Blocking TNFα attenuates progressive cartilage matrix degradation in inflammatory arthritis

Park,Jinsung; Park,Hyosun; Lee,Young Lim; Weon,Subin; Kim,Yong-Gil; Yang,Jae-Hyuk; Nam,Bora; Jo,Sungsin; Kim,Tae-Hwan

doi:10.3892/etm.2021.10240

Blocking TNFα attenuates progressive cartilage matrix degradation in inflammatory arthritis

Authors:
- Jinsung Park
- Hyosun Park
- Young Lim Lee
- Subin Weon
- Yong-Gil Kim
- Jae-Hyuk Yang
- Bora Nam
- Sungsin Jo
- Tae-Hwan Kim
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Affiliations: Hanyang University Institute for Rheumatology Research, Seoul 04763, Republic of Korea, Division of Rheumatology, Department of Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea, Department of Orthopedics, Hanyang University Guri Hospital, Guri, Gyeonggi 11923, Republic of Korea
Published online on: May 27, 2021 https://doi.org/10.3892/etm.2021.10240
Article Number: 808
Copyright: © Park et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Because damage to hyaline cartilage is irreversible, relieving progressive cartilage destruction is an important therapeutic approach for inflammatory arthritis. In the present study, human hyaline chondrocytes were isolated from total knee replacements of 15 patients with osteoarthritis (OA) and three with rheumatoid arthritis (RA). Synovial fluid of OA (n=25) and RA (n=34) were collected to measure tumor necrosis factor α (TNFα) using ELISA. Consistent with previous studies, the synovial fluid exhibited high TNFα levels and hyaline cartilage was severely destroyed in patients with RA. TNFα‑treated chondrocytes were used as model for inflammatory arthritis. TNFα did not influence proliferation or extracellular matrix expression in chondrocytes, but induced matrix metalloproteinase (MMP)1, 3 and 13 expression levels in chondrocytes, which was accompanied by activation of nuclear factor‑κB signaling. During chondrogenic differentiation, TNFα attenuated mRNA expression levels of anabolic factors (collagen type 2 and aggrecan) and enhanced mRNA expression of catabolic factors (MMP1, MMP3 and MMP13) in chondrocytes. Moreover, anti‑TNFα agents (Golimumab) inhibited the TNFα‑induced metabolic shift in chondrocytes and chondrogenic differentiation. The present study revealed a mechanism by which TNFα may induce metabolic shift in chondrocytes, leading to progressive chondrocyte destruction.

