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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Inflammation Research
Published in: Inflammation Research 4/2020

Open Access 01-04-2020 | Osteoarthrosis | Original Research Paper

Novel adipokine associated with OA: retinol binding protein 4 (RBP4) is produced by cartilage and is correlated with MMPs in osteoarthritis patients

Authors: Morena Scotece, Anna Koskinen-Kolasa, Antti Pemmari, Tiina Leppänen, Mari Hämäläinen, Teemu Moilanen, Eeva Moilanen, Katriina Vuolteenaho

Published in: Inflammation Research | Issue 4/2020

Login to get access

Abstract

Objective

Retinol binding protein 4 (RBP4) is a member of the lipocalin family and a vitamin A carrier in the blood. More recently, RBP4 has been described as an adipokine that is involved in insulin resistance and metabolic syndrome (MetS). As obesity, MetS and some adipokines contribute to the pathogenesis of osteoarthritis (OA), we investigated RBP4 in patients with OA.

Materials and methods

Cartilage, synovial fluid and blood samples were collected from 100 OA patients undergoing total knee replacement surgery. Primary chondrocytes and cartilage tissue were cultured to measure the RBP4 expression. The concentrations of RBP4, other adipokines (adipsin, adiponectin, leptin and resistin) and biomarkers of OA (COMP, MMP-1, MMP-3 and YKL-40) were measured by immunoassay, and gene expression was measured by next-generation RNA sequencing.

Results

The OA cartilage samples released RBP4 into the culture medium, and the levels correlated positively with the expression of the adipokines adipsin, adiponectin, leptin and resistin. RBP4 was the most prominently expressed of these adipokines in the OA chondrocytes, and the expression of the RBP4 receptors STRA6 (stimulated by retinoic acid gene homologue 6) and TLR4 (Toll-like receptor 4) was also detected. Within the cartilage culture medium, RBP4 showed a positive correlation with MMP-1, MMP-3 and YKL-40. RBP4 was also present in the synovial fluid from the OA patients and correlated positively with the concentrations of RBP4 found in the plasma and the cartilage culture medium. Plasma RBP4 concentrations also showed a positive correlation with MMP-3 and adipsin.

