Inhibition of osteoblastic Smurf1 promotes bone formation in mouse models of distinctive age-related osteoporosis

Chao Liang, Songlin Peng, Jie Li, Jun Lu, Daogang Guan, Feng Jiang, Cheng Lu, Fangfei Li, Xiaojuan He, Hailong Zhu, D. W. T. Au, Dazhi Yang, Bao-Ting Zhang (), Aiping Lu () and Ge Zhang ()
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Chao Liang: Hong Kong Baptist University
Songlin Peng: Hong Kong Baptist University
Jie Li: Chinese University of Hong Kong
Jun Lu: Hong Kong Baptist University
Daogang Guan: Hong Kong Baptist University
Feng Jiang: Hong Kong Baptist University
Cheng Lu: Hong Kong Baptist University
Fangfei Li: Hong Kong Baptist University
Xiaojuan He: Hong Kong Baptist University
Hailong Zhu: Hong Kong Baptist University
D. W. T. Au: City University of Hong Kong
Dazhi Yang: Ji Nan University Second College of Medicine
Bao-Ting Zhang: Chinese University of Hong Kong
Aiping Lu: Hong Kong Baptist University
Ge Zhang: Hong Kong Baptist University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Bone morphogenetic protein (BMP) signaling is essential for osteogenesis. However, recombinant human BMPs (rhBMPs) exhibit large inter-individual variations in local bone formation during clinical spinal fusion. Smurf1 ubiquitinates BMP downstream molecules for degradation. Here, we classify age-related osteoporosis based on distinct intraosseous BMP-2 levels and Smurf1 activity. One major subgroup with a normal BMP-2 level and elevated Smurf1 activity (BMP-2n/Smurf1e) shows poor response to rhBMP-2 during spinal fusion, when compared to another major subgroup with a decreased BMP-2 level and normal Smurf1 activity (BMP-2d/Smurf1n). We screen a chalcone derivative, i.e., 2-(4-cinnamoylphenoxy)acetic acid, which effectively inhibits Smurf1 activity and increases BMP signaling. For BMP-2n/Smurf1e mice, the chalcone derivative enhances local bone formation during spinal fusion. After conjugating to an osteoblast-targeting and penetrating oligopeptide (DSS)6, the chalcone derivative promotes systemic bone formation in BMP-2n/Smurf1e mice. This study demonstrates a precision medicine-based bone anabolic strategy for age-related osteoporosis.

Date: 2018
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DOI: 10.1038/s41467-018-05974-z

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