Identification of Small Molecule Activators of BMP Signaling

Abstract

Bone Morphogenetic Proteins (BMPs) are morphogens that play a major role in regulating development and homeostasis. Although BMPs are used for the treatment of bone and kidney disorders, their clinical use is limited due to the supra-physiological doses required for therapeutic efficacy causing severe side effects. Because recombinant BMPs are expensive to produce, small molecule activators of BMP signaling would be a cost-effective alternative with the added benefit of being potentially more easily deliverable. Here, we report our efforts to identify small molecule activators of BMP signaling. We have developed a cell-based assay to monitor BMP signaling by stably transfecting a BMP-responsive human cervical carcinoma cell line (C33A) with a reporter construct in which the expression of luciferase is driven by a multimerized BMP-responsive element from the Id1 promoter. A BMP-responsive clone C33A-2D2 was used to screen a bioactive library containing ∼5,600 small molecules. We identified four small molecules of the family of flavonoids all of which induced luciferase activity in a dose-dependent manner and ventralized zebrafish embryos. Two of the identified compounds induced Smad1, 5 phosphorylation (P-Smad), Id1 and Id2 expression in a dose-dependent manner demonstrating that our assays identified small molecule activators of BMP signaling.

BMP Signaling Induces Astrocytic Differentiation of Clinically Derived Oligodendroglioma Propagating Cells

“…However, it is conceivable that a similar mechanism exists in OligPCs, and that methylation of the BMPR1B promoter in the OligPCs studied by their group accounts for the disparate response they observed. Our study suggests OligPC differentiation via BMP treatment as a viable novel approach to targeted therapy in anaplastic oligodendrogliomas, perhaps taking advantage of newly-developed small molecule BMP agonists (36). An assessment of the tumorigenicity of BMP-treated OligPCs in immunocompromised mice, which was not within the scope of this study, would be of paramount interest.…”

BMP signaling is required for the generation of primordial germ cells in an insect

“…To test this hypothesis, we took two approaches to raise BMP signaling activity in early embryos above wild-type levels: (i) injecting 4′-hydroxychalcone, a recently identified chemical activator of the BMP pathway (30), and (ii) injecting recombinant D. melanogaster Decapentaplegic (Dpp) protein (Dm-Dpp) (SI Appendix, Figs. S8 and S9).…”

Small molecule delivery through nanofibrous scaffolds for musculoskeletal regenerative engineering

“…However, the utilization of small molecules for engineering musculoskeletal tissues has been largely overlooked. This trend is very likely to be reversed as advanced screening technologies have recently generated a large number of novel regenerative small molecule drugs, and advanced tissue engineering scaffolds continue to provide promise for controllable drug delivery to target tissues [8, 22, 28–30]. …”