KLF2 Protects Against Osteoarthritis by Repressing Oxidative Response Through Activation of Nrf2/ARE Signaling and

Overview

Journal Oxid Med Cell Longev

Publisher Wiley

Specialties Cell Biology
Endocrinology

Date 2019 Dec 13

PMID 31827706

Citations 28

Authors

Xiang Gao

Shuangpeng Jiang

Zhangzhen Du

Angtin Ke

Qingwei Liang

Xu Li

Affiliations

Soon will be listed here.

Abstract

Osteoarthritis (OA) is a multifactorial and inflammatory disease characterized by cartilage destruction that can cause disability among aging patients. There is currently no effective treatment that can arrest or reverse OA progression. Kruppel-like factor 2 (KLF2), a member of the zinc finger family, has emerged as a transcription factor involved in a wide variety of inflammatory diseases. Here, we identified that KLF2 expression is downregulated in IL-1-treated human chondrocytes and OA cartilage. Genetic and pharmacological overexpression of KLF2 suppressed IL-1-induced apoptosis and matrix degradation through the suppression of reactive oxygen species (ROS) production. In addition, KLF2 overexpression resulted in increased expression of heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO1) through the enhanced nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Further, Nrf2 inhibition abrogated the chondroprotective effects of KLF2. Safranin O/fast green and TUNEL staining demonstrated that adenovirus-mediated overexpression of KLF2 in joint cartilage protects rats against experimental OA by inhibiting cartilage degradation and chondrocyte apoptosis. Immunohistochemical staining revealed that KLF2 overexpression significantly decreases MMP13 expression caused by OA progression . This and study is the first to investigate the antioxidative effect and mechanisms of KLF2 in OA pathogenesis. Our results collectively provide new insights into OA pathogenesis regulated by KLF2 and a rationale for the development of effective OA intervention strategies.

Citing Articles

High expression of transcription factor EGR1 is associated with postoperative muscle atrophy in patients with knee osteoarthritis undergoing total knee arthroplasty.

Liu X, Yu Q, Guo S, Chen X, Zeng W, Zhou Z J Orthop Surg Res. 2024; 19(1):618.

PMID: 39354574 PMC: 11443708. DOI: 10.1186/s13018-024-05109-9.

Krüppel-like factors family in health and disease.

Xiang T, Yang C, Deng Z, Sun D, Luo F, Chen Y MedComm (2020). 2024; 5(9):e723.

PMID: 39263604 PMC: 11387732. DOI: 10.1002/mco2.723.

KLF transcription factors in bone diseases.

Wang H, Han J, Dmitrii G, Ning K, Zhang X J Cell Mol Med. 2024; 28(8):e18278.

PMID: 38546623 PMC: 10977429. DOI: 10.1111/jcmm.18278.

Krüppel-like Factor 15 Suppresses Ferroptosis by Activating an NRF2/GPX4 Signal to Protect against Folic Acid-Induced Acute Kidney Injury.

Yang X, Dong S, Fan Y, Xia Y, Yang F, Chen Z Int J Mol Sci. 2023; 24(19).

PMID: 37833977 PMC: 10572468. DOI: 10.3390/ijms241914530.

FGF2 Alleviates Microvascular Ischemia-Reperfusion Injury by KLF2-mediated Ferroptosis Inhibition and Antioxidant Responses.

Chen F, Zhan J, Liu M, Al Mamun A, Huang S, Tao Y Int J Biol Sci. 2023; 19(13):4340-4359.

PMID: 37705747 PMC: 10496511. DOI: 10.7150/ijbs.85692.

References

Thomas C, Fuller C, Whittles C, Sharif M . Chondrocyte death by apoptosis is associated with cartilage matrix degradation. Osteoarthritis Cartilage. 2006; 15(1):27-34. DOI: 10.1016/j.joca.2006.06.012. View

McConnell B, Yang V . Mammalian Krüppel-like factors in health and diseases. Physiol Rev. 2010; 90(4):1337-81. PMC: 2975554. DOI: 10.1152/physrev.00058.2009. View

Jiang Y, Hu C, Yu S, Yan J, Peng H, Ouyang H . Cartilage stem/progenitor cells are activated in osteoarthritis via interleukin-1β/nerve growth factor signaling. Arthritis Res Ther. 2015; 17:327. PMC: 4650403. DOI: 10.1186/s13075-015-0840-x. View

Ashraf S, Mapp P, Burston J, Bennett A, Chapman V, Walsh D . Augmented pain behavioural responses to intra-articular injection of nerve growth factor in two animal models of osteoarthritis. Ann Rheum Dis. 2013; 73(9):1710-8. PMC: 4145450. DOI: 10.1136/annrheumdis-2013-203416. View