Conclusions

We show here, for the first time, that RBP4 is produced within OA joints and that it is associated with increased levels of adipokines and MMPs. The results suggest a role for RBP4 in the pathogenesis of OA and as a possible target for the disease-modifying drugs for the treatment of OA.
Literature
1.
Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheumatol. 2008;58(1):26–35.CrossRef
2.
Chen D, Shen J, Zhao W, Wang T, Han L, Hamilton JL, et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res. 2017;5:16044.PubMedPubMedCentralCrossRef
3.
Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheumatol. 2012;64(6):1697–707.CrossRef
4.
Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12(10):580–92.PubMedPubMedCentralCrossRef
5.
Scotece M, Conde J, Vuolteenaho K, Koskinen A, López V, Gómez-Reino J, et al. Adipokines as drug targets in joint and bone disease. Drug Discov Today. 2014;19(3):241–58.PubMedCrossRef
6.
Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005;436(7049):356–62.PubMedCrossRef
7.
Tsutsumi C, Okuno M, Tannous L, Piantedosi R, Allan M, Goodman DS, et al. Retinoids and retinoid-binding protein expression in rat adipocytes. J Biol Chem. 1992;267(3):1805–10.PubMedCrossRef
8.
Newcomer ME, Ong DE. Plasma retinol binding protein: structure and function of the prototypic lipocalin. Biochim Biophys Acta. 2000;1482(1–2):57–64.PubMedCrossRef
9.
Graham TE, Yang Q, Blüher M, Hammarstedt A, Ciaraldi TP, Henry RR, et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006;354(24):2552–633.PubMedCrossRef
10.
Cho YM, Youn BS, Lee H, Lee N, Min SS, Kwak SH, et al. Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes. Diabetes Care. 2006;29(11):2457–61.PubMedCrossRef
11.
Lee D-C, Lee J-W, Im J-A. Association of serum retinol binding protein 4 and insulin resistance in apparently healthy adolescents. Metabolism. 2007;56(3):327–31.PubMedCrossRef
12.
Gómez-Ambrosi J, Rodríguez A, Catalán V, Ramírez B, Silva C, Rotellar F, et al. Serum retinol-binding protein 4 is not increased in obesity or obesity-associated type 2 diabetes mellitus, but is reduced after relevant reductions in body fat following gastric bypass. Clin Endocrinol (Oxf). 2008;69(2):208–15.CrossRef
13.
Promintzer M, Krebs M, Todoric J, Luger A, Bischof MG, Nowotny P, et al. Insulin resistance is unrelated to circulating retinol binding protein and protein C inhibitor. J Clin Endocrinol Metab. 2007;92(11):4306–12.PubMedCrossRef
14.
Ng TWK, Watts GF, Barrett PHR, Rye K-A, Chan DC. Effect of weight loss on LDL and HDL kinetics in the metabolic syndrome: associations with changes in plasma retinol-binding protein-4 and adiponectin levels. Diabetes Care. 2007;30(11):2945–50.PubMedCrossRef
15.
Qi Q, Yu Z, Ye X, Zhao F, Huang P, Hu FB, et al. Elevated retinol-binding protein 4 levels are associated with metabolic syndrome in Chinese people. J Clin Endocrinol Metab. 2007;92(12):4827–34.PubMedCrossRef
16.
Ingelsson E, Lind L. Circulating retinol-binding protein 4 and subclinical cardiovascular disease in the elderly. Diabetes Care. 2009;32(4):733–5.PubMedCrossRef
17.
Muenzner M, Tuvia N, Deutschmann C, Witte N, Tolkachov A, Valai A, et al. Retinol-binding protein 4 and its membrane receptor STRA6 control adipogenesis by regulating cellular retinoid homeostasis and retinoic acid receptor α activity. Mol Cell Biol. 2013;33(20):4068–82.PubMedPubMedCentralCrossRef
18.
Kelly M, Widjaja-Adhi MAK, Palczewski G, von Lintig J. Transport of vitamin A across blood-tissue barriers is facilitated by STRA6. FASEB J. 2016;30(8):2985–95.PubMedPubMedCentralCrossRef
19.
Norseen J, Hosooka T, Hammarstedt A, Yore MM, Kant S, Aryal P, et al. Retinol-binding protein 4 inhibits insulin signaling in adipocytes by inducing proinflammatory cytokines in macrophages through a c-Jun N-terminal kinase- and toll-like receptor 4-dependent and retinol-independent mechanism. Mol Cell Biol. 2012;32(10):2010–9.PubMedPubMedCentralCrossRef
20.
Farjo KM, Farjo RA, Halsey S, Moiseyev G, Ma J-X. Retinol-binding protein 4 induces inflammation in human endothelial cells by an NADPH oxidase- and nuclear factor kappa B-dependent and retinol-independent mechanism. Mol Cell Biol. 2012;32(24):5103–15.PubMedPubMedCentralCrossRef
21.
Gao W, Wang H, Zhang L, Cao Y, Bao J-Z, Liu Z-X, et al. Retinol-binding protein 4 induces cardiomyocyte hypertrophy by activating TLR4/MyD88 pathway. Endocrinology. 2016;157(6):2282–93.PubMedPubMedCentralCrossRef
22.
Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. 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 Rheumatol. 1986;29(8):1039–49.
23.
