Blocking the LRH-1/LCN2 axis by ML-180, an LRH-1 inverse agonist, ameliorates osteoarthritis via inhibiting the MAPK pathway

Osteoarthritis (OA) is a chronic and degenerative disease marked by inflammation and extracellular matrix (ECM) degeneration, contributing to synovial inflammation and cartilage destruction. Accumulating evidence has demonstrated that Liver receptor homolog-1 (LRH-1), an Orphan Nuclear Receptor, mediates inflammatory response. However, there is a lack of evidence regarding the regulatory role of LRH-1 in OA pathogenesis. In this study, we confirmed that chondrocytes expressed LRH-1, and observed its upregulation in both IL-1β-treated chondrocytes and cartilage of destabilization of the medial meniscus (DMM)-operated mice. Overexpression of LRH-1 promoted inflammation and dysregulation of ECM metabolism in IL-1β-induced chondrocytes, reversed by inhibition of LRH-1 with ML-180 or gene silencing to protect chondrocytes. Moreover, ML-180 treatment in vivo improved the deteriorated OA phenotypes in mouse models, alleviating OA development. Mechanistically, RNA Sequencing revealed that Lipocalin-2 (LCN2), a member of the Lipocalin Family associated with inflammation, is located downstream of LRH-1 and is positively regulated by it. Furthermore, the LRH-1/LCN2 axis mainly relied on activating the mitogen-activated protein kinase (MAPK) signaling pathway to promote inflammation and dysregulation of ECM metabolism, ultimately damaging chondrocytes. Our findings demonstrate that LRH-1 positively modulates LCN2,activating the MAPK pathway, indicating that targeting the LRH-1/LCN2/MAPK axis may represent a potential therapeutic strategy for OA.