Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2016

Open Access 01-12-2016 | Research article

Catabolic and proinflammatory effects of leptin in chondrocytes are regulated by suppressor of cytokine signaling-3

Authors: Anna Koskinen-Kolasa, Katriina Vuolteenaho, Riku Korhonen, Teemu Moilanen, Eeva Moilanen

Published in: Arthritis Research & Therapy | Issue 1/2016

Login to get access

Abstract

Background

Previous studies provide evidence that adipokine leptin increases production of catabolic and proinflammatory factors in chondrocytes and serves as a link between obesity and osteoarthritis (OA). However, the magnitude of the response to leptin treatment varies greatly between chondrocytes from different donor patients. In the present study, we investigated the regulatory role of suppressor of cytokine signaling-3 (SOCS-3) in the leptin-induced responses in OA cartilage.

Methods

Cartilage and synovial fluid samples from 97 patients with OA undergoing knee replacement surgery were collected. Cartilage samples were cultured with leptin (10 μg/ml), and the levels of proinflammatory and catabolic factors in synovial fluid and in the cartilage culture media, and SOCS-3 expression in the cartilage were measured. The role of SOCS-3 in leptin signaling was further studied in H4 murine chondrocytes by downregulating SOCS-3 with siRNA.

Results

Leptin-induced expression of matrix metalloproteinases MMP-1, MMP-3, MMP-13, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were higher in the cartilage samples with low SOCS-3 expression. Accordingly, downregulation of SOCS-3 by siRNA in H4 chondrocytes led to enhanced leptin-induced expression of MMP-3, MMP-13, IL-6 and iNOS. Synovial fluid leptin was associated positively, and cartilage SOCS-3 negatively with synovial fluid levels of MMPs in a multivariate model in obese (body mass index (BMI) >30 kg/m2) but not in non-obese (BMI <30 kg/m2) patients.

