The effect of Notch signaling pathway on apoptosis of articular chondrocytes in knee osteoarthritis_West China Medical Journal

Authors：

WU Shaojun ¹ , LIU Juncai ¹ , ZUO Yinlong ² ,  LI Zhong ¹

1. Department of Bone and Joint Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P. R. China;
2. Department of Orthopaedics, Chongqing Dazu People’s Hospital, Dazu, Chongqing 402360, P. R. China;

Corresponding author：

LI Zhong, Email: 545890312@qq.com

Keywords：

Osteoarthritis; Notch signaling pathway; Notch1; Bax; Bcl-2

DOI：

10.7507/1002-0179.201808099

Video：

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ObjectiveTo detect the expression of Notch1, Bax, Bcl-2 genes in rat knee joint cartilage cells in a state of activation and inactivation of the Notch signaling pathway, and preliminarily study the mechanism of Notch signaling pathway on experimental rat knee osteoarthritis (OA) chondrocytes apoptosis.MethodsA total of 34 specefic-pathogen-free Sprague Dawley rats were selected, of which 32 were established the right knee OA models using Hulth method, and the other 2 were normally fed. Four weeks later, two randomly selected OA rats and the two normally fed rats were put to death, to observe the morphological changes of the right knee and ensure the OA models were successfully established by pathology examination. The remaining 30 rats were randomly divided into three groups with 10 in each. The rats were injected intra-articularly on each Tuesday and Friday, with Nocth signal pathway specific activator Jagged1 protein (25 ng/kg) in the activation group, γ-secretase inhibitor DAPT (GSI-IX) (100 ng/kg) in the inhibition group, and phosphate-buffered saline in the control group, respectively. The rats were sacrificed after 8 weeks of articular cavity injection. Taking the right knee articular cartilage speciments of femoral condyle, we observed the degeneration of articular cartilage of the three groups, observed the histomorphological changes by microscope, evaluated the Mankin scores, and used the immunohistochemistry to detect the expression of Notch1, Bax, Bcl-2 proteins.ResultsAfter the 8-week articular cavity injection, the Mankin scores in the activation group, the inhibition group, and the control group were 3.40±0.84, 6.70±0.95, 11.10±1.37, respectively, and the differences between the three groups were statistically significant (P<0.05). The positive rates of Notch1 and Bax of chondrocyte in the inhibition group were lower than those in the control group and the activation group (P<0.05), while the positive rate of Bcl-2 of chondrocyte in the inhibition group was higher than that in the control group and the activation group (P<0.05).ConclusionActivating the Notch signaling pathway may facilitate the chondrocyte apoptosis and aggravate OA by up-regulating Bax protein expression and down-regulating Bcl-2 protein expression; inhibiting the Notch signaling pathway may inhibit the chondrocyte apoptosis and relieve OA by up-regulating Bcl-2 protein expression and down-regulating Bax protein expression.

Citation： WU Shaojun, LIU Juncai, ZUO Yinlong, LI Zhong. The effect of Notch signaling pathway on apoptosis of articular chondrocytes in knee osteoarthritis. West China Medical Journal, 2018, 33(9): 1162-1167. doi: 10.7507/1002-0179.201808099 Copy