Gerwin N, Bendele A, Glasson S, Carlson C . The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the rat. Osteoarthritis Cartilage. 2010; 18 Suppl 3:S24-34. DOI: 10.1016/j.joca.2010.05.030. View

Kawanami D, Mahabeleshwar G, Lin Z, Atkins G, Hamik A, Haldar S . Kruppel-like factor 2 inhibits hypoxia-inducible factor 1alpha expression and function in the endothelium. J Biol Chem. 2009; 284(31):20522-30. PMC: 2742816. DOI: 10.1074/jbc.M109.025346. View

Wu W, Geng P, Zhu J, Li J, Zhang L, Chen W . KLF2 regulates eNOS uncoupling via Nrf2/HO-1 in endothelial cells under hypoxia and reoxygenation. Chem Biol Interact. 2019; 305:105-111. DOI: 10.1016/j.cbi.2019.03.010. View

Marrone G, Maeso-Diaz R, Garcia-Cardena G, Abraldes J, Garcia-Pagan J, Bosch J . KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut. 2014; 64(9):1434-43. DOI: 10.1136/gutjnl-2014-308338. View

Khan N, Ahmad I, Haqqi T . Nrf2/ARE pathway attenuates oxidative and apoptotic response in human osteoarthritis chondrocytes by activating ERK1/2/ELK1-P70S6K-P90RSK signaling axis. Free Radic Biol Med. 2018; 116:159-171. PMC: 5815915. DOI: 10.1016/j.freeradbiomed.2018.01.013. View

10.

Habeos I, Ziros P, Chartoumpekis D, Psyrogiannis A, Kyriazopoulou V, Papavassiliou A . Simvastatin activates Keap1/Nrf2 signaling in rat liver. J Mol Med (Berl). 2008; 86(11):1279-85. DOI: 10.1007/s00109-008-0393-4. View

11.

Das H, Kumar A, Lin Z, Patino W, Hwang P, Feinberg M . Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes. Proc Natl Acad Sci U S A. 2006; 103(17):6653-8. PMC: 1458936. DOI: 10.1073/pnas.0508235103. View

12.

Thomas E, Peat G, Croft P . Defining and mapping the person with osteoarthritis for population studies and public health. Rheumatology (Oxford). 2013; 53(2):338-45. PMC: 3894672. DOI: 10.1093/rheumatology/ket346. View

13.

Lian W, Ko J, Wu R, Sun Y, Chen Y, Wu S . MicroRNA-128a represses chondrocyte autophagy and exacerbates knee osteoarthritis by disrupting Atg12. Cell Death Dis. 2018; 9(9):919. PMC: 6134128. DOI: 10.1038/s41419-018-0994-y. View

14.

Little C, Barai A, Burkhardt D, Smith S, Fosang A, Werb Z . Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum. 2009; 60(12):3723-33. PMC: 2832925. DOI: 10.1002/art.25002. View

15.

Tuomisto T, Lumivuori H, Kansanen E, Hakkinen S, Turunen M, van Thienen J . Simvastatin has an anti-inflammatory effect on macrophages via upregulation of an atheroprotective transcription factor, Kruppel-like factor 2. Cardiovasc Res. 2008; 78(1):175-84. DOI: 10.1093/cvr/cvn007. View

16.

Yudoh K, Karasawa R . Statin prevents chondrocyte aging and degeneration of articular cartilage in osteoarthritis (OA). Aging (Albany NY). 2010; 2(12):990-8. PMC: 3034187. DOI: 10.18632/aging.100213. View

17.

Wu X, Zhang J, Yang P, Huang Q, Liu J . Regulation of Kruppel-like factor 2 (KLF2) in the pathogenesis of intracranial aneurysm induced by hemodynamics. Am J Transl Res. 2018; 9(12):5452-5460. PMC: 5752895. View

18.

Das M, Laha D, Kanji S, Joseph M, Aggarwal R, Iwenofu O . Induction of Krüppel-like factor 2 reduces K/BxN serum-induced arthritis. J Cell Mol Med. 2018; 23(2):1386-1395. PMC: 6349180. DOI: 10.1111/jcmm.14041. View

19.

Collins J, Diekman B, Loeser R . Targeting aging for disease modification in osteoarthritis. Curr Opin Rheumatol. 2017; 30(1):101-107. PMC: 5886778. DOI: 10.1097/BOR.0000000000000456. View

20.

Son Y, Kim H, Choi W, Chun C, Chun J . RNA-binding protein ZFP36L1 regulates osteoarthritis by modulating members of the heat shock protein 70 family. Nat Commun. 2019; 10(1):77. PMC: 6325149. DOI: 10.1038/s41467-018-08035-7. View