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

Sep 30, 2026

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Glucocorticoid-induced osteonecrosis of the femoral head (ONFH) is a debilitating disorder marked by impaired osteogenesis and apoptosis-driven bone collapse. The study reports significantly reduced pentraxin 3 (PTX3) levels in patient samples and models. Recombinant PTX3 (rPTX3) reverses dexamethasone-induced suppression of osteogenic activity and apoptosis in vitro through TLR4/NF-κB signaling, lowering FGF21. In Ptx3 knockout mice, glucocorticoid damage worsens, whereas PTX3 maintains bone architecture. Blocking TLR4/NF-κB eliminates PTX3 protection, while FGF21 suppression via ATF3 preserves protection even without PTX3, establishing a PTX3-TLR4/NF-κB-FGF21 axis and suggesting PTX3 supplementation as a therapeutic strategy.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Background

Osteonecrosis of the femoral head (ONFH)

Glucocorticoids and GIONFH mechanisms

PTX3 and the TLR4/NF-κB/FGF21 axis

communications biology Article | A Nature Portfolio journal | | | | --- | --- | --- | | [https://doi.org/10.1038/s42003-025-09282-3](https://doi.org/10.1038/s42003-025-09282-3) | | | | Pentraxin 3 ameliorates glucocorticoidinduced osteonecrosis of the femoral head via TLR4/NF-κB/FGF21 signaling axis
Check for updates | | | | Jinxu Li1,2,11, Zhonghua Zhou1,2,11, Yan Kong3, Yang Li1, Zhe Wang1, Yongkang Yang2,4, Jingyi Wang2,4, Tianyi Liu 5, Xinyu Wang6, Dan Luo7,8, Fan Zhang2,4, Cheng Qiu 9,10 & Jingwei Liu 1,2,9,11 | | | | 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. | | | | Osteonecrosis of the femoral head (ONFH) is a common and refractory disease in orthopedicsand the number of patients with ONFH is increasing every year worldwide1. Hip pain and dysfunction due to ONFH places a heavy burden on patients, families, and society. According to the etiological classiﬁcation, ONFH can be divided into traumatic and non-traumatic osteonecrosis of the femoral head (NONFH)2. Epidemiological studies of NONFH in recent years have shown that hormones and alcohol have become the main causative factors of femoral head necrosis3–5.
Glucocorticoids(GC) are steroid hormones secreted by the adrenal cortex that play a key role in regulating a variety of developmental, metabolic, and immune functions6,7. However, long-term use ofglucocorticoids induces GIONFH, which is a frequently occurring type of NONFH3. Ifleft | untreated, it can eventually lead to a collapse of the subchondral bone structure4. The pathological mechanisms of GIONFH include decreased osteogenesis, lipid accumulation, elevated intraosseous pressure, and microcirculatory disruption8,9. The core histological features of GIONFHare structural destruction of bone tissue and ineffective repair responses caused by osteocyte death. Its characteristic pathological changes can be divided into the following key aspects: necrosis of bone marrow and osteocytes, including adipocyte necrosis and osteocyte apoptosis/necrosis; repair reactions secondary to necrosis, including vascular ingrowth with granulation tissue formation, and imbalance between bone resorption and formation;microfractureswith subchondralbone plate fracture and femoral head collapse. The detrimental effects of glucocorticoids on the proximal | | 1Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, PR China. 2Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China. 3Department of General Surgery, Muping District Traditional Chinese Medicine Hospital of Yantai City, Yantai, Shandong, PR China. 4Department of Burn and Plastic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, PR China. 5Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China. 6Department ofAnaesthesia, National Center for Orthopaedics, Beiji

FAQs

What role does PTX3 play in glucocorticoid-induced ONFH?

PTX3 levels are significantly reduced in patient samples and models. Restoring PTX3 with recombinant PTX3 alleviates glucocorticoid-induced osteogenic suppression and apoptosis and preserves bone architecture.

Which signaling pathway mediates PTX3’s protective effects?

PTX3 activates the TLR4/NF-κB pathway to downregulate FGF21. Pharmacological blockade of TLR4/NF-κB abolishes PTX3’s protective effects.

How does FGF21 relate to PTX3 protection when PTX3 is absent?

In PTX3-deficient models, suppression of FGF21 by activating transcription factor 3 (ATF3) retains bone-protective effects, indicating FGF21 acts as a downstream effector.

Sep 30, 2026

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