Osteoprotegerin and Denosumab Stimulate Human Beta Cell Proliferation through Inhibition of the Receptor Activator of NF-κB Ligand Pathway.
Osteoprotegerin and Denosumab Stimulate Human Beta Cell Proliferation through Inhibition of the Receptor Activator of NF-κB Ligand Pathway.
复制标题
骨保护素和地诺单抗通过抑制核因子κB受体活化因子配体通路刺激人β细胞增殖。
DOI：
10.1016/j.cmet.2015.05.021
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发表时间：
2015-07-07
期刊：
影响因子：
29
通讯作者：
Vasavada RC
中科院分区：
文献类型：
--
作者：
Kondegowda NG;Fenutria R;Pollack IR;Orthofer M;Garcia-Ocaña A;Penninger JM;Vasavada RC
糖尿病是由胰腺β细胞减少引起的。刺激复制可以使β细胞质量正常化。然而，成人β细胞难以增殖。我们鉴定出骨保护素（一种与骨相关的诱饵受体）作为 β 细胞有丝分裂原。护骨素由催乳素介导的啮齿动物 β 细胞复制诱导，并且是其所必需的。骨保护素可增强年轻、老年和糖尿病小鼠的 β 细胞增殖。这导致年轻小鼠的β细胞质量增加，并显着延迟糖尿病小鼠的高血糖。骨保护素刺激成人 β 细胞的复制，但不会引起去分化。从机制上讲，骨保护素通过结合 NF-κB 受体激活剂 (RANK) 配体 (RANKL)（抑制 β 细胞增殖）调节 CREB 和 GSK3 通路，诱导人类和啮齿动物 β 细胞复制。 Denosumab 是 FDA 批准的骨质疏松症药物和 RANKL 特异性抗体，在人源化小鼠体内和体外诱导人类 β 细胞增殖。因此，骨保护素和狄诺塞麦可阻止 RANKL/RANK 相互作用来刺激 β 细胞复制，凸显了重新利用骨质疏松症药物治疗糖尿病的潜力。
Diabetes results from a reduction of pancreatic β-cells. Stimulating replication could normalize β-cell mass. However, adult human β-cells are recalcitrant to proliferation. We identified osteoprotegerin, a bone-related decoy receptor, as a β-cell mitogen. Osteoprotegerin was induced by and required for lactogen-mediated rodent β-cell replication. Osteoprotegerin enhanced β-cell proliferation in young, aged, and diabetic mice. This resulted in increased β-cell mass in young mice and significantly delayed hyperglycemia in diabetic mice. Osteoprotegerin stimulated replication of adult human β-cells, without causing dedifferentiation. Mechanistically, osteoprotegerin induced human and rodent β-cell replication by modulating CREB and GSK3 pathways, through binding Receptor Activator of NF-κB (RANK) Ligand (RANKL), a brake in β-cell proliferation. Denosumab, an FDA-approved osteoporosis drug, and RANKL-specific antibody, induced human β-cell proliferation in vitro, and in vivo, in humanized mice. Thus, osteoprotegerin and Denosumab prevent RANKL/RANK interaction to stimulate β-cell replication, highlighting the potential for repurposing an osteoporosis drug to treat diabetes.