Lovastatin impairs cellular proliferation and enhances hyaluronic acid production in fibroblast-like synoviocytes

Introduction: Statins have demonstrated chondroprotective effects by reducing inflammation and mitigating extracellular matrix degradation. However, statins are also reported to be cytotoxic to several types of cells. Early-onset osteoarthritis (OA) is characterized by synovial inflammation, which adversely affects hyaluronan (HA) production in fibroblast-like synoviocytes (FLSs). Nevertheless, the precise effects of statins on the synovium remain unclear. Methods: This study investigated the impact of lovastatin on human FLSs, and HA secretion-related genes, signaling pathways, and production were evaluated. Results: The findings revealed that high doses of lovastatin (20 or 40 μM) decreased FLS viability and increased cell death. FLS proliferation ceased when cultured in a medium containing 5 or 10 μM lovastatin. mRNA expression analysis demonstrated that lovastatin (5 and 10 μM) upregulated the gene level of hyaluronan synthase 1 (HAS1), HAS2, and proteoglycan 4 (PRG4), but not HAS3. While the expression of multidrug resistance-associated protein 5 transporter gene remained unaffected, both inward-rectifying potassium channel and acid-sensing ion channel 3 were upregulated. Western blot further confirmed that lovastatin increased the production of HAS1 and PRG4, and activated the PKC-α, ERK1/2, and p38-MAPK signaling pathways. Additionally, lovastatin elevated intracellular cAMP levels and HA production in FLSs. Conclusion: Lovastatin impairs cellular proliferation but enhances HA production in human FLSs.