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Attenuation of osteoarthritis progression by reduction of discoidin domain receptor 2 in mice
Lin Xu1, Jacqueline Servais, Ilona Polur
1Harvard School of Dental Medicine, Boston, Massachusetts 02115, USA.
Objective:
To investigate whether the reduction of discoidin domain receptor 2 (DDR-2), a cell membrane tyrosine kinase receptor for native type II collagen, attenuates the progression of articular cartilage degeneration in mouse models of osteoarthritis (OA).
Methods:
Double-heterozygous (type XI collagen-deficient [Col11a1(+/-)] and Ddr2-deficient [Ddr2(+/-)]) mutant mice were generated. Knee joints of Ddr2(+/-) mice were subjected to microsurgical destabilization of the medial meniscus. Conditions of the articular cartilage from the knee joints of the double-heterozygous mutant and surgically treated mice were examined by histology, evaluated using a modified Mankin scoring system, and characterized by immunohistochemistry.
Results:
The rate of progressive degeneration in knee joints was dramatically reduced in the double-heterozygous mutant mice compared with that in the type XI collagen-deficient mice. The progression in the double-heterozygous mutant mice was delayed by ∼6 months. Following surgical destabilization of the medial meniscus, the progressive degeneration toward OA was dramatically delayed in the Ddr2(+/-) mice compared with that in their wild-type littermates. The articular cartilage damage present in the knee joints of the mice was directly correlated with the expression profiles of DDR-2 and matrix metalloproteinase 13.
Conclusion:
Reduction of DDR-2 expression attenuates the articular cartilage degeneration of knee joints induced either by type XI collagen deficiency or by surgical destabilization of the medial meniscus.
Insights
Reducing discoidin domain receptor 2 (DDR-2) expression significantly delays osteoarthritis progression in mouse models. This finding offers potential therapeutic targets for articular cartilage degeneration.
Area of Science:
- Biochemistry
- Molecular Biology
- Orthopedics
Background:
- Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage breakdown.
- Discoidin domain receptor 2 (DDR-2) is a tyrosine kinase receptor for type II collagen, implicated in matrix remodeling.
- Understanding DDR-2's role in OA pathogenesis is crucial for developing targeted therapies.
Purpose of the Study:
- To determine if reducing discoidin domain receptor 2 (DDR-2) expression mitigates articular cartilage degeneration in mouse models of osteoarthritis (OA).
- To investigate the impact of DDR-2 deficiency on OA progression induced by collagen deficiency and surgical destabilization.
Main Methods:
- Generated double-heterozygous mutant mice (type XI collagen-deficient and Ddr2-deficient).
- Subjected Ddr2(+/-) mice knee joints to surgical destabilization of the medial meniscus.
- Evaluated articular cartilage degeneration using histology, modified Mankin scoring, and immunohistochemistry.
Main Results:
- Double-heterozygous mutant mice exhibited a dramatically reduced rate of knee joint degeneration compared to collagen-deficient mice, with progression delayed by approximately 6 months.
- Surgical destabilization of the medial meniscus showed dramatically delayed OA progression in Ddr2(+/-) mice versus wild-type littermates.
- Articular cartilage damage correlated directly with DDR-2 and matrix metalloproteinase 13 expression levels.
Conclusions:
- Reduction of DDR-2 expression attenuates articular cartilage degeneration in knee joints.
- This protective effect was observed in models of both type XI collagen deficiency and surgical destabilization.
- DDR-2 is a potential therapeutic target for managing osteoarthritis progression.
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