OTUB1 promotes osteoblastic bone formation through stabilizing FGFR2.
OTUB1 promotes osteoblastic bone formation through stabilizing FGFR2.
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OTUB1通过稳定FGFR2促进成骨细胞骨形成。
DOI：
10.1038/s41392-023-01354-2
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发表时间：
2023-04-07
影响因子：
39.3
通讯作者：
Zhang, Lingqiang
中科院分区：
文献类型：
--
作者：
Zhu, Qiong;Fu, Yesheng;Cui, Chun-Ping;Ding, Yi;Deng, Zhikang;Ning, Chao;Hu, Fan;Qiu, Chen;Yu, Biyue;Zhou, Xuemei;Yang, Guan;Peng, Jiang;Zou, Weiguo;Liu, Cui Hua;Zhang, Lingqiang
骨稳态是通过成骨细胞骨形成和骨吸收之间的平衡来维持的。这一过程的失调导致多种疾病，包括骨质疏松症。然而，潜在的分子机制尚未完全理解。在这里，我们表明，全球和条件成骨细胞敲除的去泛素化酶Otub1导致低骨量和骨强度差，由于成骨分化和矿化缺陷。从机制上讲，FGFR 2（骨生成的关键调节因子）的稳定性由OTUB 1维持。OTUB 1通过抑制SMURF 1的E2结合来减弱E3连接酶SMURF 1介导的FGFR 2泛素化。在不存在OTUB 1的情况下，FGFR 2被SMURF 1过度泛素化，随后发生溶酶体降解。一致地，腺相关病毒血清型9（AAV9）在膝关节中递送的FGFR 2挽救了成骨细胞特异性Otub1缺失小鼠的骨量损失。此外，Otub1 mRNA水平在骨质疏松小鼠的骨中显著下调，并且通过卵巢切除术诱导的骨质疏松小鼠中的AAV 9递送系统恢复OTUB 1水平减轻骨质疏松症。总之，我们的研究结果表明，OTUB 1积极调节成骨分化和矿化骨稳态通过控制FGFR 2的稳定性，这提供了一个光学治疗策略，以减轻骨质疏松症。
Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption. Dysregulation of this process leads to multiple diseases, including osteoporosis. However, the underlying molecular mechanisms are not fully understood. Here, we show that the global and conditional osteoblast knockout of a deubiquitinase Otub1 result in low bone mass and poor bone strength due to defects in osteogenic differentiation and mineralization. Mechanistically, the stability of FGFR2, a crucial regulator of osteogenesis, is maintained by OTUB1. OTUB1 attenuates the E3 ligase SMURF1-mediated FGFR2 ubiquitination by inhibiting SMURF1’s E2 binding. In the absence of OTUB1, FGFR2 is ubiquitinated excessively by SMURF1, followed by lysosomal degradation. Consistently, adeno-associated virus serotype 9 (AAV9)-delivered FGFR2 in knee joints rescued the bone mass loss in osteoblast-specific Otub1-deleted mice. Moreover, Otub1 mRNA level was significantly downregulated in bones from osteoporotic mice, and restoring OTUB1 levels through an AAV9-delivered system in ovariectomy-induced osteoporotic mice attenuated osteopenia. Taken together, our results suggest that OTUB1 positively regulates osteogenic differentiation and mineralization in bone homeostasis by controlling FGFR2 stability, which provides an optical therapeutic strategy to alleviate osteoporosis.
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DOI：
10.1038/nrd.2017.152
发表时间：
2018-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Harrigan JA;Jacq X;Martin NM;Jackson SP
通讯作者：
Jackson SP
影响因子：
14.9
作者：
Ma J;Chen T;Wu S;Yang C;Bai M;Shu K;Li K;Zhang G;Jin Z;He F;Hermjakob H;Zhu Y
通讯作者：
Zhu Y
影响因子：
24.1
作者：
Mulas F;Wang X;Song S;Nishanth G;Yi W;Brunn A;Larsen PK;Isermann B;Kalinke U;Barragan A;Naumann M;Deckert M;Schlüter D
通讯作者：
Schlüter D
影响因子：
7.7
作者：
Balakirev, MY;Tcherniuk, SO;Chroboczek, J
通讯作者：
Chroboczek, J
LIS1/NDE1 复合物通过调节 FGF 受体细胞内运输对 FGF 信号传导至关重要。
影响因子：
8.8
作者：
Liu, Liansheng;Lu, Jinqiu;Song, Hai
通讯作者：
Song, Hai