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Hepatocyte growth factor overexpression promotes osteoclastogenesis and exacerbates bone loss in CIA mice
Chaoming Huang1,2, Yufan Zheng3, Jinyu Bai1
1Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China.
Insights
Hepatocyte growth factor (HGF) drives bone loss in rheumatoid arthritis (RA). Inhibiting HGF/c-Met signaling reduces bone breakdown and inflammation in RA models, suggesting a new therapeutic target.
Area of Science:
- Immunology
- Rheumatology
- Bone Biology
Background:
- Hepatocyte growth factor (HGF) is a key regulator of biological processes.
- The role of HGF in rheumatoid arthritis (RA)-associated bone metabolism is not well understood.
Purpose of the Study:
- To investigate the function of HGF in osteoclastogenesis and bone resorption in RA.
- To explore HGF/c-Met signaling as a potential therapeutic target for RA bone loss.
Main Methods:
- Examined HGF expression in RA patients and collagen-induced arthritis (CIA) mice.
- Assessed HGF's impact on osteoclastogenesis and bone resorption in vitro.
- Evaluated HGF inhibition using SU11274 in a CIA mouse model.
Main Results:
- HGF was upregulated in CIA and RA models.
- HGF promoted osteoclastogenesis and bone resorption.
- HGF inhibition via SU11274 blocked these effects and protected against bone loss in CIA mice.
- HGF signaling involved JNK and AKT-GSK-3β-NFATc1 pathways.
Conclusions:
- Elevated HGF in RA contributes to pathological bone loss.
- HGF/c-Met inhibition offers a promising strategy to mitigate bone loss and inflammation in RA.
- Targeting the HGF/c-Met pathway presents a novel therapeutic avenue for RA treatment.
Background:
Hepatocyte growth factor (HGF) is a multifunctional growth factor that promotes various biological processes. However, the effect of HGF on bone metabolism in rheumatoid arthritis (RA) remains unknown. Here, we investigated the role of HGF in regulating osteoclastogenesis and bone resorption in RA.
Methods:
The expression of HGF in RA patients and collagen-induced arthritis (CIA) mice was examined. The role of HGF on osteoclastogenesis was analysed by osteoclastogenesis and bone resorption assays. The effect of HGF inhibition was evaluated in a CIA mice model. The mechanism of HGF in regulating osteoclastogenesis and bone resorption was explored by a series of in vitro studies.
Results:
HGF was overexpressed in CIA and RA. HGF stimulated osteoclastogenesis in vitro. SU11274, a selective small molecule blocker of c-Met, impeded the effect of HGF on osteoclastogenesis and bone resorption. HGF regulated osteoclastogenesis by JNK and AKT-GSK-3β-NFATc1 signallings. SU11274 protected CIA mice from pathological bone loss.
Conclusions:
These data strongly suggest that the highly expressed HGF in the joint tissues contributes to bone loss in RA. Inhibition of HGF/c-Met could effectively alleviate pathological bone loss and inflammatory symptoms in CIA mice. HGF/c-Met may be used as a new target for the treatment of bone loss in RA.
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