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1	Goldring MB: Articular cartilage degradation in osteoarthritis. HSS J. 8:7–9. 2012.PubMed/NCBI View Article : Google Scholar
2	Goldring MB and Marcu KB: Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther. 11(224)2009.PubMed/NCBI View Article : Google Scholar
3	Langer R and Vacanti JP: Tissue engineering. Science. 260:920–926. 1993.PubMed/NCBI View Article : Google Scholar
4	Mao AS and Mooney DJ: Regenerative medicine: Current therapies and future directions. Proc Natl Acad Sci USA. 112:14452–14459. 2015.PubMed/NCBI View Article : Google Scholar
5	Jiang S, Guo W, Tian G, Luo X, Peng L, Liu S, Sui X, Guo Q and Li X: Clinical application status of articular cartilage regeneration techniques: Tissue-engineered cartilage brings new hope. Stem Cells Int. 2020(5690252)2020.PubMed/NCBI View Article : Google Scholar
6	Malda J, Groll J and van Weeren PR: Rethinking articular cartilage regeneration based on a 250-year-old statement. Nat Rev Rheumatol. 15:571–572. 2019.PubMed/NCBI View Article : Google Scholar
7	Mueller MB and Tuan RS: Anabolic/Catabolic balance in pathogenesis of osteoarthritis: Identifying molecular targets. PM R. 3 (Suppl 1):S3–S11. 2011.PubMed/NCBI View Article : Google Scholar
8	Little CB, Flannery CR, Hughes CE, Mort JS, Roughley PJ, Dent C and Caterson B: Aggrecanase versus matrix metalloproteinases in the catabolism of the interglobular domain of aggrecan in vitro. Biochem J. 344:61–68. 1999.PubMed/NCBI
9	Matyas JR, Ehlers PF, Huang D and Adams ME: The early molecular natural history of experimental osteoarthritis. I. Progressive discoordinate expression of aggrecan and type II procollagen messenger RNA in the articular cartilage of adult animals. Arthritis Rheum. 42:993–1002. 1999.PubMed/NCBI View Article : Google Scholar
10	Park EH, Kim JS, Lee JS, Lee YJ, Song YW and Lee EY: Compound K inhibits interleukin-1β-induced expression of inflammatory mediators and matrix metalloproteinases by inhibiting mitogen-activated protein kinase activation in chondrocytes. J Rheumatic Dis. 25(188)2018.
11	Billinghurst RC, Dahlberg L, Ionescu M, Reiner A, Bourne R, Rorabeck C, Mitchell P, Hambor J, Diekmann O, Tschesche H, et al: Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. J Clin Invest. 99:1534–1545. 1997.PubMed/NCBI View Article : Google Scholar
12	Shlopov BV, Gumanovskaya ML and Hasty KA: Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis. Arthritis Rheum. 43:195–205. 2000.PubMed/NCBI View Article : Google Scholar
13	Tetlow LC, Adlam DJ and Woolley DE: Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: Associations with degenerative changes. Arthritis Rheum. 44:585–594. 2001.PubMed/NCBI View Article : Google Scholar
14	Aigner T, Fundel K, Saas J, Gebhard PM, Haag J, Weiss T, Zien A, Obermayr F, Zimmer R and Bartnik E: Large-scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis. Arthritis Rheum. 54:3533–3544. 2006.PubMed/NCBI View Article : Google Scholar
15	Tracey KJ and Cerami A: Tumor necrosis factor: A pleiotropic cytokine and therapeutic target. Annu Rev Med. 45:491–503. 1994.PubMed/NCBI View Article : Google Scholar
16	Liu G: Molecular mechanism and TNF signaling and beyond. Cell Res. 15:24–27. 2005.PubMed/NCBI View Article : Google Scholar
17	Kammermann JR, Kincaid SA, Rumph PF, Baird DK and Visco DM: Tumor necrosis factor-alpha (TNF-alpha) in canine osteoarthritis: Immunolocalization of TNF-alpha, stromelysin and TNF receptors in canine osteoarthritic cartilage. Osteoarthritis Cartilage. 4:23–34. 1996.PubMed/NCBI View Article : Google Scholar
18	Arend WP and Dayer JM: Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum. 38:151–160. 1995.PubMed/NCBI View Article : Google Scholar
19	Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP and Fahmi H: Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 7:33–42. 2011.PubMed/NCBI View Article : Google Scholar
20	Jo S, Yoon S, Lee SY, Kim SY, Park H, Han J, Choi SH, Han JS, Yang JH and Kim TH: DKK1 induced by 1,25D3 is required for the mineralization of osteoblasts. Cells. 9(236)2020.PubMed/NCBI View Article : Google Scholar