1.	Hayes AJ, Dowthwaite GP, Webster SV, et al. The distribution of Notch receptors and their ligands during articular cartilage development. J Anat, 2003, 202(6): 495-502.
2.	Dowthwaite GP, Bishop JC, Redman SN, et al. The surface of articular cartilage contains a progenitor cell population. J Cell Sci, 2004, 117(Pt 6): 889-897.
3.	马钢, 任明姬. 骨性关节炎软骨细胞凋亡的研究. 中国组织化学与细胞化学杂志, 2012, 21(2): 196-200.
4.	张荣凯, 杨禄坤, 叶志强, 等. 以关节不稳建立的大鼠骨关节炎模型. 中国组织工程研究, 2013, 17(37): 6628-6635.
5.	Ahmad I, Balasubramanian S, Del Debbio CB, et al. Regulation of ocular angiogenesis by Notch signaling: implications in neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci, 2011, 52(6): 2868-2878.
6.	Bobinac D, Spanjol J, Zoricic S, et al. Changes in articular cartilage and subchondral bone histomorphometry in osteoarthritic knee joints in humans. Bone, 2003, 32(3): 284-290.
7.	中华医学会骨科分会. 骨关节炎诊治指南(2007 年版). 中华骨科杂志, 2007, 27(10): 793-796.
8.	谢丹. 关节软骨细胞凋亡与骨性关节炎的相关机制. 现代康复, 2001, 5(5): 111.
9.	刘永刚, 鲍隽君, 邢自宝, 等. 骨性关节炎与细胞因子相关性研究进展. 骨科, 2010, 1(2): 105-107.
10.	张衣北, 陈安民, 郭风劲, 等. 激活的 Notch1 信号系统抑制前软骨干细胞凋亡及其机制研究. 中华小儿外科杂志, 2006, 27(11): 592-595.
11.	Kohn A, Dong Y, Mirando AJ, et al. Cartilage-specific RBPjk-dependent and -independent Notch signals regulate cartilage and bone development. Development, 2012, 139(6): 1198-1212.
12.	Mirando AJ, Liu Z, Moore T, et al. RBP-Jk-dependent Notch signaling is required for murine articular cartilage and joint maintenance. Arthritis Rheum, 2013, 65(10): 2623-2633.
13.	Caliceti C, Nigro P, Rizzo P, et al. ROS, Notch, and Wnt signaling pathways: crosstalk between three major regulators of cardiovascular biology. Biomed Res Int, 2014: 318714.
14.	Mahjoub M, Sassi N, Driss M, et al. Expression patterns of Notch receptors and their ligands in human osteoarthritic and healthy articular cartilage. Tissue Cell, 2012, 44(3): 182-194.
15.	Hosaka Y, Saito T, Sugita S, et al. Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development. Proc Natl Acad Sci USA, 2013, 110(5): 1875-1880.
16.	雷鸣, 郭风劲. 骨关节炎中影响软骨细胞凋亡的因素. 中国临床康复, 2005, 9(30): 184-186.
17.	Blanco FJ, Guitian R, Vázquez-Martul E, et al. Osteoarthritis chondrocytes die by apoptosis. A possible pathway for osteoarthritis pathology. Arthritis Rheum, 1998, 41(2): 284-289.
18.	Kim DY, Taylor HW, Moore RM, et al. Articular chondrocyte apoptosis in equine osteoarthritis. Vet J, 2003, 166(1): 52-57.
19.	马春辉, 阎作勤, 郭常安, 等. 凋亡相关基因 Bax 和 bcl-2 在骨关节炎软骨中的作用. 中华关节外科杂志: 电子版, 2007, 10(4): 232-237.
20.	申徐良, 王椿, 乔振华. Bcl-2 基因家族的生物学功能及其调控机制. 肿瘤研究与临床, 1999, 11(1): 65-67.
21.	Yin XM, Oltvai ZN, Korsmeyer SJ. BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature, 1994, 369(6478): 321-323.
22.	Ferreira AC, Suriano G, Mendes N, et al. E-cadherin impairment increases cell survival through Notch-dependent upregulation of Bcl-2. Hum Mol Genet, 2012, 21(2): 334-343.

