Regulating p21 Expression to Increase Chondrogenic Potential in Human Mesenchymal Progenitor Cells

Abstract

Cartilage does not regenerate in humans, and therefore cartilage degeneration is a problem that affects a significant percentage of the population, including those with diseases such as Osteoarthritis (OA). The p21 knockout (p21-/-) mouse contains the only known single mutation in mammals that can induce a cartilage regenerative phenotype. Work in this thesis aims to identify p21 expression inhibitors for use in humans and to characterize their effects on human synovial mesenchymal progenitor cells (MPCs) during culture and chondrogenesis. I have identified one putative p21 expression inhibitor (acting through HSP90), that induces human synovial MPCs to display phenotypic properties similar to fibroblasts from p21-/- mice. Additionally, this inhibitor promotes cartilage formation in a mouse cartilage injury model. These results indicate that p21 inhibition through HSP90 may be a potential pharmaceutical target for stimulating chondrogenic regeneration for the treatment of cartilage defects or in cartilage degenerating diseases such as OA.