Although osteoarthritis (OA) is the most prevalent degenerative joint disease, there is no effective disease-modifying therapy. I'm reporting on the potential of an empty self-assembled hyaluronic acid nanoparticle (HA-NP) as a therapeutic agent for OA treatment. In experiments with mouse primary articular chondrocytes, I found that HA-NPs blocked the receptor-mediated cellular uptake of free low-molecular-weight (LMW) HA. The cellular uptake of HA-NPs increased with ectopic expression of CD44, achieved through an adenoviral delivery system. I observed that HA-NP demonstrated resistance to digestion with hyaluronidase and a long-term retention ability in the knee joint, unlike free high-molecular-weight (HMW) HA. In damaged articular cartilage of patients and mice with OA, CD44 expression increased. Ad-Cd44 infection and IL-1β treatment induced in vitro phenotypes of OA by enhancing catabolic gene expression in primary articular chondrocytes, and these effects were attenuated by HA-NP, but not HMW HA. Both the deficiency in Cd44 and intra-articular injection of HA-NP protected joint cartilage from OA development in the mouse model. I found that NF-kB mediated the CD44-induced catabolic factor expression, and HA-NP inhibited CD44-induced NF-kB activation in chondrocytes. These findings suggest that an empty HA-NP could be a potential therapeutic agent targeting CD44 for OA treatment, and reveal the CD44-NF-κB-catabolic gene axis as a potential mechanism underlying destructive cartilage disorders.
