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Orthotopic Implantation and Peripheral Immune Cell Monitoring in the II-45 Syngeneic Rat Mesothelioma Model
Published on: October 2, 2015
Mesothelin as a biomarker and potential therapeutic target in rheumatoid arthritis bone destruction
Xiaohui Su1, Qian Wang1, Jingbo Wang1
1State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Abstract:
Mesothelin (MSLN) is implicated in multiple biological processes, notably in modulating immune responses. However, the role of MSLN in osteoclastogenesis remains underexplored. Here we reveal that the level of MSLN was significantly elevated in rheumatoid arthritis (RA) patients, as well as in collagen-induced arthritis (CIA) animals. Pharmacological and genetic inhibition of MSLN significantly impair osteoclast differentiation and bone resorption. In the animal model, down-regulation of MSLN effectively alleviates bone destruction. Further investigation unravels that MSLN directly interacts with phosphatidylinositol 3-kinase (PI3K), resulting in the activation of the PI3K/protein kinase B (AKT) signaling pathway, which subsequently induces the expression and translocation of nuclear factor of activated T cells 1 (NFATc1), thereby promoting osteoclast differentiation. Overall, our findings indicate that MSLN could serve as a valuable prognostic marker for bone destruction in RA, and targeting MSLN may offer a therapeutic strategy for RA-related bone destruction.
Insights
Mesothelin (MSLN) is elevated in rheumatoid arthritis, driving bone destruction by promoting osteoclast differentiation. Inhibiting MSLN alleviates bone damage, suggesting it as a therapeutic target.
Area of Science:
- Immunology
- Rheumatology
- Bone Biology
Background:
- Mesothelin (MSLN) plays a role in immune responses.
- The function of MSLN in osteoclastogenesis is not well understood.
- Rheumatoid arthritis (RA) is characterized by joint inflammation and bone erosion.
Purpose of the Study:
- To investigate the role of Mesothelin (MSLN) in osteoclastogenesis and bone destruction in rheumatoid arthritis (RA).
- To explore MSLN as a potential therapeutic target for RA-related bone damage.
Main Methods:
- Quantified MSLN levels in RA patients and collagen-induced arthritis (CIA) animal models.
- Utilized pharmacological and genetic inhibition of MSLN.
- Investigated the molecular mechanism involving PI3K/AKT/NFATc1 signaling pathway.
Main Results:
- MSLN levels were significantly elevated in RA patients and CIA animals.
- Inhibition of MSLN impaired osteoclast differentiation and bone resorption.
- Down-regulation of MSLN reduced bone destruction in the animal model.
- MSLN was found to activate the PI3K/AKT pathway, promoting NFATc1 expression and osteoclast differentiation.
Conclusions:
- MSLN is a key regulator of osteoclastogenesis and bone destruction in RA.
- MSLN levels can serve as a prognostic marker for bone destruction in RA.
- Targeting MSLN presents a potential therapeutic strategy for mitigating bone damage in RA.
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