2. Academic Validation
  3. OTUB1 promotes osteoblastic bone formation through stabilizing FGFR2

OTUB1 promotes osteoblastic bone formation through stabilizing FGFR2

  • Signal Transduct Target Ther. 2023 Apr 7;8(1):142. doi: 10.1038/s41392-023-01354-2.
Qiong Zhu # 1,  Yesheng Fu # 1,  Chun-Ping Cui 1,  Yi Ding 1,  Zhikang Deng 1,  Chao Ning 2,  Fan Hu 3,  Chen Qiu 1,  Biyue Yu 4,  Xuemei Zhou 1,  Guan Yang 1,  Jiang Peng 2,  Weiguo Zou 5,  Cui Hua Liu 6 7,  Lingqiang Zhang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China.
  • 2 Lab of Orthopedics of Department of Orthopedics, Beijing Key Lab of Regenerative Medicine in Orthopedics, Chinese PLA General Hospital, Beijing, 100853, China.
  • 3 Department of Endocrinology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China.
  • 4 School of Life Sciences, Hebei University, Baoding, Hebei, 071002, China.
  • 5 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
  • 6 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China. liucuihua@im.ac.cn.
  • 7 Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 101408, China. liucuihua@im.ac.cn.
  • 8 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China. zhanglq@nic.bmi.ac.cn.
  • # Contributed equally.
PMID: 37024477 DOI: 10.1038/s41392-023-01354-2
Abstract

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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