Inhibition of osteoblastic Smurf1 promotes bone formation in mouse models of distinctive age-related osteoporosis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30143635.
- Also identified by DOI 10.1038/s41467-018-05974-z and PMC identifier 6109183.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>n</sup>/Smurf1<sup>e</sup>) 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<sup>d</sup>/Smurf1<sup>n</sup>). We screen a chalcone derivative, i.e., 2-(4-cinnamoylphenoxy)acetic acid, which effectively inhibits Smurf1 activity and increases BMP signaling. For BMP-2<sup>n</sup>/Smurf1<sup>e</sup> mice, the chalcone derivative enhances local bone formation during spinal fusion. After conjugating to an osteoblast-targeting and penetrating oligopeptide (DSS)<sub>6</sub>, the chalcone derivative promotes systemic bone formation in BMP-2<sup>n</sup>/Smurf1<sup>e</sup> mice. This study demonstrates a precision medicine-based bone anabolic strategy for age-related osteoporosis.
Medical subject headings
- Bone Morphogenetic Protein 2
- Osteoblasts
- Osteogenesis
- Osteoporosis
- Ubiquitin-Protein Ligases