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01-11-2015 | Original Article

Hyperleptinemia suppresses aggravation of arthritis of collagen-antibody-induced arthritis in mice

Authors: Tadashi Okano, Tatsuya Koike, Masahiro Tada, Yuko Sugioka, Kenji Mamoto, Kentaro Inui, Hiroyuki Okihana, Ken Ebihara, Kazuwa Nakao, Hiroaki Nakamura

Published in: Journal of Orthopaedic Science | Issue 6/2015

Abstract

Background

Leptin is an adipocytokine produced by adipocytes and controlling body weight. It is unclear whether leptin works as a proinflammatory or an anti-inflammatory cytokine. We investigated the effects of hyperleptinemia on leptin transgenic (LepTg) mice in terms of cartilage destruction, bone destruction, joint synovitis, and serum cytokine levels by using a mouse model of collagen-antibody-induced arthritis (CAIA).

Methods

CAIA was induced for female age-matched 6- to 8-week-old C57BL/6 J control mice and LepTg mice. Mice were injected intraperitoneally with 5 mg of a combination of monoclonal antibody specific for type II collagen on day 0 and 12.5 mg of lipopolysaccharide (LPS) on day 3. Clinical evaluation of arthritis was monitored for 14 days, and hind paws were examined clinically and histologically. Serum cytokine levels of interleukin (IL)-1β, IL-6, IL-10, and IL-17 and tumor necrosis factor alpha (TNF-α) were also analyzed on days 0 and 5. Moreover, THP-1 cells, which are human monocytic cell line derived from an acute monocytic leukemia patient, were cultured and differentiated into macrophages. The effects of leptin on messenger RNA (mRNA) expression of IL-6 were examined by real-time quantitative polymerase chain reaction (RT-PCR).

Results

Serum leptin concentrations were approximately ninefold higher in LepTg mice (62.0 ± 20.7 ng/ml) than in control mice (7.2 ± 0.5 ng/ml). Severity of clinical paw swelling, arthritis score, synovial hyperplasia, and cartilage damage were suppressed in LepTg mice with CAIA. Although serum cytokine levels of IL-1β, IL-17, and IL-10 and TNF-α showed no significant changes in two mice, serum levels of IL-6 in LepTg mice were suppressed at day 5. Moreover, in vitro study showed that IL-6 elevation following LPS exposure in THP-1 cells was suppressed with high leptin concentrations.

Conclusion

Our finding suggests that hyperleptinemia suppress IL-6 responses and progression of joint inflammation. Leptin may play an anti-inflammatory role under hyperleptinemia.

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(6505):425–32.CrossRefPubMed

Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269(5223):543–6.CrossRefPubMed

Janik JE, Curti BD, Considine RV, Rager HC, Powers GC, Alvord WG, Smith JW, Gause BL, Kopp WC. Interleukin 1 alpha increases serum leptin concentrations in humans. J Clin Endocrinol Metab. 1997;82(9):3084–6.PubMed

Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol. 2000;68(4):437–46.PubMed

Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS, Bulkley GB, Bao C, Noble PW, Lane MD, Diehl AM. Leptin regulates proinflammatory immune responses. FASEB J. 1998;12(1):57–65.PubMed

Faggioni R, Fantuzzi G, Gabay C, Moser A, Dinarello CA, Feingold KR, Grunfeld C. Leptin deficiency enhances sensitivity to endotoxin-induced lethality. Am J Physiol. 1999;276(1 Pt 2):R136–42.PubMed

Popa C, Netea MG, Radstake TR, van Riel PL, Barrera P, van der Meer JW. Markers of inflammation are negatively correlated with serum leptin in rheumatoid arthritis. Ann Rheum Dis. 2005;64(8):1195–8.PubMedCentralCrossRefPubMed

Bokarewa M, Bokarew D, Hultgren O, Tarkowski A. Leptin consumption in the inflamed joints of patients with rheumatoid arthritis. Ann Rheum Dis. 2003;62(10):952–6.PubMedCentralCrossRefPubMed

Hultgren OH, Tarkowski A. Leptin in septic arthritis: decreased levels during infection and amelioration of disease activity upon its administration. Arthritis Res. 2001;3(6):389–94.PubMedCentralCrossRefPubMed

10.

Otero M, Lago R, Gomez R, Lago F, Dieguez C, Gómez-Reino JJ, Gualillo O. Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65(9):1198–201.PubMedCentralCrossRefPubMed

11.

Rho YH, Solus J, Sokka T, Oeser A, Chung CP, Gebretsadik T, Shintani A, Pincus T, Stein CM. Adipocytokines are associated with radiographic joint damage in rheumatoid arthritis. Arthritis Rheum. 2009;60(7):1906–14.PubMedCentralCrossRefPubMed

12.

Hizmetli S, Kisa M, Gokalp N, Bakici MZ. Are plasma and synovial fluid leptin levels correlated with disease activity in rheumatoid arthritis ? Rheumatol Int. 2007;27(4):335–8.CrossRefPubMed

13.

Wisłowska M, Rok M, Jaszczyk B, Stepień K, Cicha M. Serum leptin in rheumatoid arthritis. Rheumatol Int. 2007;27(10):947–54.CrossRefPubMed

14.

Baker JF, Ostergaard M, George M, Shults J, Emery P, Baker DG, Conaghan PG. Greater body mass independently predicts less radiographic progression on X-ray and MRI over 1–2 years. Ann Rheum Dis. 2014;73(11):1923–8.CrossRefPubMed

15.

