Abstract：
Several members of the transforming growth factor beta (TGF-β) superfamily regulate the proliferation, differentiation, and function of bone-forming osteoblasts and bone-resorbing osteoclasts. However, it is still unknown whether Nodal, a member of the TGF-β superfamily, serves a function in bone cells. In this study, we found that Nodal did not have any function in osteoblasts but instead negatively regulated osteoclast differentiation. Nodal inhibited RANKL-induced osteoclast differentiation by downregulating the expression of pro-osteoclastogenic genes, including c-fos, Nfatc1, and Blimp1, and upregulating the expression of antiosteoclastogenic genes, including Bcl6 and Irf8. Nodal activated STAT1 in osteoclast precursor cells, and STAT1 downregulation significantly reduced the inhibitory effect of Nodal on osteoclast differentiation. These findings indicate that Nodal activates STAT1 to downregulate or upregulate the expression of pro-osteoclastogenic or antiosteoclastogenic genes, respectively, leading to the inhibition of osteoclast differentiation. Moreover, the inhibitory effect of Nodal on osteoclast differentiation contributed to the reduction of RANKL-induced bone loss in vivo.
摘要：
转化生长因子β（TGF-β）超家族的几个成员调节增殖，分化,骨形成成骨细胞和骨吸收破骨细胞的功能。然而,它仍然是未知的节点，TGF-β超家族的成员,在骨细胞中发挥作用。在这项研究中,我们发现Nodal在成骨细胞中没有任何功能，而是负向调节破骨细胞的分化。Nodal通过下调促破骨细胞基因的表达抑制RANKL诱导的破骨细胞分化,包括c-fos,Nfatc1和Blimp1，并上调抗破骨细胞基因的表达，包括Bcl6和Irf8。破骨细胞前体细胞中激活STAT1，STAT1下调显著降低了Nodal对破骨细胞分化的抑制作用。这些发现表明，Nodal激活STAT1下调或上调促破骨细胞或抗破骨细胞基因的表达，分别,导致破骨细胞分化的抑制。此外，Nodal对破骨细胞分化的抑制作用有助于减少RANKL诱导的体内骨丢失。
