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

Nature Communications
Chao LiangGe Zhang

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.

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Citations

Sep 17, 2020·Journal of Developmental Biology·Daniel HalloranAnja Nohe
Dec 31, 2020·Acta Biochimica Et Biophysica Sinica·Zhen ZhangWei Hong
Jun 28, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Chang SongXiao Zhu

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Methods Mentioned

BETA
ubiquitination
X-ray
immunoprecipitation
DARTS
PCR
scraping
FACS
ELISA
transcription factor assay
Transfection

Software Mentioned

SPSS
MODELER
SDS
Leica
BIOQUANT OSTEO

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