Inhibition of Heat Shock Protein 90β by Catalpol: A Potential Therapeutic Approach for Alleviating Inflammation-Induced Cartilage Injuries in Osteoarthritis.

Abstract

Osteoarthritis (OA) is a degenerative joint disease characterized by the metabolic dysfunction of chondrocytes. A promising therapeutic strategy for OA involves suppressing the catabolism of the chondrocyte and promoting its anabolism to restore joint homeostasis. Here, it is demonstrated that Catalpol, a natural compound, can promote chondrocyte anabolic and proliferation, while inhibiting the catabolic activities and oxidative stress, thereby maintaining the dynamic balance of the extracellular matrix and alleviating inflammation-induced cartilage damage. Mechanistically, it has been discovered that Catalpol acts as a direct inhibitor of heat shock protein 90β (Hsp90β), and the amino acids ASP88, THR179, ASP49, and ASN46 of N-terminal domain-Hsp90β are confirmed as the binding sites for Catalpol. Knockdown of Hsp90β in primary chondrocytes demonstrates a similar biological effect as Catalpol treatment. Moreover, to develop a nanoparticle-based interventional platform for OA management, biodegradable mesoporous silica nanoparticles (bMSN) are prepared to load Catalpol (Ca-bMSN). The engineered Ca-bMSN is able to penetrate into the chondrocytes, prolong retention in the joint space, and mitigate OA progression. These findings shed light on a potential mechanism by which Catalpol modulates chondrocyte metabolism, offering a promising therapeutic strategy for OA treatment.