| Title | Inhibition of osteoblastic Smurf1 promotes bone formation in mouse models of distinctive age-related osteoporosis |
| Authors | Liang, Chao Peng, Songlin Li, Jie Lu, Jun Guan, Daogang Jiang, Feng Lu, Cheng Li, Fangfei He, Xiaojuan Zhu, Hailong Au, D. W. T. Yang, Dazhi Zhang, Bao-Ting Lu, Aiping Zhang, Ge |
| Affiliation | Hong Kong Baptist Univ, Sch Chinese Med, Law Sau Fai Inst Adv Translat Med Bone & Joint Di, Hong Kong 999077, Hong Kong, Peoples R China. Hong Kong Baptist Univ, Sch Chinese Med, Inst Integrated Bioinfomed & Translat Sci, Hong Kong 999077, Hong Kong, Peoples R China. HKBU Inst Res & Continuing Educ, Inst Precis Med & Innovat Drug Discovery, Shenzhen 518000, Peoples R China. Ji Nan Univ, Shenzhen Peoples Hosp, Dept Spine Surg, Coll Med 2, Shenzhen 518020, Peoples R China. Chinese Univ Hong Kong, Sch Chinese Med, Fac Med, Hong Kong 999077, Hong Kong, Peoples R China. Peking Univ, Shenzhen Hosp, Clin Med Lab, Shenzhen 518036, Peoples R China. Zhejiang Pharmaceut Coll, Ningbo 315100, Zhejiang, Peoples R China. China Acad Chinese Med Sci, Inst Basic Res Clin Med, Beijing 100700, Peoples R China. City Univ Hong Kong, Dept Biol & Chem, Hong Kong 999077, Hong Kong, Peoples R China. Shanghai Acad Chinese Med Sci, Inst Arthrit Res, Shanghai 200032, Peoples R China. Hong Kong Baptist Univ, Sch Chinese Med, Law Sau Fai Inst Adv Translat Med Bone & Joint Di, Hong Kong 999077, Hong Kong, Peoples R China. Lu, AP Zhang, G (reprint author), Hong Kong Baptist Univ, Sch Chinese Med, Inst Integrated Bioinfomed & Translat Sci, Hong Kong 999077, Hong Kong, Peoples R China. Lu, AP Zhang, G (reprint author), HKBU Inst Res & Continuing Educ, Inst Precis Med & Innovat Drug Discovery, Shenzhen 518000, Peoples R China. Zhang, BT (reprint author), Chinese Univ Hong Kong, Sch Chinese Med, Fac Med, Hong Kong 999077, Hong Kong, Peoples R China. Lu, AP (reprint author), Shanghai Acad Chinese Med Sci, Inst Arthrit Res, Shanghai 200032, Peoples R China. |
| Keywords | UBIQUITIN LIGASE SMURF1 TARGET STABILITY DARTS MORPHOGENETIC PROTEINS TGF-BETA CLINICAL-APPLICATIONS DEGRADATION DIFFERENTIATION HOMEOSTASIS GROWTH IDENTIFICATION |
| Issue Date | 2018 |
| Publisher | NATURE COMMUNICATIONS |
| Citation | NATURE COMMUNICATIONS. 2018, 9. |
| 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-2(n)/Smurf1(e)) 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-2(d)/Smurf1(n)). We screen a chalcone derivative, i.e., 2-(4-cinnamoylphenoxy) acetic acid, which effectively inhibits Smurf1 activity and increases BMP signaling. For BMP-2(n)/Smurf1(e) 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-2(n)/Smurf1(e) mice. This study demonstrates a precision medicine-based bone anabolic strategy for age-related osteoporosis. |
| URI | http://hdl.handle.net/20.500.11897/516836 |
| ISSN | 2041-1723 |
| DOI | 10.1038/s41467-018-05974-z |
| Indexed | SCI(E) |
| Appears in Collections: | 深圳医院 |