1. Hayes AJ, Dowthwaite GP, Webster SV, et al. The distribution of Notch receptors and their ligands during articular cartilage development. J Anat, 2003, 202(6): 495-502.
2. Dowthwaite GP, Bishop JC, Redman SN, et al. The surface of articular cartilage contains a progenitor cell population. J Cell Sci, 2004, 117(Pt 6): 889-897.
3. 马钢, 任明姬. 骨性关节炎软骨细胞凋亡的研究. 中国组织化学与细胞化学杂志, 2012, 21(2): 196-200.
4. 张荣凯, 杨禄坤, 叶志强, 等. 以关节不稳建立的大鼠骨关节炎模型. 中国组织工程研究, 2013, 17(37): 6628-6635.
5. Ahmad I, Balasubramanian S, Del Debbio CB, et al. Regulation of ocular angiogenesis by Notch signaling: implications in neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci, 2011, 52(6): 2868-2878.
6. Bobinac D, Spanjol J, Zoricic S, et al. Changes in articular cartilage and subchondral bone histomorphometry in osteoarthritic knee joints in humans. Bone, 2003, 32(3): 284-290.
7. 中华医学会骨科分会. 骨关节炎诊治指南(2007 年版). 中华骨科杂志, 2007, 27(10): 793-796.
8. 谢丹. 关节软骨细胞凋亡与骨性关节炎的相关机制. 现代康复, 2001, 5(5): 111.
9. 刘永刚, 鲍隽君, 邢自宝, 等. 骨性关节炎与细胞因子相关性研究进展. 骨科, 2010, 1(2): 105-107.
10. 张衣北, 陈安民, 郭风劲, 等. 激活的 Notch1 信号系统抑制前软骨干细胞凋亡及其机制研究. 中华小儿外科杂志, 2006, 27(11): 592-595.
11. Kohn A, Dong Y, Mirando AJ, et al. Cartilage-specific RBPjk-dependent and -independent Notch signals regulate cartilage and bone development. Development, 2012, 139(6): 1198-1212.
12. Mirando AJ, Liu Z, Moore T, et al. RBP-Jk-dependent Notch signaling is required for murine articular cartilage and joint maintenance. Arthritis Rheum, 2013, 65(10): 2623-2633.
13. Caliceti C, Nigro P, Rizzo P, et al. ROS, Notch, and Wnt signaling pathways: crosstalk between three major regulators of cardiovascular biology. Biomed Res Int, 2014: 318714.
14. Mahjoub M, Sassi N, Driss M, et al. Expression patterns of Notch receptors and their ligands in human osteoarthritic and healthy articular cartilage. Tissue Cell, 2012, 44(3): 182-194.
15. Hosaka Y, Saito T, Sugita S, et al. Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development. Proc Natl Acad Sci USA, 2013, 110(5): 1875-1880.
16. 雷鸣, 郭风劲. 骨关节炎中影响软骨细胞凋亡的因素. 中国临床康复, 2005, 9(30): 184-186.
17. Blanco FJ, Guitian R, Vázquez-Martul E, et al. Osteoarthritis chondrocytes die by apoptosis. A possible pathway for osteoarthritis pathology. Arthritis Rheum, 1998, 41(2): 284-289.
18. Kim DY, Taylor HW, Moore RM, et al. Articular chondrocyte apoptosis in equine osteoarthritis. Vet J, 2003, 166(1): 52-57.
19. 马春辉, 阎作勤, 郭常安, 等. 凋亡相关基因 Bax 和 bcl-2 在骨关节炎软骨中的作用. 中华关节外科杂志: 电子版, 2007, 10(4): 232-237.
20. 申徐良, 王椿, 乔振华. Bcl-2 基因家族的生物学功能及其调控机制. 肿瘤研究与临床, 1999, 11(1): 65-67.
21. Yin XM, Oltvai ZN, Korsmeyer SJ. BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature, 1994, 369(6478): 321-323.
22. Ferreira AC, Suriano G, Mendes N, et al. E-cadherin impairment increases cell survival through Notch-dependent upregulation of Bcl-2. Hum Mol Genet, 2012, 21(2): 334-343.

West China Medical Journal

The effect of Notch signaling pathway on apoptosis of articular chondrocytes in knee osteoarthritis

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