Pentraxin 3 ameliorates glucocorticoid-induced osteonecrosis of the femoral head via TLR4/NF-κB/FGF21 signaling axis.

Glucocorticoid-induced osteonecrosis of the femoral head (ONFH) is a debilitating bone disorder characterized by impaired osteogenesis and apoptosis-driven bone collapse. This study identifies significantly reduced pentraxin 3 (PTX3) levels in patient samples and models. Recombinant PTX3 (rPTX3) alleviated dexamethasone-induced osteogenic suppression and apoptosis in vitro by activating TLR4/NF-κB pathway to downregulate fibroblast growth factor 21 (FGF21). In Ptx3-knockout mice, glucocorticoid-induced bone deterioration was exacerbated, while PTX3 administration preserved bone architecture. Pharmacological blockade of TLR4/NF-κB signaling abolished PTX3's protective effects. Notably, FGF21 suppression by activating transcription factor 3 (ATF3) retained bone-protective effects even in PTX3-deficient models, underscoring its role as a downstream effector. These findings establish the PTX3-TLR4/NF-κB-FGF21 axis as a key mechanism and suggest PTX3 supplementation as a potential therapeutic strategy against glucocorticoid-induced ONFH.