From precision medicine to drug discovery: osteoblast-specific inhibition of Smurf1 activity promotes bone formation in distinctive rats with age-related osteoporosis

Project: Research project

Project Details


Age-related osteoporosis affects 20% of elderly population in mainland of China and Hong Kong. The only FDA-approved bone anabolic agent PTH also stimulates bone resorption after long-term use. Thus, it is urgent to develop alternative bone anabolic drugs for age-related osteoporosis.

Bone morphogenetic protein (BMP) signaling plays an essential role in osteoblast-mediated bone formation. Smurf1 ubiquitinates BMP downstream molecules and acts as a suppressor of BMP signaling. In 2002, recombinant human BMPs (rhBMPs) were approved for promoting local bone formation during spinal fusion. However, increasing evidence demonstrates large inter-individual variations in their bone anabolic potential for patients with age-related osteoporosis. Our data showed that the age-related osteoporotic individuals (human and rodents) could be classified into different subgroups based on distinct intraosseous BMP-2 levels and Smurf1 activity. One major subgroup showed a normal BMP-2 level and elevated Smurf1 activity (BMP-2normal/Smurf1elevated; BMP-2n/Smurf1e), whereas another major subgroup exhibited a decreased BMP-2 level and normal Smurf1 activity (BMP-2decreased/Smurf1normal; BMP-2d/Smurf1n). Serum osteocalcin with discriminated reduction extents could be a biomarker in stratifying the two subgroups. BMP-2n/Smurf1e subgroup of age-related osteoporotic human and rodents showed poor bone anabolic response to rhBMP-2 during spinal fusion when compared to BMP-2d/Smurf1n subgroup. Silencing Smurf1 enhanced BMP signaling and promoted osteogenic differentiation in primary osteoblasts isolated from BMP- 2n/Smurf1e subgroup, suggesting that Smurf1 inhibition in osteoblasts could be a precision medicine-based strategy to promote bone formation for the BMP-2n/Smurf1e subgroup of age- related osteoporosis. All the above results have been accepted by Science Translational Medicine.

By molecular docking-based virtual screening, we identified a chalcone derivative, i.e., 2-(4- cinnamoylphenoxy)acetic acid, which effectively targeted Smurf1 for inhibition. After local administration, the chalcone derivative promoted bone formation during spinal fusion for the BMP-2n/Smurf1e subgroup of age-related osteoporotic rats. To achieve the osteoblast-specific distribution of the chalcone derivative after systemic administration, we conjugated the chalcone derivative with an osteoblast-targeting and cell-penetrating oligopeptide (DSS)6. (DSS)6 facilitated the chalcone derivative inhibiting Smurf1 activity and enhancing in vitro osteogenic differentiation in primary osteoblasts isolated from rat BMP-2n/Smurf1e subgroup. In vivo, (DSS)6 facilitated the chalcone derivative accumulating in bone of the BMP- 2n/Smurf1e subgroup of age-related osteoporotic rats. Thus, we hypothesize that (DSS)6 could facilitate the chalcone derivative targeting osteoblasts and promoting systemic bone formation for the BMP-2n/Smurf1e subgroup in rats with age-related osteoporosis.

To test the above hypothesis, 6-month-old female rats will be ovariectomized to induce age- related osteoporosis according to our established protocol (Zhang G. Nat Med 2012; Wang X. Nat Med 2013). The following four specific aims will be examined in BMP-2n/Smurf1e subgroup of age-related osteoporotic rats in vivo:
1) Osteoblast-specific distribution of the (DSS)6-chalcone derivative conjugate;
2) Dose-response pattern and persistence time of the (DSS)6-chalcone derivative conjugate; 3) Bone anabolic action of the (DSS)6-chalcone derivative conjugate;
4) Toxicity of the (DSS)6-chalcone derivative conjugate.

The current proposal would advance the precision medicine-based bone anabolic strategy, i.e., osteoblast-specific inhibition of Smurf1 activity by the (DSS)6-chalcone derivative conjugate, for the BMP-2n/Smurf1e subgroup of age-related osteoporosis.
Effective start/end date1/01/1931/12/22

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being


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