ELAVL1 promotes ferroptosis-induced inhibition of osteogenic differentiation in diabetic osteoporosis by downregulating SIRT1.

OBJECTIVE

Ferroptosis can implicate in the pathogenesis of diabetic osteoporosis (DOP). This study aimed to determine whether Sirtuin 1 (SIRT1) modulates DOP through ELAV-like RNA binding protein 1 (ELAVL1)-mediated ferroptosis.

METHODS

MC3T3-E1 cells were cultured in high glucose (HG) medium, and osteogenic differentiation was assessed by evaluating RUNX2, OCN, ALP activity, and calcium deposition via Alizarin Red S staining. Ferroptosis was evaluated by measuring GPX4, ACSL4, ROS, MDA, and Fe2 + . A DOP mouse model was established using C57BL/6 J mice fed a high-fat diet combined with 1 % streptozotocin injection. Femoral histopathology, body weight, fasting blood glucose (FBG), and ferroptosis were analyzed.

RESULTS

HG exposure inhibited osteogenic differentiation, characterized by the reduction in RUNX2, OCN ALP activity and calcium accumulation in MC3T3-E1 cells (P < 0.05); it induced ferroptosis, including the decrease in GPX4 and the increase in ACSL4, ROS, MDA and Fe2+ (P < 0.05). SIRT1 overexpression or treatment with Fer-1 reversed HG-induced ferroptosis and restored osteogenic differentiation (P < 0.05). SIRT1 was shown to bind ELAVL1, and its overexpression suppressed ELAVL1(P < 0.05). In HG-stimulated cells co-overexpressing SIRT1 and ELAVL1, both ferroptosis and osteogenic markers resembled those in cells exposed to HG (P < 0.05). DOP mice exhibited elevated FBG, reduced body weight, increased ELAVL1, and decreased SIRT1(P < 0.05); these mice showed impaired femoral histology. Ferroptosis was evident in DOP mice (P < 0.05). Silencing ELAVL1 improved femoral tissue integrity, inhibited ferroptosis, promoted osteogenic differentiation, restored body weigh, and upregulated SIRT1 in DOP mice (P < 0.05).

CONCLUSION

ELAVL1 repressed SIRT1 translation to interrupt ferroptosis-mediated osteoblastic differentiation, thereby inhibiting DOP progression.