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An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
4,4'-Dimethoxychalcone ameliorates estrogen-deficient osteoporosis by targeting PTP1B to inhibit the c-Src/NFATc1
Xu Han1, Mingming Xu1, Yongyan Chen2
1Department of Orthopedics, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China; Shanghai Clinical Research Center for Aging and Medicine, Shanghai, China; Center of Community-Based Health Research, Fudan University, Shanghai, China.
Abstract:
Postmenopausal osteoporosis (PMOP) is a skeletal disease linked to immune dysregulation, characterized by the overactivation of myeloid-lineage osteoclasts. To address the limitations of current therapies, this study investigated the immunomodulatory potential and molecular mechanism of the natural flavonoid 4,4'-dimethoxychalcone (DMC). Using in vitro and in vivo models, we found that DMC exhibited a desirable dual-action profile, potently inhibiting osteoclast differentiation while also promoting osteogenesis. Mechanistically, we identified Protein Tyrosine Phosphatase 1B (PTP1B) as a novel, direct target of DMC. We demonstrated that DMC inhibits PTP1B activity, preventing Proto-oncogene tyrosine-protein kinase Src (c-Src) activation and thereby blocking the downstream calcium/ Nuclear Factor of Activated T-cells, cytoplasmic 1 (NFATc1) signaling cascade essential for osteoclastogenesis; an effect that was reversed by PTP1B knockdown. In vivo, DMC administration rescued bone loss and restored bone strength in an ovariectomy (OVX) mouse model. In conclusion, this work establishes DMC as a potent immunomodulatory agent for treating osteoporosis and validates PTP1B as a new pharmacological target within the osteoimmune system.
Insights
This study reveals that 4,4'-dimethoxychalcone (DMC) treats postmenopausal osteoporosis by inhibiting osteoclast overactivation and promoting bone formation. DMC targets Protein Tyrosine Phosphatase 1B (PTP1B), offering a novel therapeutic approach for this skeletal disease.
Area of Science:
- Immunology
- Pharmacology
- Bone Biology
Background:
- Postmenopausal osteoporosis (PMOP) is associated with immune dysregulation and excessive osteoclast activity.
- Current PMOP therapies have limitations, necessitating novel therapeutic strategies.
- Natural compounds offer potential for developing new treatments for skeletal diseases.
Purpose of the Study:
- To investigate the immunomodulatory effects and molecular mechanisms of the flavonoid 4,4'-dimethoxychalcone (DMC) in PMOP.
- To explore DMC's potential as a dual-action agent promoting osteogenesis and inhibiting osteoclast differentiation.
- To identify novel molecular targets for DMC in the context of osteoimmunology.
Main Methods:
- In vitro studies using cell cultures to assess osteoclast differentiation and osteogenesis.
- In vivo studies utilizing an ovariectomy (OVX) mouse model to evaluate bone loss and strength.
- Molecular analyses to identify and validate the direct target of DMC, including PTP1B and downstream signaling pathways (c-Src, NFATc1).
Main Results:
- DMC demonstrated potent inhibition of osteoclast differentiation and promotion of osteogenesis.
- Protein Tyrosine Phosphatase 1B (PTP1B) was identified as a direct molecular target of DMC.
- DMC inhibited PTP1B activity, blocking c-Src activation and the calcium/NFATc1 pathway, thereby suppressing osteoclastogenesis.
- In vivo, DMC treatment reversed bone loss and improved bone strength in OVX mice.
Conclusions:
- DMC is a potent immunomodulatory agent with therapeutic potential for postmenopausal osteoporosis.
- DMC acts by directly inhibiting PTP1B, highlighting PTP1B as a viable pharmacological target in osteoimmunology.
- This study provides a mechanistic basis for using DMC to treat osteoporosis by modulating the osteoimmune system.
