Researcher(s)
- Samantha Ingerson, Biomedical Engineering, University of Delaware
Faculty Mentor(s)
- Justin Parreno, Biological Sciences, University of Delaware
Abstract
Osteoarthritis (OA) is a debilitating degenerative joint disease with no successful reparative therapies currently available. An emerging biological alternative involves transplanting a monolayer of expanded (passaged) chondrocytes into damaged articular cartilage. While chondrocyte transplantation stimulates cartilage repair, the tissue formed is fibrocartilage, which is biomechanically inferior to native articular cartilage. Cartilage in vivo is in a hypoxic environment and previous studies have demonstrated that hypoxia enhances the production of articular cartilage matrix by monolayer expanded cells.
In this study, we aimed to chemically induce hypoxic cellular signaling as a proxy to storing cells in hypoxic chambers. Prolyl Hydroxylase Domain enzymes (PHDs) are enzymes that regulate the degradation of hypoxia-inducible factors (HIFs) in oxygen rich environments. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor developed for chronic kidney disease that pharmacologically mimics hypoxia under normoxic conditions. To assess its effect on chondrocytes, we cultured 2D monolayers with varying concentrations of Roxadustat (0–50 μM). Real-time RT-PCR analysis revealed a concentration-dependent increase in chondrogenic (aggrecan, chondroadherin, and SOX9) mRNA levels. Roxadustat also reduced proliferation molecule (Ki67) and degradative enzyme (Matrix Metalloproteinase 3) mRNA levels. Therefore, Roxadustat appears to stimulate redifferentiation of passaged chondrocytes. Currently, we are assessing the efficacy of Roxadustat treatment on improving the quality of in vitro grown tissue by passaged chondrocytes.