Effects of A Novel Smurf1 Inhibitor Loaded in Alginate Hydrogel on Local Bone Formation in Distinctive Age-related Osteoporosis During Spinal Fusion

Age-related osteoporosis accelerates the development of spinal degenerative diseases. Spinal fusion, which is widely applied in treatment of these diseases, requires osteoinductive factors to promote local bone formation. Recombinant human bone morphogenetic proteins (rhBMPs) have been approved to promote local bone formation during spinal fusion. However, emerging evidence demonstrates large inter-individual variations in therapeutic action of rhBMPs. Smurf1 ubiquitinates BMP transducers (Smad1/5/8) for proteasomal degradation and is a bone formation suppressor. We classified age-related osteoporotic individuals into different subgroups based on intraosseous BMP-2 levels and Smurf1 activity. One major subgroup with a normal BMP-2 level and elevated Smurf1 activity (BMP-2n/Smurf1e) 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-2d/Smurf1n). We identified a chalcone derivative as the Smurf1 inhibitor, which effectively inhibited Smurf1 activity, increased BMP signaling and promoted osteogenic differentiation for osteoblasts from BMP-2n/Smurf1e subgroup in vitro. The injectable alginate-based hydrogels are used as the loading materials for bone regeneration agents with sustainable drug release, controllable degradability and in vivo biocompatibility. In this project, we will develop injectable alginate-based hydrogels loading the chalcone derivative and examine the physicochemical characterizations, degradable properties and biocompatible capacity of the hydrogels, as well as the in vivo effects of the injectable hydrogels on Smurf1 activity and BMP signaling, local bone formation during spinal fusion and toxicity in BMP-2n/Smurf1e subgroup of aged osteoporotic mice. This project will provide a precision medicine-based bone anabolic strategy. The injectable alginate-based hydrogels loaded with the chalcone derivative will be a novel agent for spinal fusion in BMP-2n/Smurf1e subgroup of individuals with age-related osteoporosis.

Funding

Innovation and Technology Commission - Guangdong - Hong Kong Technology Cooperation Funding Scheme