Sugioka Y, Tada M, Okano T, Nakamura H, Koike T. Acquired leptin resistance by high-fat feeding reduces inflammation from collagen antibody-induced arthritis in mice. Clin Exp Rheumatol. 2012;30(5):707–13.PubMed

16.

Ogawa Y, Masuzaki H, Hosoda K, Aizawa-Abe M, Suga J, Suda M, Ebihara K, Iwai H, Matsuoka N, Satoh N, Odaka H, Kasuga H, Fujisawa Y, Inoue G, Nishimura H, Yoshimasa Y, Nakao K. Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin. Diabetes. 1999;48(9):1822–9.CrossRefPubMed

17.

Terato K, Hasty KA, Reife RA, Cremer MA, Kang AH, Stuart JM. Induction of arthritis with monoclonal antibodies to collagen. J Immunol. 1992;148(7):2103–8.PubMed

18.

Mankin HJ, Dorfman H, Lippiello L, Zarins A. Biochemical and metabolic abnormalities in articular cartilage from osteo-arthritic human hips. II. Correlation of morphology with biochemical and metabolic data. J Bone Joint Surg Am. 1971;53(3):523–37.PubMed

19.

Su J, Xie Q, Wilson I, Li L. Differential regulation and role of interleukin-1 receptor associated kinase-M in innate immunity signaling. Cell Signal. 2007;19(7):1596–601.PubMedCentralCrossRefPubMed

20.

Kim SJ. Leptin potentiates Prevotella intermedia lipopolysaccharide-induced production of TNF-alpha in monocyte-derived macrophages. J Periodontal Implant Sci. 2010;40(3):119–24.PubMedCentralCrossRefPubMed

21.

Gabay C, Dreyer M, Pellegrinelli N, Chicheportiche R, Meier CA. Leptin directly induces the secretion of interleukin 1 receptor antagonist in human monocytes. J Clin Endocrinol Metab. 2001;86(2):783–91.PubMed

22.

Nowell MA, Williams AS, Carty SA, Scheller J, Hayes AJ, Jones GW, Richards PJ, Slinn S, Ernst M, Jenkins BJ, Topley N, Rose-John S, Jones SA. Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis. J Immunol. 2009;182(1):613–22.CrossRefPubMed

23.

Anandacoomarasamy A, Caterson I, Sambrook P, Fransen M, March L. The impact of obesity on the musculoskeletal system. Int J Obes (Lond). 2008;32(2):211–22.CrossRef

24.

Felson DT, Anderson JJ, Naimark A, Walker AM, Meenan RF. Obesity and knee osteoarthritis. The Framingham Study. Ann Intern Med. 1988;109(1):18–24.CrossRefPubMed

25.

Toyoda T, Kamei Y, Kato H, Sugita S, Takeya M, Suganami T, Ogawa Y. Effect of peroxisome proliferator-activated receptor-alpha ligands in the interaction between adipocytes and macrophages in obese adipose tissue. Obesity (Silver Spring). 2008;16(6):1199–207.CrossRef

26.

Otero M, Lago R, Lago F, Casanueva FF, Dieguez C, Gómez-Reino JJ, Gualillo O. Leptin, from fat to inflammation: old questions and new insights. FEBS Lett. 2005;579(2):295–301.CrossRefPubMed

27.

Bernotiene E, Palmer G, Gabay C. The role of leptin in innate and adaptive immune responses. Arthritis Res Ther. 2006;8(5):217.PubMedCentralCrossRefPubMed

28.

Deng J, Liu Y, Yang M, Wang S, Zhang M, Wang X, Ko KH, Hua Z, Sun L, Cao X, Lu L. Leptin exacerbates collagen-induced arthritis via enhancement of Th17 cell response. Arthritis Rheum. 2012;64(11):3564–73.CrossRefPubMed

29.

Tian G, Liang JN, Wang ZY, Zhou D. Emerging role of leptin in rheumatoid arthritis. Clin Exp Immunol. 2014;177(3):557–70.PubMedCentralCrossRefPubMed

30.

Lee FY, Li Y, Yang EK, Yang SQ, Lin HZ, Trush MA, Dannenberg AJ, Diehl AM. Phenotypic abnormalities in macrophages from leptin-deficient, obese mice. Am J Physiol. 1999;276(2 Pt 1):C386–94.PubMed

31.

Muraoka S, Kusunoki N, Takahashi H, Tsuchiya K, Kawai S. Leptin stimulates interleukin-6 production via janus kinase 2/signal transducer and activator of transcription 3 in rheumatoid synovial fibroblasts. Clin Exp Rheumatol. 2013;31(4):589–95.PubMed

Title: Hyperleptinemia suppresses aggravation of arthritis of collagen-antibody-induced arthritis in mice
Authors: Tadashi Okano
Tatsuya Koike
Masahiro Tada
Yuko Sugioka
Kenji Mamoto
Kentaro Inui
Hiroyuki Okihana
Ken Ebihara
Kazuwa Nakao
Hiroaki Nakamura
Publication date: 01-11-2015
Publisher: Springer Japan
Published in: Journal of Orthopaedic Science / Issue 6/2015
Print ISSN: 0949-2658
Electronic ISSN: 1436-2023
DOI: https://doi.org/10.1007/s00776-015-0768-7

At a glance: The STEP trials

Springer Medicine

Hyperleptinemia suppresses aggravation of arthritis of collagen-antibody-induced arthritis in mice

Abstract

Background

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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