Intracellular iron uptake is favored in Hfe‐KO mouse primary chondrocytes mimicking an osteoarthritis‐related phenotype

HFE‐hemochromatosis is a disease characterized by a systemic iron overload phenotype mainly associated with mutations in the HFE protein (HFE) gene. Osteoarthritis (OA) has been reported as one of the most prevalent complications in HFE‐hemochromatosis patients, but the mechanisms associated with its onset and progression remain incompletely understood. In this study, we have characterized the response to high iron concentrations of a primary culture of articular chondrocytes isolated from newborn Hfe‐KO mice and compared the results with that of a similar experiment developed in cells from C57BL/6 wild‐type (wt) mice. Our data provide evidence that both wt‐ and Hfe‐KO‐derived chondrocytes, when exposed to 50 μM iron, develop characteristics of an OA‐related phenotype, such as an increased expression of metalloproteases, a decreased extracellular matrix production, and a lower expression level of aggrecan. In addition, Hfe‐KO cells also showed an increased expression of iron metabolism markers and MMP3, indicating an increased susceptibility to intracellular iron accumulation and higher levels of chondrocyte catabolism. Accordingly, upon treatment with 50 μM iron, these chondrocytes were found to preferentially differentiate toward hypertrophy with increased expression of collagen I and transferrin and downregulation of SRY (sex‐determining region Y)‐box containing gene 9 (Sox9). In conclusion, high iron exposure can compromise chondrocyte metabolism, which, when simultaneously affected by an Hfe loss of function, appears to be more susceptible to the establishment of an OA‐related phenotype.