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Deletion of Panx3 Prevents the Development of Surgically Induced Osteoarthritis
Paxton M Moon1, Silvia Penuela, Kevin Barr
1Departments of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
Unlabelled:
Osteoarthritis (OA) is a highly prevalent, disabling joint disease with no existing therapies to slow or halt its progression. Cartilage degeneration hallmarks OA pathogenesis, and pannexin 3 (Panx3), a member of a novel family of channel proteins, is upregulated during this process. The function of Panx3 remains poorly understood, but we consistently observed a strong increase in Panx3 immunostaining in OA lesions in both mice and humans. Here, we developed and characterized the first global and conditional Panx3 knockout mice to investigate the role of Panx3 in OA. Interestingly, global Panx3 deletion produced no overt phenotype and had no obvious effect on early skeletal development. Mice lacking Panx3 specifically in the cartilage and global Panx3 knockout mice were markedly resistant to the development of OA following destabilization of medial meniscus surgery. These data indicate a specific catabolic role of Panx3 in articular cartilage and identify Panx3 as a potential therapeutic target for OA. Lastly, while Panx1 has been linked to over a dozen human pathologies, this is the first in vivo evidence for a role of Panx3 in disease.
Key Message:
Panx3 is localized to cartilage lesions in mice and humans. Global Panx3 deletion does not result in any developmental abnormalities. Mice lacking Panx3 are resistant to the development of osteoarthritis. Panx3 is a novel therapeutic target for the treatment of osteoarthritis.
Insights
Pannexin 3 (Panx3) is upregulated in osteoarthritis. Removing Panx3 in mice prevents osteoarthritis development, identifying it as a potential therapeutic target for this disabling joint disease.
Area of Science:
- Biochemistry and Molecular Biology
- Orthopedics and Musculoskeletal Diseases
- Cell Biology
Background:
- Osteoarthritis (OA) is a prevalent degenerative joint disease with no current treatments to halt its progression.
- Cartilage degeneration is a key feature of OA pathogenesis.
- Pannexin 3 (Panx3), a novel channel protein, is found at higher levels in OA lesions.
Purpose of the Study:
- To investigate the role of Panx3 in OA pathogenesis.
- To develop and characterize the first global and conditional Panx3 knockout mouse models for OA research.
Main Methods:
- Development of global and conditional Panx3 knockout mice.
- Induction of OA using destabilization of the medial meniscus (DMM) surgery in mice.
- Immunohistochemical analysis of Panx3 expression in OA lesions.
Main Results:
- Global Panx3 deletion showed no adverse effects on skeletal development.
- Mice lacking Panx3, either globally or specifically in cartilage, were resistant to OA development after DMM surgery.
- Panx3 expression was significantly increased in OA cartilage lesions in both mice and humans.
Conclusions:
- Panx3 plays a specific catabolic role in articular cartilage.
- Panx3 is a potential novel therapeutic target for osteoarthritis treatment.
- This study provides the first in vivo evidence for Panx3's role in disease.