Conclusions

Our results show, for the first time, that SOCS-3 regulates leptin-induced responses in cartilage, and could thus be a future drug target in the treatment or prevention of OA, especially in obese patients.
Literature
1.
Vuolteenaho K, Koskinen A, Moilanen E. Leptin - a link between obesity and osteoarthritis. Applications for prevention and treatment. Basic Clin Pharmacol Toxicol. 2014;114:103–8.CrossRefPubMed
2.
Scotece M, Conde J, Vuolteenaho K, Koskinen A, Lopez V, Gomez-Reino J, Lago F, Moilanen E, Gualillo O. Adipokines as drug targets in joint and bone disease. Drug Discov Today. 2014;19:241–58.CrossRefPubMed
3.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–32.CrossRefPubMed
4.
Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334:292–5.CrossRefPubMed
5.
Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P, Pottie P. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum. 2003;48:3118–29.CrossRefPubMed
6.
Simopoulou T, Malizos KN, Iliopoulos D, Stefanou N, Papatheodorou L, Ioannou M, Tsezou A. Differential expression of leptin and leptin's receptor isoform (Ob-Rb) mRNA between advanced and minimally affected osteoarthritic cartilage; effect on cartilage metabolism. Osteoarthritis Cartilage. 2007;15:872–83.CrossRefPubMed
7.
Iliopoulos D, Malizos KN, Tsezou A. Epigenetic regulation of leptin affects MMP-13 expression in osteoarthritic chondrocytes: possible molecular target for osteoarthritis therapeutic intervention. Ann Rheum Dis. 2007;66:1616–21.CrossRefPubMedPubMedCentral
8.
Vuolteenaho K, Koskinen A, Moilanen T, Moilanen E. Leptin levels are increased and its negative regulators, SOCS-3 and sOb-R are decreased in obese patients with osteoarthritis: a link between obesity and osteoarthritis. Ann Rheum Dis. 2012;71:1912–3.CrossRefPubMed
9.
Blagojevic M, Jinks C, Jeffery A, Jordan KP. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage. 2010;18:24–33.CrossRefPubMed
10.
Kloppenburg M, Kwok WY. Hand osteoarthritis–a heterogeneous disorder. Nat Rev Rheumatol. 2011;8:22–31.CrossRefPubMed
11.
Otero M, Gomez Reino JJ, Gualillo O. Synergistic induction of nitric oxide synthase type II: in vitro effect of leptin and interferon-gamma in human chondrocytes and ATDC5 chondrogenic cells. Arthritis Rheum. 2003;48:404–9.CrossRefPubMed
12.
Otero M, Lago R, Lago F, Reino JJ, Gualillo O. Signalling pathway involved in nitric oxide synthase type II activation in chondrocytes: synergistic effect of leptin with interleukin-1. Arthritis Res Ther. 2005;7:R581–91.CrossRefPubMedPubMedCentral
13.
Otero M, Lago R, Gomez R, Lago F, Gomez-Reino JJ, Gualillo O. Phosphatidylinositol 3-kinase, MEK-1 and p38 mediate leptin/interferon-gamma synergistic NOS type II induction in chondrocytes. Life Sci. 2007;81:1452–60.CrossRefPubMed
14.
Tong KM, Shieh DC, Chen CP, Tzeng CY, Wang SP, Huang KC, Chiu YC, Fong YC, Tang CH. Leptin induces IL-8 expression via leptin receptor, IRS-1, PI3K, Akt cascade and promotion of NF-kappaB/p300 binding in human synovial fibroblasts. Cell Signal. 2008;20:1478–88.CrossRefPubMed
15.
Vuolteenaho K, Koskinen A, Kukkonen M, Nieminen R, Päivärinta U, Moilanen T, Moilanen E. Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage--mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production. Mediators Inflamm. 2009;2009:345838.
16.
Bao JP, Chen WP, Feng J, Hu PF, Shi ZL, Wu LD. Leptin plays a catabolic role on articular cartilage. Mol Biol Rep. 2010;37:3265–72.CrossRefPubMed
17.
Pallu S, Francin PJ, Guillaume C, Gegout-Pottie P, Netter P, Mainard D, Terlain B, Presle N. Obesity affects the chondrocyte responsiveness to leptin in patients with osteoarthritis. Arthritis Res Ther. 2010;12:R112.CrossRefPubMedPubMedCentral
18.
Koskinen A, Vuolteenaho K, Nieminen R, Moilanen T, Moilanen E. Leptin enhances MMP-1, MMP-3 and MMP-13 production in human osteoarthritic cartilage and correlates with MMP-1 and MMP-3 in synovial fluid from OA patients. Clin Exp Rheumatol. 2011;29:57–64.PubMed
19.
Hui W, Litherland GJ, Elias MS, Kitson GI, Cawston TE, Rowan AD, Young DA. Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases. Ann Rheum Dis. 2012;71:455–62.CrossRefPubMed
20.
21.
Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol. 2007;7:454–65.CrossRefPubMed
22.
St-Pierre J, Tremblay ML. Modulation of leptin resistance by protein tyrosine phosphatases. Cell Metab. 2012;15:292–7.CrossRefPubMed
