Biomechanics of Cartilage: Roles of Decorin in ECM Assembly and Degradation

About This Grant

ABSTRACT The development of effective therapies for cartilage regeneration and osteoarthritis (OA) treatment is challenged by our limited understanding of the complex molecular interactions that regulate the assembly, maintenance and degradation of the extracellular matrix (ECM). During the first funding cycle of this project, we identified a crucial role for decorin, a small proteoglycan, in regulating cartilage ECM integrity by providing physical linkages to stabilize aggrecan network and its fragments. In addition, we found that loss of decorin results in aberrant cartilage surface fibril remodeling during aging and after injury, contributing to full cartilage erosion and accelerated OA development. Building on these findings, our updated central hypothesis for this renewal is that, in addition to stabilizing the aggrecan assembly, decorin also attenuates aberrant cartilage surface fibril remodeling, and that increasing decorin content can ameliorate cartilage degradation in OA and improve the quality of tissue repair post-injury. To test this hypothesis, we will pinpoint the role of decorin in regulating collagen fibril structure on the cartilage surface, and evaluate the effects of increasing decorin levels in slowing OA progression and improving the repair of cartilage tissue after injury. In Aim 1, we will determine whether targeted ablation of decorin in cartilage superficial layer cells accelerates cartilage surface fibril remodeling and degradation in aged mice and in injury-induced post- traumatic OA using the destabilization of the medial meniscus (DMM) model. Next, we will elucidate if decorin directly attenuates force-induced collagen II fibril alignment at both the nanoscale individual fibril level and microscale cellular spheroid level, and if decorin directly strengthens the collagen II fibril network on the cartilage surface. In Aim 2, we will determine whether the overexpression of decorin by adeno-associated virus (AAV) therapy can ameliorate cartilage degradation and surface remodeling in a murine DMM model, in which, AAV-decorin will be intra-articularly administered at either an early “preventative” (before DMM) or a delayed “treatment” timepoint (4 weeks after DMM). Next, we will test if increasing decorin levels by AAV-decorin attenuates the degradation of cartilage explants under catabolic stimulation by inflammatory cytokine IL-1β. In Aim 3, we will test if increasing decorin in porcine chondrocytes by AAV-decorin improves the quality of nascent pericellular matrix and if AAV-decorin increases the preservation of degenerative cartilage matrix when integrated with our established matrix reinforcing tissue-penetrating hyaluronan (tpHA) hydrogel in explant culture. Lastly, we will evaluate if delivering AAV-decorin within the reinforcing tpHA-hydrogel further increases the quality of repair cartilage in a minipig partial thickness defect model in vivo. Validating our central hypothesis will establish decorin as an indispensable cartilage ECM constituent and will validate its therapeutic potential in slowing OA progression and improving the quality of regenerating cartilage.