Sclerostin regulates bone morphogenetic protein ( BMP ) bioavailability through interactions with BMP complexes and fibrillin microfibrils

Sclerostin (SOST) is a secreted glycoprotein that antagonizes Wnt and BMP signaling, however, the molecular mechanisms regulating its extracellular distribution and growth factor (GF) interactions remain poorly understood. Here, we identify fibrillin microfibrils as high-affinity extracellular binding partners of SOST. Recombinant SOST bound specifically to fibrillin-1 positive fibers in cell culture and localized near the bead region of purified tissue fibrillin microfibrils. Surface plasmon resonance (SPR) mapping revealed that SOST recognizes the N-terminal regions of fibrillin-1 and fibrillin-2 with nanomolar affinity, and deletion analysis identified the fibrillin-unique N-terminal (FUN) domain as the primary SOST binding site. Our findings further extend the SOST binding repertoire to include BMP-10 GF, as well as the prodomains (PDs) and PD-GF complexes (CPLXs) of BMP-7 and BMP-10. Heparin interfered with SOST binding to BMP-7 PDs and CPLXs but not with the SOST-fibrillin-1 interaction. SPR interaction experiments showed that SOST binding to fibrillin-1 occludes the BMP PD targeting site and that fibrillin-1-bound SOST is unable to engage BMP-7 PDs. Molecular docking further supported this competitive mechanism by revealing overlapping interaction interfaces among SOST, BMP-7 CPLX, and fibrillin-1. Together, these findings establish SOST as a multifunctional ECM-associated BMP modulator that links fibrillin microfibril scaffolds to the fine-tuning of BMP and Wnt signaling.