23.
24.
Myers Jr MG. Leptin receptor signaling and the regulation of mammalian physiology. Recent Prog Horm Res. 2004;59:287–304.CrossRefPubMed
25.
Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, Torisu T, Chien KR, Yasukawa H, Yoshimura A. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med. 2004;10:739–43.CrossRefPubMed
26.
Dubern B, Clement K. Leptin and leptin receptor-related monogenic obesity. Biochimie. 2012;94:2111–5.CrossRefPubMed
27.
Smeets RL, Veenbergen S, Arntz OJ, Bennink MB, Joosten LA, van den Berg WB, van de Loo FA. A novel role for suppressor of cytokine signaling 3 in cartilage destruction via induction of chondrocyte desensitization toward insulin-like growth factor. Arthritis Rheum. 2006;54:1518–28.CrossRefPubMed
28.
de Andres MC, Imagawa K, Hashimoto K, Gonzalez A, Goldring MB, Roach HI, Oreffo RO. Suppressors of cytokine signalling (SOCS) are reduced in osteoarthritis. Biochem Biophys Res Commun. 2011;407:54–9.CrossRefPubMedPubMedCentral
29.
van de Loo FA, Veenbergen S, van den Brand B, Bennink MB, Blaney-Davidson E, Arntz OJ, van Beuningen HM, van der Kraan PM, van den Berg WB. Enhanced suppressor of cytokine signaling 3 in arthritic cartilage dysregulates human chondrocyte function. Arthritis Rheum. 2012;64:3313–23.CrossRefPubMed
30.
Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, Christy W, Cooke TD, Greenwald R, Hochberg M. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 1986;29:1039–49.CrossRefPubMed
31.
van Beuningen HM, Stoop R, Buma P, Takahashi N, van der Kraan PM, van den Berg WB. Phenotypic differences in murine chondrocyte cell lines derived from mature articular cartilage. Osteoarthritis Cartilage. 2002;10:977–86.CrossRefPubMed
32.
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15 N]nitrate in biological fluids. Anal Biochem. 1982;126:131–8.CrossRefPubMed
33.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001;25:402–8.CrossRefPubMed
34.
Hovsepian E, Penas F, Siffo S, Mirkin GA, Goren NB. IL-10 inhibits the NF-kappaB and ERK/MAPK-mediated production of pro-inflammatory mediators by up-regulation of SOCS-3 in Trypanosoma cruzi-infected cardiomyocytes. PLoS One. 2013;8:e79445.CrossRefPubMedPubMedCentral
35.
Chhabra JK, Chattopadhyay B, Paul BN. SOCS3 dictates the transition of divergent time-phased events in granulocyte TNF-alpha signaling. Cell Mol Immunol. 2014;11:105–6.CrossRefPubMed
36.
Isomäki P, Alanära T, Isohanni P, Lagerstedt A, Korpela M, Moilanen T, Visakorpi T, Silvennoinen O. The expression of SOCS is altered in rheumatoid arthritis. Rheumatology (Oxford). 2007;46:1538–46.
37.
Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, Komiya S, Kosai K, Hanakawa Y, Hashimoto K, Nagata K, Yoshimura A. Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest. 2001;108:1781–8.CrossRefPubMedPubMedCentral
38.
Veenbergen S, Bennink MB, Affandi AJ, Bessis N, Biton J, Arntz OJ, van den Berg WB, van de Loo FA. A pivotal role for antigen-presenting cells overexpressing SOCS3 in controlling invariant NKT cell responses during collagen-induced arthritis. Ann Rheum Dis. 2011;70:2167–75.CrossRefPubMed
39.
Wong PK, Egan PJ, Croker BA, O'Donnell K, Sims NA, Drake S, Kiu H, McManus EJ, Alexander WS, Roberts AW, Wicks IP. SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis. J Clin Invest. 2006;116:1571–81.CrossRefPubMedPubMedCentral
40.
White CA, Nicola NA. SOCS3: An essential physiological inhibitor of signaling by interleukin-6 and G-CSF family cytokines. JAKSTAT. 2013;2:e25045.PubMedPubMedCentral
41.
Tsuchida AI, Beekhuizen M, ’t Hart MC, Radstake TR, Dhert WJ, Saris DB, van Osch GJ, Creemers LB. Cytokine profiles in the joint depend on pathology, but are different between synovial fluid, cartilage tissue and cultured chondrocytes. Arthritis Res Ther. 2014;16:441. doi:10.​1186/​s13075-014-0441-0.CrossRefPubMedPubMedCentral
42.
White GE, Cotterill A, Addley MR, Soilleux EJ, Greaves DR. Suppressor of cytokine signalling protein SOCS3 expression is increased at sites of acute and chronic inflammation. J Mol Histol. 2011;42:137–51.CrossRefPubMedPubMedCentral
43.
Holter K, Wermter AK, Scherag A, Siegfried W, Goldschmidt H, Hebebrand J, Hinney A. Analysis of sequence variations in the suppressor of cytokine signaling (SOCS)-3 gene in extremely obese children and adolescents. BMC Med Genet. 2007;8:21.CrossRefPubMedPubMedCentral
