇产生，而不改变孕酮产量。T3预处理减弱了KGN细胞中BMP-6诱导的Smad1/5/9磷酸化，同时抑制性Smad6上调，BMP II型受体下调。相反，BMP-6刺激提高了甲状腺激素受体β的表达，表明甲状腺激素和BMP信号通路之间存在相互调节作用。总的来说，这些发现表明甲状腺激素至少部分地通过抑制颗粒细胞内源性BMP-6信号来调节类固醇生成。
