Millions of Americans and people worldwide suffer bone diseases due to injuries, bone defects, and spinal defects, and therefore are in great need of effective treatments to regenerate bone and promote bone growth. Among treatments being explored in modern medicine, administration of growth factors that prompt our own body to regrow bone represents an attractive direction due to its non-invasiveness and utilization of our own cells, including bone- forming stem cells. Such treatment with bone growth factors has been approved by the FDA and is successfully used in clinics, however a recognized drawback of this treatment is that the administration of extremely high doses of very pure growth factor inevitably causes severe side effects in some patients. Our team believes current high doses are not necessary, with better tactics to present growth factors to cells, e.g. 5 growth factors bound together as a well-defined cluster versus 1000 individual growth factor molecules swimming around the cells. With this research, we hope to develop more effective ways to present growth factors than the current approach of injecting high dosage. Our approach is inspired by the way nature itself ‘administers’ these growth factors, which is always in combination with other proteins that provide the necessary context and help fine-tune cellular responses. This proposal builds on our discovery that COMP, a protein originally isolated from cartilage, can bind to multiple bone growth factors all at once. We plan to study how the COMP binds to growth factors, how many growth factors each COMP can carry (1 to 10), and which of the situations work best towards bone regeneration. We believe our results shall demonstrate that this multi-valent binding provides a new platform to present the growth factors to stem cells, to which cells respond with dramatically enhanced activities including robust bone formation and growth. The results from this investigation shall greatly enhance our current understanding of how bone growth factors regulate bone formation at the cellular level, and bring us a giant step closer to non-invasive and stem cell based therapy for bone regeneration.