44.
Toivanen AT, Heliövaara M, Impivaara O, Arokoski JP, Knekt P, Lauren H, Kröger H. Obesity, physically demanding work and traumatic knee injury are major risk factors for knee osteoarthritis–a population-based study with a follow-up of 22 years. Rheumatology (Oxford). 2010;49:308–14.
45.
Ding C, Parameswaran V, Cicuttini F, Burgess J, Zhai G, Quinn S, Jones G. Association between leptin, body composition, sex and knee cartilage morphology in older adults: the Tasmanian older adult cohort (TASOAC) study. Ann Rheum Dis. 2008;67:1256–61.CrossRefPubMed
46.
Ku JH, Lee CK, Joo BS, An BM, Choi SH, Wang TH, Cho HL. Correlation of synovial fluid leptin concentrations with the severity of osteoarthritis. Clin Rheumatol. 2009;28:1431–5.CrossRefPubMed
47.
Gandhi R, Takahashi M, Smith H, Rizek R, Mahomed NN. The synovial fluid adiponectin-leptin ratio predicts pain with knee osteoarthritis. Clin Rheumatol. 2010;29:1223–8.CrossRefPubMed
48.
Berry PA, Jones SW, Cicuttini FM, Wluka AE, Maciewicz RA. Temporal relationship between serum adipokines, biomarkers of bone and cartilage turnover, and cartilage volume loss in a population with clinical knee osteoarthritis. Arthritis Rheum. 2011;63:700–7.CrossRefPubMed
49.
Yusuf E, Ioan-Facsinay A, Bijsterbosch J, Klein-Wieringa I, Kwekkeboom J, Slagboom PE, Huizinga TW, Kloppenburg M. Association between leptin, adiponectin and resistin and long-term progression of hand osteoarthritis. Ann Rheum Dis. 2011;70:1282–4.CrossRefPubMed
50.
de Boer TN, van Spil WE, Huisman AM, Polak AA, Bijlsma JW, Lafeber FP, Mastbergen SC. Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage. Osteoarthritis Cartilage. 2012;20:846–53.CrossRefPubMed
51.
Massengale M, Reichmann WM, Losina E, Solomon DH, Katz JN. The relationship between hand osteoarthritis and serum leptin concentration in participants of the Third National Health and Nutrition Examination Survey. Arthritis Res Ther. 2012;14:R132.PubMedPubMedCentral
52.
53.
Karvonen-Gutierrez CA, Harlow SD, Mancuso P, Jacobson J, de Leon CFM, Nan B. Association of leptin levels with radiographic knee osteoarthritis among a cohort of midlife women. Arthritis Care Res (Hoboken). 2013;65:936–44.CrossRef
54.
Karvonen-Gutierrez CA, Harlow SD, Jacobson J, Mancuso P, Jiang Y. The relationship between longitudinal serum leptin measures and measures of magnetic resonance imaging-assessed knee joint damage in a population of mid-life women. Ann Rheum Dis. 2013;73:883–9.CrossRefPubMedPubMedCentral
55.
Fowler-Brown A, Kim DH, Shi L, Marcantonio E, Wee CC, Shmerling RH, Leveille S. The mediating effect of leptin on the relationship between body weight and knee osteoarthritis in older adults. Arthritis Rheumatol. 2015;67:169–75.CrossRefPubMedPubMedCentral
56.
Griffin TM, Huebner JL, Kraus VB, Guilak F. Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis. Arthritis Rheum. 2009;60:2935–44.CrossRefPubMedPubMedCentral
Metadata
Title
Catabolic and proinflammatory effects of leptin in chondrocytes are regulated by suppressor of cytokine signaling-3
Authors
Anna Koskinen-Kolasa
Katriina Vuolteenaho
Riku Korhonen
Teemu Moilanen
Eeva Moilanen
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2016
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-016-1112-0

Other articles of this Issue 1/2016

Arthritis Research & Therapy 1/2016 Go to the issue

Research article

Exercise therapy after ultrasound-guided corticosteroid injections in patients with subacromial pain syndrome: a randomized controlled trial

Research article

MMP-3 as a predictor for structural remission in RA patients treated with MTX monotherapy

Erratum

Erratum to: Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney

Research article

Collagen triple helix repeat containing 1 is a new promigratory marker of arthritic pannus

Research article

Antibodies to carbamylated α-enolase epitopes in rheumatoid arthritis also bind citrullinated epitopes and are largely indistinct from anti-citrullinated protein antibodies

Research article

Single-cell antibody nanowells: a novel technology in detecting anti-SSA/Ro60- and anti-SSB/La autoantibody-producing cells in peripheral blood of rheumatic disease patients
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits