Department of Oral Biology, Yonsei University College of Dentistry, Seoul, Korea.
BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea.
J Endocrinol. 2019 Sep;242(3):241-249. doi: 10.1530/JOE-19-0123.
The receptor activator of nuclear factor-kappa B ligand (RANKL) induces osteoclastogenesis by induction of Ca2+ oscillation, calcineurin activation and translocation into the nucleus of nuclear factor of activated T cells type c1 (NFATc1). Homer proteins are scaffold proteins. They regulate Ca2+ signaling by modulating the activity of multiple Ca2+ signaling proteins. Homers 2 and 3, but not Homer1, also independently affect the interaction between NFATc1 and calcineurin. However, to date, whether and how the Homers are involved in osteoclastogenesis remains unknown. In the present study, we investigated Homer2 and Homer3 roles in Ca2+ signaling and NFATc1 function during osteoclast differentiation. Deletion of Homer2/Homer3 (Homer2/3) markedly decreased the bone density of the tibia, resulting in bone erosion. RANKL-induced osteoclast differentiation is greatly facilitated in Homer2/3 DKO bone marrow-derived monocytes/macrophages (BMMs) due to increased NFATc1 expression and nuclear translocation. However, these findings did not alter RANKL-induced Ca2+ oscillations. Of note, RANKL treatment inhibited Homer proteins interaction with NFATc1, but it was restored by cyclosporine A treatment to inhibit calcineurin. Finally, RANKL treatment of Homer2/3 DKO BMMs significantly increased the formation of multinucleated cells. These findings suggest a novel potent mode of bone homeostasis regulation through osteoclasts differentiation. Specifically, we found that Homer2 and Homer3 regulate NFATc1 function through its interaction with calcineurin to regulate RANKL-induced osteoclastogenesis and bone metabolism.
核因子-κ B 受体激活剂配体（RANKL）通过诱导 Ca2+ 振荡、钙调神经磷酸酶激活和核因子活化 T 细胞 c1（NFATc1）入核来诱导破骨细胞生成。 Homer 蛋白是支架蛋白。它们通过调节多种 Ca2+ 信号蛋白的活性来调节 Ca2+ 信号。 Homer2 和 Homer3，但不是 Homer1，也独立影响 NFATc1 与钙调神经磷酸酶的相互作用。然而，迄今为止， Homer 是否以及如何参与破骨细胞生成仍然未知。在本研究中，我们研究了 Homer2 和 Homer3 在破骨细胞分化过程中 Ca2+ 信号和 NFATc1 功能中的作用。 Homer2/3 缺失（Homer2/3）显着降低了胫骨的骨密度，导致骨侵蚀。由于 NFATc1 表达和核易位增加，RANKL 诱导的破骨细胞分化在 Homer2/3 DKO 骨髓来源的单核细胞/巨噬细胞（BMM）中得到极大促进。然而，这些发现并没有改变 RANKL 诱导的 Ca2+ 振荡。值得注意的是，RANKL 处理抑制了 Homer 蛋白与 NFATc1 的相互作用，但通过抑制钙调神经磷酸酶的环孢素 A 处理得到恢复。最后，RANKL 处理 Homer2/3 DKO BMM 显着增加多核细胞的形成。这些发现表明通过破骨细胞分化调节骨稳态的一种新的有效模式。具体而言，我们发现 Homer2 和 Homer3 通过与钙调神经磷酸酶的相互作用调节 NFATc1 功能，从而调节 RANKL 诱导的破骨细胞生成和骨代谢。
