Ferroptosis Mechanisms in Osteoarthritis and Bone Disorders

Ferroptosis is emerging as a pivotal form of regulated cell death in skeletal tissues, distinguished by iron‐dependent lipid peroxidation and accumulation of reactive oxygen species. In osteoarthritis, disrupted iron homeostasis and reduced antioxidant defences drive chondrocyte ferroptosis, accelerating cartilage degradation through increased matrix metalloproteinase activity and loss of collagen integrity. In parallel, bone disorders such as osteoporosis and peri‐implant osteolysis involve ferroptotic demise of osteoblasts and osteocytes, undermining bone formation and microstructural resilience. Central to these processes are the cystine/glutamate antiporter system Xc− and the selenoenzyme glutathione peroxidase 4 (GPX4), which together regulate cellular glutathione pools and detoxify lipid hydroperoxides. Epigenetic repression of GPX4, aberrant iron transporter expression and imbalances in redox signalling further sensitize skeletal cells to ferroptosis. Recent discoveries have delineated signalling axes—including Nrf2/HO-1, ETV4/SLC7A11/GPX4 and HIF-2α—that modulate ferroptotic susceptibility in cartilage and bone. Therapeutic modulation of these pathways offers promise for preserving joint integrity, preventing implant‐related bone loss and combating metabolic bone disease.

Research from Nature Portfolio

Foundational work demonstrated that extracellular vesicles from endothelial progenitor cells can protect against steroid‐induced osteoporosis by delivering bioactive molecules that restore GPX4 and system Xc− expression in osteoblasts. Treatment in animal models reversed glucocorticoid‐triggered downregulation of key anti‐ferroptosis factors, reduced lipid peroxidation and iron overload, and improved trabecular thickness, connectivity and overall bone volume. This cell‐free strategy highlights the potential of targeting ferroptosis to treat glucocorticoid‐associated bone loss.

Ferroptosis Mechanisms in Osteoarthritis and Bone Disorders publication trend

The graph below shows the total number of articles in ferroptosis mechanisms in osteoarthritis and bone disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: Regulated cell death dependent on iron and lipid peroxidation.

Glutathione peroxidase 4 (GPX4): Enzyme that reduces lipid hydroperoxides, preventing ferroptosis.

System Xc−: Membrane antiporter importing cystine for glutathione synthesis and antioxidant defence.

Lipid peroxidation: Oxidative degradation of polyunsaturated fatty acids leading to membrane damage.

Reactive oxygen species (ROS): Highly reactive oxygen‐containing molecules that can induce oxidative stress.

References

1. Fighting age-related orthopedic diseases: focusing on ferroptosis. Bone Research (2023).
2. DNA Methylation-Mediated GPX4 Transcriptional Repression and Osteoblast Ferroptosis Promote Titanium Particle-Induced Osteolysis. Research (2024).
3. α-Ketoglutarate alleviates osteoarthritis by inhibiting ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway. Cellular & Molecular Biology Letters (2024).
4. Targeting ferroptosis suppresses osteocyte glucolipotoxicity and alleviates diabetic osteoporosis. Bone Research (2022).
5. D‐mannose alleviates osteoarthritis progression by inhibiting chondrocyte ferroptosis in a HIF‐2α‐dependent manner. Cell Proliferation (2021).
6. Extracellular vesicles from endothelial progenitor cells prevent steroid-induced osteoporosis by suppressing the ferroptotic pathway in mouse osteoblasts based on bioinformatics evidence. Scientific Reports (2019).