Methyl gallate and hyaluronic acid-nanoconjugate targeting HSP90β for osteoarthritis therapy

Background: Osteoarthritis (OA) is a joint disease with complicated pathophysiologic process, however, the lack of effective therapeutic targets and corresponding pharmaceuticals severely limits treatment options.

Results: Methyl gallate (MG) could delay the pathological changes of OA by reducing cartilage inflammation and degeneration at both cellular and animal levels. Using drug affinity responsive target stability assay and mass spectrometry analysis, we identified HSP90β as a key target of MG in chondrocytes. The interaction between MG and heat shock protein 90β（HSP90β）was further validated by surface-plasmon resonance and cellular thermal shift assay experiments. In OA rat models, a positive correlation between HSP90β and cartilage degeneration was confirmed and upregulated expression of HSP90β and its related pathways was revealed through antibody chip monitoring and KEGG analysis. Moreover, clinical analysis of 53 OA patients showed a positive association between HSP90β expression and pain scores. Conversely, silencing HSP90β in rat chondrocytes significantly reduced the mRNA levels of Matrix Metalloproteinases and IL-6, and decreased the expression of PI3K/Akt pathway-related proteins. To achieve more effective OA therapy, MG was conjugated to hyaluronic acid (HA) via a reduction-responsive disulfide linker. In an OA mouse model, HA-MG exhibited enhanced therapeutic efficacy compared to free MG, leading to increased accumulation and retention of the conjugate in the joint cavity, as demonstrated by in-situ long-term fluorescence imaging.

Conclusions: This study has identified the important role of HSP90β as a therapeutic target for OA and provided a robust approach to attenuate OA progression using a polysaccharide nanoconjugate.