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.	馬鋼, 任明姬. 骨性關節炎軟骨細胞凋亡的研究. 中國組織化學與細胞化學雜志, 2012, 21(2): 196-200.
4.	張榮凱, 楊祿坤, 葉志強, 等. 以關節不穩建立的大鼠骨關節炎模型. 中國組織工程研究, 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.	中華醫學會骨科分會. 骨關節炎診治指南(2007 年版). 中華骨科雜志, 2007, 27(10): 793-796.
8.	謝丹. 關節軟骨細胞凋亡與骨性關節炎的相關機制. 現代康復, 2001, 5(5): 111.
9.	劉永剛, 鮑雋君, 邢自寶, 等. 骨性關節炎與細胞因子相關性研究進展. 骨科, 2010, 1(2): 105-107.
10.	張衣北, 陳安民, 郭風勁, 等. 激活的 Notch1 信號系統抑制前軟骨干細胞凋亡及其機制研究. 中華小兒外科雜志, 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.	雷鳴, 郭風勁. 骨關節炎中影響軟骨細胞凋亡的因素. 中國臨床康復, 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.	馬春輝, 閻作勤, 郭常安, 等. 凋亡相關基因 Bax 和 bcl-2 在骨關節炎軟骨中的作用. 中華關節外科雜志: 電子版, 2007, 10(4): 232-237.
20.	申徐良, 王椿, 喬振華. Bcl-2 基因家族的生物學功能及其調控機制. 腫瘤研究與臨床, 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. 馬鋼, 任明姬. 骨性關節炎軟骨細胞凋亡的研究. 中國組織化學與細胞化學雜志, 2012, 21(2): 196-200.
4. 張榮凱, 楊祿坤, 葉志強, 等. 以關節不穩建立的大鼠骨關節炎模型. 中國組織工程研究, 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. 中華醫學會骨科分會. 骨關節炎診治指南(2007 年版). 中華骨科雜志, 2007, 27(10): 793-796.
8. 謝丹. 關節軟骨細胞凋亡與骨性關節炎的相關機制. 現代康復, 2001, 5(5): 111.
9. 劉永剛, 鮑雋君, 邢自寶, 等. 骨性關節炎與細胞因子相關性研究進展. 骨科, 2010, 1(2): 105-107.
10. 張衣北, 陳安民, 郭風勁, 等. 激活的 Notch1 信號系統抑制前軟骨干細胞凋亡及其機制研究. 中華小兒外科雜志, 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. 雷鳴, 郭風勁. 骨關節炎中影響軟骨細胞凋亡的因素. 中國臨床康復, 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. 馬春輝, 閻作勤, 郭常安, 等. 凋亡相關基因 Bax 和 bcl-2 在骨關節炎軟骨中的作用. 中華關節外科雜志: 電子版, 2007, 10(4): 232-237.
20. 申徐良, 王椿, 喬振華. Bcl-2 基因家族的生物學功能及其調控機制. 腫瘤研究與臨床, 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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