HRX-215 attenuates cartilage fibrosis in osteoarthritis progression and microfracture repair by targeting MKK4

Osteoarthritis (OA) is a common degenerative joint disease characterized by progressive cartilage degeneration. Cartilage fibrosis is one of the key pathological events and is also the direct cause of repair failure due to fibrocartilage formation after microfracture surgery. Mitogen-activated protein kinase kinase 4 (MKK4) is a MAP2 kinase that activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase. It is a key kinase in the stress-activated protein kinase (SAPK)/mitogen-activated protein kinase (MAPK) signaling network. The OA-related data set from the GEO database showed that MKK4 expression was upregulated in the cartilage of OA patients. This phenomenon was also confirmed in the clinical samples we collected. Therefore, inhibiting MKK4 is a potential strategy for the treatment of cartilage fibrosis. HRX-215 is a recently discovered inhibitor of MKK4 that has been shown to have anti-fibrotic activity, but its therapeutic potential in osteoarthritis is not yet clear. This study found that HRX-215 promoted chondrocyte proliferation, increased the proportion of S-phase cells, and slowed down oxidative stress-driven extracellular matrix degradation by inhibiting MKK4. In in vivo experiments, HRX-215 significantly delayed cartilage degeneration and fibrosis in both the rat ACLT osteoarthritis model and the rat microfracture model. HRX-215 also has an inhibitory effect on the expression of MKK4 in human chondrocytes. Taken together, the results of this study indicate that HRX-215 inhibits cartilage fibrosis by targeting MKK4, providing a promising therapeutic candidate for osteoarthritis and microfracture repair.