Vertebral Osteoporosis in Systemic Lupus Erythematosus: A Possible Involvement of Inflammation-Related Osteoblast Ferroptosis.

BACKGROUND

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by immune system dysregulation and the production of autoantibodies, leading to widespread inflammation and multi-organ damage. Despite clinical observations have shown that approximately 1.4-68.7% of SLE patients develop vertebral osteoporosis (OP), the underlying mechanisms remain poorly defined. This study utilized the MRL/ mouse model, which effectively replicates human SLE manifestations, to investigate the impact of SLE on vertebral bone homeostasis.

METHODS

Female MRL/ mice were employed to investigate SLE-induced bone loss. The study comprehensively evaluated bone structural changes through micro-CT analysis, histological assessment, and bone metabolic markers. Specifically, we analyzed trabecular parameters (TV, BV, BV/TV, Tb.Th), inflammatory cytokine profiles (TNF-α, IL-6, IL-1β, IL-18), osteogenic markers (RUNX2, OSTERIX, ALP, OPG), osteoclastogenic indicators (TRAP, RANKL, CTSK), and ferroptosis-related proteins (FACL4, FTH1, GPX4).

RESULTS

SLE progression in MRL/ mice led to significant vertebral bone loss and OP phenotype, evidenced by reduced bone volume fraction (BV/TV) and trabecular thickness (Tb.Th). The inflammatory microenvironment was characterized by elevated TNF-α and IL-6 levels, which disrupted bone homeostasis by suppressing RUNX2, OSTERIX, and OPG expression while enhancing RANKL signaling. Mechanistically, SLE induced ferroptosis through increased FACL4 and FTH1 expression coupled with decreased GPX4 levels, leading to impaired osteoblast function and enhanced osteoclast activity.

CONCLUSION

SLE-associated vertebral OP is mediated by inflammation-driven ferroptosis, disrupting the balance between bone formation and resorption, offering novel insights into potential therapeutic strategies for managing bone loss in SLE patients.