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
22	Jo S, Wang SE, Lee YL, Kang S, Lee B, Han J, Sung IH, Park YS, Bae SC and Kim TH: IL-17A induces osteoblast differentiation by activating JAK2/STAT3 in ankylosing spondylitis. Arthritis Res Ther. 20(115)2018.PubMed/NCBI View Article : Google Scholar
23	Koontz L: TCA precipitation. Methods Enzymol. 541:3–10. 2014.PubMed/NCBI View Article : Google Scholar
24	Kim H, Chung H, Kim HJ, Lee JY, Oh MY, Kim Y and Kong G: Id-1 regulates Bcl-2 and Bax expression through p53 and NF-kappaB in MCF-7 breast cancer cells. Breast Cancer Res Treat. 112:287–296. 2008.PubMed/NCBI View Article : Google Scholar
25	Lee JK, Jo S, Lee YL, Park H, Song JS, Sung IH and Kim TH: Anterior cruciate ligament remnant cells have different potentials for cell differentiation based on their location. Sci Rep. 10(3097)2020.PubMed/NCBI View Article : Google Scholar
26	Li X, Du W, Ma FX, Feng X, Bayard F and Han ZC: High concentrations of TNF-α induce cell death during interactions between human umbilical cord mesenchymal stem cells and peripheral blood mononuclear cells. PLoS One. 10(e0128647)2015.PubMed/NCBI View Article : Google Scholar
27	Li P, Gan Y, Xu Y, Song L, Wang L, Ouyang B, Zhang C and Zhou Q: The inflammatory cytokine TNF-α promotes the premature senescence of rat nucleus pulposus cells via the PI3K/Akt signaling pathway. Sci Rep. 7(42938)2017.PubMed/NCBI View Article : Google Scholar
28	Kishimoto H, Akagi M, Zushi S, Teramura T, Onodera Y, Sawamura T and Hamanishi C: Induction of hypertrophic chondrocyte-like phenotypes by oxidized LDL in cultured bovine articular chondrocytes through increase in oxidative stress. Osteoarthritis Cartilage. 18:1284–1290. 2010.PubMed/NCBI View Article : Google Scholar
29	Borzi RM, Olivotto E, Pagani S, Vitellozzi R, Neri S, Battistelli M, Falcieri E, Facchini A, Flamigni F, Penzo M, et al: Matrix metalloproteinase 13 loss associated with impaired extracellular matrix remodeling disrupts chondrocyte differentiation by concerted effects on multiple regulatory factors. Arthritis Rheum. 62:2370–2381. 2010.PubMed/NCBI View Article : Google Scholar
30	Jung SM, Kim KW, Yang CW, Park SH and Ju JH: Cytokine-mediated bone destruction in rheumatoid arthritis. J Immunol Res. 2014(263625)2014.PubMed/NCBI View Article : Google Scholar
31	Karmakar S, Kay J and Gravallese EM: Bone damage in rheumatoid arthritis: Mechanistic insights and approaches to prevention. Rheum Dis Clin North Am. 36:385–404. 2010.PubMed/NCBI View Article : Google Scholar
32	Azuma Y, Kaji K, Katogi R, Takeshita S and Kudo A: Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem. 275:4858–4864. 2000.PubMed/NCBI View Article : Google Scholar
33	Gilbert L, He X, Farmer P, Boden S, Kozlowski M, Rubin J and Nanes MS: Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. Endocrinology. 141:3956–3964. 2000.PubMed/NCBI View Article : Google Scholar
34	Lofvall H, Newbould H, Karsdal MA, Dziegiel MH, Richter J, Henriksen K and Thudium CS: Osteoclasts degrade bone and cartilage knee joint compartments through different resorption processes. Arthritis Res Ther. 20(67)2018.PubMed/NCBI View Article : Google Scholar
35	van Schouwenburg PA, Rispens T and Wolbink GJ: Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol. 9:164–172. 2013.PubMed/NCBI View Article : Google Scholar
36	Scott DL and Kingsley GH: Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med. 355:704–712. 2006.
37	Bedair H, Cha TD and Hansen VJ: Economic benefit to society at large of total knee arthroplasty in younger patients: A Markov analysis. J Bone Joint Surg Am. 96:119–126. 2014.PubMed/NCBI View Article : Google Scholar
38	Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet. 386:743–800. 2015.PubMed/NCBI View Article : Google Scholar
39	Chow YY and Chin KY: The role of inflammation in the pathogenesis of osteoarthritis. Mediators Inflamm. 2020(8293921)2020.PubMed/NCBI View Article : Google Scholar
40	Chisari E, Yaghmour KM and Khan WS: The effects of TNF-alpha inhibition on cartilage: A systematic review of preclinical studies. Osteoarthritis Cartilage. 28:708–718. 2020.PubMed/NCBI View Article : Google Scholar