A novel inhibitor of NF-κB-inducing kinase prevents bone loss by inhibiting osteoclastic bone resorption in ovariectomized mice
A novel inhibitor of NF-κB-inducing kinase prevents bone loss by inhibiting osteoclastic bone resorption in ovariectomized mice
复制标题
DOI：
10.1016/j.bone.2020.115316
复制
发表时间：
2020-06-01
期刊：
影响因子：
4.1
通讯作者：
Jimi, Eijiro
中科院分区：
文献类型：
--
作者：
Takakura, Nana;Matsuda, Miho;Jimi, Eijiro
包括骨质疏松症和类风湿性关节炎在内的肌肉骨骼疾病和病症是威胁健康预期寿命的疾病，为了延长老年人的健康预期寿命，预防骨骼和关节疾病和病症是重要的。我们以前报道过，发育不全（aly/aly）小鼠，在NF-κ B通路中参与p100到p52加工的Nik基因中存在功能缺失突变，表现出轻度的骨硬化症，破骨细胞数量减少，这表明NF-κ B通路是改善骨疾病的潜在药物靶点。最近，开发了新型NF-κ B诱导激酶（NIK）特异性抑制剂化合物33（Cpd 33），我们在体外和体内检测了其对破骨细胞骨吸收的影响。Cpd 33以剂量依赖性方式抑制NF-κ B配体受体激活剂（RANKL）诱导的破骨细胞生成，同时伴有破骨细胞分化标志物nfatc 1、dc-stamp和组织蛋白酶K表达的降低，而不影响细胞活力。Cdp 33特异性抑制RANKL诱导的p100到p52的加工，但不抑制破骨细胞前体中p65的磷酸化或I κ B α的降解或再合成。Cpd 33还抑制成熟破骨细胞的骨吸收活性。此外，Cdp 33治疗通过抑制破骨细胞形成而不影响卵巢切除小鼠中的成骨细胞骨形成来防止骨丢失。总之，NIK抑制剂可能是对常规药物治疗反应降低或有严重副作用的患者的新选择。
Musculoskeletal diseases and disorders, including osteoporosis and rheumatoid arthritis are diseases that threaten a healthy life expectancy, and in order to extend the healthy life expectancy of elderly people, it is important to prevent bone and joint diseases and disorders. We previously reported that alymphoplasia (aly/aly) mice, which have a loss-of-function mutation in the Nik gene involved in the processing of p100 to p52 in the alternative NF-kappa B pathway, show mild osteopetrosis with a decrease in the osteoclast number, suggesting that the alternative NF-kappa B pathway is a potential drug target for ameliorating bone diseases. Recently, the novel NF-kappa B-inducing kinase (NIK)-specific inhibitor compound 33 (Cpd33) was developed, and we examined its effect on osteoclastic bone resorption in vitro and in vivo. Cpd33 inhibited the receptor activator of NF-kappa B ligand (RANKL)induced osteoclastogenesis accompanied by a decrease in the expression of nfatc1, dc-stamp, and cathepsin K, markers of osteoclast differentiation, without affecting the cell viability, in a dose-dependent manner. Cdp33 specifically suppressed the RANKL-induced processing of p100 to p52 but not the phosphorylation of p65 or the degradation or resynthesis of I kappa B alpha in osteoclast precursors. Cpd33 also suppressed the bone-resorbing activity in mature osteoclasts. Furthermore, Cdp33 treatment prevented bone loss by suppressing the osteoclast formation without affecting the osteoblastic bone formation in ovariectomized mice. Taken together, NIK inhibitors may be a new option for patients with a reduced response to conventional pharmacotherapy or who have serious side effects.