Staphylococcus aureus Infection Initiates Hypoxia-Mediated Transforming Growth Factor-β1 Upregulation to Trigger Osteomyelitis

by Selleckchem | Nov 09 2023

Little is unknown about the regulatory mechanisms underlying the pathogenesis of osteomyelitis induced by Staphylococcus aureus. Hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor β1 (TGF-β1) were both upregulated in S. aureus-infected MC3T3-E1 cells and osteomyelitis patients. HIF-1α directly targets the hypoxia-responsive elements (HREs) of TGF-β1 mRNA to induce its expression. Silencing HIF-1α and TGF-β1, as well as treatment of hypoxia inhibitor IDF-11774, consistently elevated OPN and RUNX2 expression and alizarin Red S (ARS) and alkaline phosphatase (ALP) staining levels in MC3T3-E1 cells with S. aureus infection. S. aureus infection increased HIF-1α expression and serum TGF-β1 concentration in a mouse model of osteomyelitis. Hypoxia inhibitor IDF-11774 treatment reduced serum levels of interleukin (IL)-6, IL-1β, and C-reactive protein. Upon S. aureus infection, hypoxia was activated to trigger TGF-β1 upregulation through direct targeting of HRE on TGF-β1 mRNA by HIF-1α, eventually leading to osteomyelitis symptoms in terms of osteogenesis and mineralization deficiencies as well as elevated inflammation. This study hereby suggests a novel signaling cascade involving hypoxia/HIF-1α/TGF-β1 in osteomyelitis pathogenesis, which could potentially serve as a target for therapeutic measures.

IMPORTANCE The pathogenesis of osteomyelitis induced by Staphylococcus aureus remains unclear. To develop therapeutic approaches for osteomyelitis, it is important to understand the molecular mechanisms of its pathogenesis. Our results suggests that hypoxia/HIF-1α/TGF-β1 signaling is involved in osteomyelitis pathogenesis. Thus, these findings highlight the potential of this signaling components as therapeutic targets for the treatment of osteomyelitis.

Comments:

The passage you provided outlines a research study that investigates the regulatory mechanisms involved in the pathogenesis of osteomyelitis induced by Staphylococcus aureus. Here's a summary of the key findings and implications of the study:

1. **Background**: Osteomyelitis is a bone infection caused by Staphylococcus aureus, but the regulatory mechanisms underlying its development are not well understood. Understanding these mechanisms is crucial for developing effective therapeutic approaches.

2. **HIF-1α and TGF-β1 Upregulation**: The study found that both hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor β1 (TGF-β1) were upregulated in S. aureus-infected MC3T3-E1 cells (a type of bone cell) and in osteomyelitis patients.

3. **HIF-1α's Role**: HIF-1α was shown to directly target the hypoxia-responsive elements (HREs) of TGF-β1 mRNA, leading to the induction of TGF-β1 expression.

4. **Effect of Silencing and Inhibitors**: Silencing HIF-1α and TGF-β1, as well as treatment with a hypoxia inhibitor called IDF-11774, consistently increased the expression of osteopontin (OPN) and runt-related transcription factor 2 (RUNX2) in MC3T3-E1 cells infected with S. aureus. This was accompanied by higher levels of alizarin Red S (ARS) and alkaline phosphatase (ALP) staining, which are indicative of improved osteogenesis.

5. **Mouse Model Confirmation**: In a mouse model of osteomyelitis induced by S. aureus infection, it was observed that S. aureus infection increased HIF-1α expression and serum TGF-β1 concentration. Treatment with the hypoxia inhibitor IDF-11774 reduced serum levels of inflammatory markers such as interleukin-6 (IL-6), interleukin-1β (IL-1β), and C-reactive protein.

6. **Hypoxia/HIF-1α/TGF-β1 Signaling**: The study concludes that S. aureus infection activates hypoxia, which in turn triggers the upregulation of TGF-β1 through direct targeting of HRE on TGF-β1 mRNA by HIF-1α. This signaling cascade ultimately leads to osteomyelitis symptoms, including deficiencies in osteogenesis and mineralization, as well as increased inflammation.

7. **Therapeutic Implications**: The study highlights the potential of targeting the hypoxia/HIF-1α/TGF-β1 signaling cascade as a therapeutic approach for osteomyelitis. Understanding these molecular mechanisms could pave the way for the development of new treatments for this bone infection.

In summary, this research suggests a novel signaling pathway involving hypoxia, HIF-1α, and TGF-β1 in the pathogenesis of osteomyelitis induced by Staphylococcus aureus. These findings have important implications for potential therapeutic interventions in the treatment of osteomyelitis.