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.

Abstract

BackgroundDiscoidin 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.MethodsMice Acan+/CreERT2 were bred with Ddr2flox/flox mice to generate Acan+/CreERT2;Ddr2+/flox mice. Acan+/CreERT2;Ddr2+/flox mice were crossed with Ddr2flox/flox mice to produce Acan+/CreERT2;Ddr2flox/flox mice. A similar breeding procedure was used to generate Col11a1+/−;Ddr2flox/flox mice, in which Acan+/CreERT2 mice were replaced by Col11a1+/− mice. Acan+/CreERT2;Ddr2flox/flox mice were bred with Col11a1+/−;Ddr2flox/flox mice to produce Acan+/CreERT2;Ddr2flox/flox;Col11a1+/− mice that were then treated with tamoxifen or oil at the age of 10 weeks. Knee joints from oil- and tamoxifen-treated Acan+/CreERT2;Ddr2flox/flox;Col11a1+/− mice, and Acan+/CreERT2;Ddr2flox/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.ResultsThe cartilage degeneration was significantly delayed in tamoxifen-treated Acan+/CreERT2;Ddr2flox/flox;Col11a1+/− mice. The scores, representing the severity of the cartilage damage, between oil- and tamoxifen-treated 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 tamoxifen-treated mice.ConclusionsThe removal of Ddr2 could significantly attenuate the cartilage degeneration in Col11a1+/− mice.