Delay in articular cartilage degeneration of the knee joint by the conditional removal of discoidin domain receptor 2 in a spontaneous mouse model of osteoarthritis

Background: Discoidin domain receptor 2 (Ddr2) is a rate-limiting factor in articular cartilage degeneration, a condition which normally leads to joint destruction. In human osteoarthritic tissues and mouse models of osteoarthritis (OA), the expression of Ddr2 increases and interacts with collagen type II, inducing the expression of matrix metalloproteinase 13 (MMP-13) and the receptor itself in chondrocytes. Moreover, conditional deletion of Ddr2 can significantly delay the progression of articular cartilage degeneration in post-traumatic OA mouse models. However, the biological effect of the conditional removal of Ddr2 in aging-related OA is still unknown. Therefore, this investigation was to determine whether the conditional removal of Ddr2 in articular cartilage could delay the cartilage degeneration in an aging-related mouse model (Col11a1(+/-)) of OA. Methods: Mice Acan(+/CreERT2) were bred with Ddr2(flox/flox) mice to generate Acan(+/CreERT2);Ddr2(+/flox) mice. Acan(+/CreERT2); Ddr2(+/flox) mice were crossed with Ddr2(flox/flox) mice to produce Acan(+/CreERT2);Ddr2(flox/flox) mice. A similar breeding procedure was used to generate Col11a1(+/-);Ddr2(flox/flox) mice, in which Acan(+/CreERT2) mice were replaced by Col11a1(+/-) mice. Acan(+/CreERT2);Ddr2(flox/flox) mice were bred with Col11a1(+/-);Ddr2(flox/flox) mice to produce Acan(+/ CreERT2);Ddr2(flox/flox);Col11a1(+/-) mice that were then treated with tamoxifen or oil at the age of 10 weeks. Knee joints from oiland tamoxifen-treated Acan(+/CreERT2);Ddr2(flox/flox);Col11a1(+/-) mice, and Acan(+/CreERT2);Ddr2(flox/flox) mice at the ages of 3, 9 and 15 months were collected for histology and immunohistochemistry analyses. The protein expressions of Ddr2 and Mmp-13 and the degraded collagen type II were examined. Results: The cartilage degeneration was significantly delayed in tamoxifen-treated Acan(+/CreERT2);Ddr2(flox/flox); Col11a1(+/-) mice. The scores, representing the severity of the cartilage damage, between oiland tamoxifentreated mice were: (mean +/- SD) 1.33 +/- 0.47 vs. 1.29 +/- 0.45 (P 0.05) at the age of 3 months, 3.50 +/- 0.50 vs. 2.14 +/- 0.35 (P<0.001) at the age of 9 months, and 5.33 +/- 0.47 vs. 2.71 +/- 0.55 (P<0.001) at the age of 15 months. The protein expressions of Ddr2, Mmp-13 and the degraded collagen type II were significantly decreased in tamoxifentreated mice. Conclusions: The removal of Ddr2 could significantly attenuate the cartilage degeneration in Col11a1(+/-) mice.