TY - JOUR
T1 - Inhibition of osteoblastic Smurf1 promotes bone formation in mouse models of distinctive age-related osteoporosis
AU - Liang, Chao
AU - Peng, Songlin
AU - Li, Jie
AU - Lu, Jun
AU - Guan, Daogang
AU - Jiang, Feng
AU - Lu, Cheng
AU - Li, Fangfei
AU - He, Xiaojuan
AU - Zhu, Hailong
AU - Au, D. W. T.
AU - Yang, Dazhi
AU - Zhang, Bao Ting
AU - Lu, Aiping
AU - Zhang, Ge
N1 - Funding Information:
We thank technical staffs (Ms. Yeuk Siu Cheung and Mr. Chi Leung Chan) from Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University for providing technical support. This work was supported by the Ministry of Science and Technology of China (2013ZX09301307 to A.L.), the Hong Kong General Research Fund (HKBU12100918 to G.Z., HKBU479111 to G.Z., HKBU478312 to G.Z., HKBU262913 to G.Z., HKBU12102914 to G.Z., HKBU261113 to A.L., CUHK14112915 to B.-T.Z., and CUHK489213 to B.-T.Z.), the Natural Science Foundation Council of China (81272045 to G.Z., 81700780 to C. L., 81371989 to S.P., 81272045 to B.G., 81401833 to B.G., and 81470072 to X.H.), the Research Grants Council and Natural Science Foundation Council of China (N_HKBU435/12 to G.Z.), the Croucher Foundation (Gnt#CAS14BU/CAS14201 to A.L.), the Interdisciplinary Research Matching Scheme (IRMS) of Hong Kong Baptist University (RC-IRMS/12-13/02 to A.L. and RC-IRMS/13-14/02 to G.Z.), the Hong Kong Baptist University Strategic Development Fund (SDF13-1209-P01 to A.L. and SDF15-0324-P02(b) to A.L.), the Hong Kong Research Grants Council Early Career Scheme (489213 to G.Z.), the Inter-institutional Collaborative Research Scheme of Hong Kong Baptist University (RC-ICRS/14-15/01 to G.Z. and RC-ICRS/16-17/01 to A.L.), the Faculty Research Grant of Hong Kong Baptist University (FRG1/13-14/024 to G.Z., FRG2/13-14/006 to G.Z., and FRG2/14-15/010 to G.Z.), the China Academy of Chinese Medical Sciences (Z0252 and Z0293 to A.L.).
Publisher copyright:
© The Author(s) 2018
PY - 2018/8/24
Y1 - 2018/8/24
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85052247473
U2 - 10.1038/s41467-018-05974-z
DO - 10.1038/s41467-018-05974-z
M3 - Journal article
C2 - 30143635
AN - SCOPUS:85052247473
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
M1 - 3428
ER -
SDG 3 Good Health and Well-being