Vuolteenaho K, Koskinen A, Kukkonen M, Nieminen R, Päivärinta U, Moilanen T, et al. Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage—mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production. Mediat Inflamm. 2009;2009:345838.CrossRef
24.
Koskinen A, Juslin S, Nieminen R, Moilanen T, Vuolteenaho K, Moilanen E. Adiponectin associates with markers of cartilage degradation in osteoarthritis and induces production of proinflammatory and catabolic factors through mitogen-activated protein kinase pathways. Arthritis Res Ther. 2011;13(6):R184.PubMedPubMedCentralCrossRef
25.
26.
27.
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–211.PubMedCrossRef
28.
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30(7):923–30.PubMedCrossRef
29.
30.
Kallio MA, Tuimala JT, Hupponen T, Klemelä P, Gentile M, Scheinin I, et al. Chipster: user-friendly analysis software for microarray and other high-throughput data. BMC Genomics. 2011;12:507.PubMedPubMedCentralCrossRef
31.
Jia W, Wu H, Bao Y, Wang C, Lu J, Zhu J, et al. Association of serum retinol-binding protein 4 and visceral adiposity in Chinese subjects with and without type 2 diabetes. J Clin Endocrinol Metab. 2007;92(8):3224–9.PubMedCrossRef
32.
Conde J, Scotece M, López V, Gómez R, Lago F, Pino J, et al. Adiponectin and leptin induce VCAM-1 expression in human and murine chondrocytes. PLoS One. 2012;7(12):e52533.PubMedPubMedCentralCrossRef
33.
Francin P-J, Abot A, Guillaume C, Moulin D, Bianchi A, Gegout-Pottie P, et al. Association between adiponectin and cartilage degradation in human osteoarthritis. Osteoarthr Cartil. 2014;22(3):519–26.CrossRef
34.
Scotece M, Pérez T, Conde J, Abella V, López V, Pino J, et al. Adipokines induce pro-inflammatory factors in activated CD4+ T cells from osteoarthritis patient. J Orthop Res. 2017;35(6):1299–303.PubMedCrossRef
35.
Koskinen A, Vuolteenaho K, Moilanen T, Moilanen E. Resistin as a factor in osteoarthritis: synovial fluid resistin concentrations correlate positively with interleukin 6 and matrix metalloproteinases MMP-1 and MMP-3. Scand J Rheumatol. 2014;43(3):249–53.PubMedCrossRef
36.
Philp AM, Collier RL, Grover LM, Davis ET, Jones SW. Resistin promotes the abnormal Type I collagen phenotype of subchondral bone in obese patients with end stage hip osteoarthritis. Sci Rep. 2017;7(1):4042.PubMedPubMedCentralCrossRef
37.
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(1):57–64.
38.
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(11):1912–3.PubMedCrossRef
39.
Vuolteenaho K, Koskinen A, Moilanen E. Leptin—a link between obesity and osteoarthritis. Applications for prevention and treatment. Basic Clin Pharmacol Toxicol. 2014;114(1):103–8.CrossRef
40.
Scotece M, Mobasheri A. Leptin in osteoarthritis: focus on articular cartilage and chondrocytes. Life Sci. 2015;140:75–8.PubMedCrossRef
41.
Martel-Pelletier J, Raynauld J-P, Dorais M, Abram F, Pelletier J-P. The levels of the adipokines adipsin and leptin are associated with knee osteoarthritis progression as assessed by MRI and incidence of total knee replacement in symptomatic osteoarthritis patients: a post hoc analysis. Rheumatology (Oxford). 2016;55(4):680–8.CrossRef
42.
Valverde-Franco G, Tardif G, Mineau F, Paré F, Lussier B, Fahmi H, et al. High in vivo levels of adipsin lead to increased knee tissue degradation in osteoarthritis: data from humans and animal models. Rheumatology (Oxford). 2018;57(10):1851–60.CrossRef
43.
Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P, et al. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheumatol. 2003;48(11):3118–299.CrossRef
44.
Moraes-Vieira PM, Yore MM, Dwyer PM, Syed I, Aryal P, Kahn BB. RBP4 activates antigen-presenting cells, leading to adipose tissue inflammation and systemic insulin resistance. Cell Metab. 2014;19(3):512–26.PubMedPubMedCentralCrossRef
45.
Sakkas LI, Scanzello C, Johanson N, Burkholder J, Mitra A, Salgame P, et al. T cells and T-cell cytokine transcripts in the synovial membrane in patients with osteoarthritis. Clin Diagn Lab Immunol. 1998;5(4):430–7.PubMedPubMedCentralCrossRef
46.
47.
Nakamura H, Yoshino S, Kato T, Tsuruha J, Nishioka K. T-cell mediated inflammatory pathway in osteoarthritis. Osteoarthr Cartil. 1999;7(4):401–2.CrossRef
48.
Ishii H, Tanaka H, Katoh K, Nakamura H, Nagashima M, Yoshino S. Characterization of infiltrating T cells and Th1/Th2-type cytokines in the synovium of patients with osteoarthritis. Osteoarthr Cartil. 2002;10(4):277–81.CrossRef
49.
Abella V, Scotece M, Conde J, Pino J, Gonzalez-Gay MA, Gómez-Reino JJ, et al. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat Rev Rheumatol. 2017;13(2):100–9.PubMedCrossRef
50.
