PPARγ mediated ferroptosis in metabolic bone diseases
Abstract
Metabolic bone disease results from the imbalance between bone formation and bone resorption and has core pathological features of gradual bone mass loss, damaged bone microstructure and bone marrow adipose infiltration. Ferroptosis is iron-dependent regulated cell death driven by lipid peroxidation and plays a key regulatory role in bone metabolic homeostasis. Peroxisome proliferator-activated receptor γ (PPARγ) acts as a core link among ferroptosis, lipid metabolism and bone cell fate. PPARγ induces ferroptosis in osteoblasts and bone marrow mesenchymal stem cells (BMSCs) by regulating antioxidant defense, lipid metabolism and iron homeostasis and produces two different effects on osteoclasts based on PPARγ activation level and local bone microenvironment. This mechanism causes reduced osteoblast numbers, abnormal osteoclast function, increased empty osteocyte lacunae, thinner bone trabeculae, accumulated lipid peroxidation products, increased iron deposition and enhanced bone marrow adipogenesis at the histopathological level. The PPARγ-ferroptosis axis participates in the development of osteoporosis, osteonecrosis, inflammatory bone diseases and iron overload-related bone diseases. This pathway connects with inflammation and oxidative stress and promotes continuous disease progression. This review fully explains the structure and biological functions of PPARγ and its pathological roles in various bone diseases. This review also summarizes PPARγ antagonists, ferroptosis…
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