Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA.
Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
FASEB J. 2020 Feb;34(2):2392-2407. doi: 10.1096/fj.201902227R. Epub 2019 Dec 23.
Bone resorption is a severe consequence of inflammatory diseases associated with osteolysis, such as rheumatoid arthritis (RA), often leading to disability in patients. In physiological conditions, the differentiation of bone-resorbing osteoclasts is delicately regulated by the balance between osteoclastogenic and anti-osteoclastogenic mechanisms. Inflammation has complex impact on osteoclastogenesis and bone destruction, and the underlying mechanisms of which, especially feedback inhibition, are underexplored. Here, we identify a novel regulatory network mediated by RBP-J/NFATc1-miR182 in TNF-induced osteoclastogenesis and inflammatory bone resorption. This network includes negative regulator RBP-J and positive regulators, NFATc1 and miR182, of osteoclast differentiation. In this network, miR182 is a direct target of both RBP-J and NFATc1. RBP-J represses, while NFATc1 activates miR182 expression through binding to specific open chromatin regions in the miR182 promoter. Inhibition of miR182 by RBP-J servers as a critical mechanism that limits TNF-induced osteoclast differentiation and inflammatory bone resorption. Inflammation, such as that which occurs in RA, shifts the expression levels of the components in this network mediated by RBP-J/NFATc1-miR182-FoxO3/PKR (previously identified miR182 targets) towards more osteoclastogenic, rather than healthy conditions. Treatment with TNF inhibitors in RA patients reverses the expression changes of the network components and osteoclastogenic potential. Thus, this network controls the balance between activating and repressive signals that determine the extent of osteoclastogenesis. These findings collectively highlight the biological significance and translational implication of this newly identified intrinsic regulatory network in inflammatory osteoclastogenesis and osteolysis.
破骨细胞骨吸收是与骨溶解相关的炎症性疾病的严重后果，例如类风湿关节炎（RA），常导致患者残疾。在生理条件下，破骨细胞骨吸收的分化受破骨细胞生成和抗破骨细胞生成机制之间的平衡精细调节。炎症对破骨细胞生成和骨破坏有复杂的影响，其潜在机制，尤其是反馈抑制，尚未得到充分探索。在这里，我们确定了一个由 RBP-J/NFATc1-miR182 介导的在 TNF 诱导的破骨细胞生成和炎症性骨吸收中起作用的新的调节网络。该网络包括破骨细胞分化的负调节因子 RBP-J 和正调节因子 NFATc1 和 miR182。在该网络中，miR182 是 RBP-J 和 NFATc1 的直接靶标。RBP-J 抑制 miR182 的表达，而 NFATc1 通过与 miR182 启动子上的特定开放染色质区域结合来激活 miR182 的表达。RBP-J 对 miR182 的抑制是限制 TNF 诱导的破骨细胞分化和炎症性骨吸收的关键机制。炎症，如 RA 中发生的炎症，通过 RBP-J/NFATc1-miR182-FoxO3/PKR（先前鉴定的 miR182 靶标）介导的网络成分的表达水平向更有利于破骨细胞生成的方向转移，而不是健康状态。RA 患者使用 TNF 抑制剂治疗可逆转网络成分的表达变化和破骨细胞生成能力。因此，该网络控制着激活和抑制信号之间的平衡，决定了破骨细胞生成的程度。这些发现共同强调了这个新发现的内在调节网络在炎症性破骨细胞生成和骨溶解中的生物学意义和转化意义。