Du M, Martin A, Hays F, Johnson J, Farjo RA, Farjo KM. Serum retinol-binding protein-induced endothelial inflammation is mediated through the activation of toll-like receptor 4. Mol Vis. 2017;23:185–97.PubMedPubMedCentral
51.
52.
Li H, Cao G, Zhang N, Lou T, Wang Q, Zhang Z, et al. RBP4 regulates trophoblastic cell proliferation and invasion via the PI3K/AKT signaling pathway. Mol Med Rep. 2018;18(3):2873–9.PubMedPubMedCentral
53.
Kraus VB, Burnett B, Coindreau J, Cottrell S, Eyre D, Gendreau M, et al. Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis. Osteoarthr Cartil. 2011;19(5):515–42.CrossRef
54.
Lohmander LS, Brandt KD, Mazzuca SA, Katz BP, Larsson S, Struglics A, et al. Use of the plasma stromelysin (matrix metalloproteinase 3) concentration to predict joint space narrowing in knee osteoarthritis. Arthritis Rheumatol. 2005;52(10):3160–7.CrossRef
55.
Aeberli I, Biebinger R, Lehmann R, L’allemand D, Spinas GA, Zimmermann MB. Serum retinol-binding protein 4 concentration and its ratio to serum retinol are associated with obesity and metabolic syndrome components in children. J Clin Endocrinol Metab. 2007;92(11):4359–65.CrossRef
56.
Reinehr T, Stoffel-Wagner B, Roth CL. Retinol-binding protein 4 and its relation to insulin resistance in obese children before and after weight loss. J Clin Endocrinol Metab. 2008;93(6):2287–93.PubMedPubMedCentralCrossRef
57.
Friebe D, Neef M, Erbs S, Dittrich K, Kratzsch J, Kovacs P, et al. Retinol binding protein 4 (RBP4) is primarily associated with adipose tissue mass in children. Int J Pediatr Obes. 2011;6(2–2):e345–e352352.PubMedCrossRef
58.
Gavi S, Qurashi S, Stuart LM, Lau R, Melendez MM, Mynarcik DC, et al. Influence of age on the association of retinol-binding protein 4 with metabolic syndrome. Obesity (Silver Spring). 2008;16(4):893–5.CrossRef
59.
Lim S, Yoon JW, Choi SH, Park YJ, Lee JJ, Park JH, et al. Combined impact of adiponectin and retinol-binding protein 4 on metabolic syndrome in elderly people: the Korean Longitudinal Study on Health and Aging. Obesity (Silver Spring). 2010;18(4):826–32.CrossRef
60.
Sun L, Qi Q, Zong G, Ye X, Li H, Liu X, et al. Elevated plasma retinol-binding protein 4 is associated with increased risk of type 2 diabetes in middle-aged and elderly Chinese adults. J Nutr. 2014;144(5):722–8.PubMedCrossRef
61.
Bobbert P, Weithäuser A, Andres J, Bobbert T, Kühl U, Schultheiss HP, et al. Increased plasma retinol binding protein 4 levels in patients with inflammatory cardiomyopathy. Eur J Heart Fail. 2009;11(12):1163–8.PubMedCrossRef
62.
Huang G, Wang D, Khan UI, Zeb I, Manson JE, Miller V, et al. Associations between retinol-binding protein 4 and cardiometabolic risk factors and subclinical atherosclerosis in recently postmenopausal women: cross-sectional analyses from the KEEPS study. Cardiovasc Diabetol. 2012;11:52.PubMedPubMedCentralCrossRef
63.
Lambadiari V, Kadoglou NPE, Stasinos V, Maratou E, Antoniadis A, Kolokathis F, et al. Serum levels of retinol-binding protein-4 are associated with the presence and severity of coronary artery disease. Cardiovasc Diabetol. 2014;13:121.PubMedPubMedCentralCrossRef
Metadata
Title
Novel adipokine associated with OA: retinol binding protein 4 (RBP4) is produced by cartilage and is correlated with MMPs in osteoarthritis patients
Authors
Morena Scotece
Anna Koskinen-Kolasa
Antti Pemmari
Tiina Leppänen
Mari Hämäläinen
Teemu Moilanen
Eeva Moilanen
Katriina Vuolteenaho
Publication date
01-04-2020
Publisher
Springer International Publishing
Published in
Inflammation Research / Issue 4/2020
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-020-01326-0

Other articles of this Issue 4/2020

Inflammation Research 4/2020 Go to the issue

Original Research Paper

NKp46+ lamina propria natural killer cells undergo metabolic reprogramming in a mouse experimental colitis model

Original Research Paper

Chondro-protective effects of celastrol on osteoarthritis through autophagy activation and NF-κB signaling pathway inhibition

Original Research Paper

Emodin alleviated pulmonary inflammation in rats with LPS-induced acute lung injury through inhibiting the mTOR/HIF-1α/VEGF signaling pathway

Original Research Paper

Aloperine suppresses LPS-induced macrophage activation through inhibiting the TLR4/NF-κB pathway

Review

Macrophage mediation in normal and diabetic wound healing responses

Review

Association between serum amyloid A levels and coronary heart disease: a systematic review and meta-analysis of 26 studies

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

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

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