Background/Aims: Chronic inflammation during childhood often leads to impaired bone growth and reduced adult height. Proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α synergistically impair bone growth in vitro. We hypothesized that biologic agents may rescue bones from cytokine-induced growth impairment and that insulin growth factor (IGF)-I may potentiate such an effect. Methodology: Metatarsal bones from fetal Sprague-Dawley rats (19–20 days p.c.) were treated with IL-1β plus TNF-α, or the combination of these cytokines with anakinra (IL-1 receptor antagonist), etanercept (TNF-inhibitor) and/or IGF-I. The bones were measured and growth expressed as percent increase in bone length over the 7-day culture period. Results: When exposed to IL-1β plus TNF-α (10 + 10 ng/ml), bone growth was markedly suppressed (6.6 ± 1.4 vs. 50.6 ± 2.5% in control bones; p < 0.001). The growth of cytokine exposed bones (IL-1β plus TNF-α) was dose-dependently rescued by anakinra (0.05–500 µg/ml) or etanercept (0.5–500 µg/ml); at the highest concentrations, growth was similar as in control bones never exposed to cytokines. Also when combining IGF-I (100 ng/ml) and relatively low concentrations of anakinra (0.05 µg/ml) or etanercept (5 µg/ml), growth was rescued in an additive way. Conclusion: Etanercept and anakinra efficiently and dose-dependently prevent cytokine-induced bone growth impairment, and combination with IGF-I further improves bone growth.

Keywords:
Anakinra, Etanercept, Impaired bone growth, Reduced adult height
1.
Cezard JP, Touati G, Alberti C, Hugot JP, Brinon C, Czernichow P: Growth in paediatric Crohn’s disease. Horm Res 2002;58(suppl 1):11–15.
2.
Simon D, Fernando C, Czernichow P, Prieur AM: Linear growth and final height in patients with systemic juvenile idiopathic arthritis treated with longterm glucocorticoids. J Rheumatol 2002;29:1296–1300.
3.
Polito C, Strano CG, Olivieri AN, Alessio M, Iammarrone CS, Todisco N, Papale MR: Growth retardation in non-steroid treated juvenile rheumatoid arthritis. Scand J Rheumatol 1997;26:99–103.
4.
Ballinger AB, Azooz O, El-Haj T, Poole S, Farthing MJ: Growth failure occurs through a decrease in insulin-like growth factor 1 which is independent of undernutrition in a rat model of colitis. Gut 2000;46:694–700.
5.
Funakoshi K, Sugimura K, Anezaki K, Bannai H, Ishizuka K, Asakura H: Spectrum of cytokine gene expression in intestinal mucosal lesions of Crohn’s disease and ulcerative colitis. Digestion 1998;59:73–78.
6.
Kutukculer N, Caglayan S, Aydogdu F: Study of pro-inflammatory (TNF-alpha, IL-1alpha, IL-6) and T-cell-derived (IL-2, IL-4) cytokines in plasma and synovial fluid of patients with juvenile chronic arthritis: correlations with clinical and laboratory parameters. Clin Rheumatol 1998;17:288–292.
7.
Yilmaz M, Kendirli SG, Altintas D, Bingol G, Antmen B: Cytokine levels in serum of patients with juvenile rheumatoid arthritis. Clin Rheumatol 2001;20:30–35.
8.
Macrae VE, Wong SC, Smith W, Gracie A, McInnes I, Galea P, Gardner-Medwin J, Farquharson C, Ahmed SF: Cytokine profiling and in vitro studies of murine bone growth using biological fluids from children with juvenile idiopathic arthritis. Clin Endocrinol (Oxf) 2007;67:442–448.
9.
De Benedetti F, Alonzi T, Moretta A, Lazzaro D, Costa P, Poli V, Martini A, Ciliberto G, Fattori E: Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation. J Clin Invest 1997;99:643–650.
10.
Mainardi GL, Saleri R, Tamanini C, Baratta M: Effects of interleukin-1-beta, interleukin-6 and tumor necrosis factor-alpha, alone or in association with hexarelin or galanin, on growth hormone gene expression and growth hormone release from pig pituitary cells. Horm Res 2002;58:180–186.
11.
Martensson K, Chrysis D, Sävendahl L: Interleukin-1beta and TNF-alpha act in synergy to inhibit longitudinal growth in fetal rat metatarsal bones. J Bone Miner Res 2004;19:1805–1812.
12.
MacRae VE, Farquharson C, Ahmed SF: The restricted potential for recovery of growth plate chondrogenesis and longitudinal bone growth following exposure to pro-inflammatory cytokines. J Endocrinol 2006;189:319–328.
13.
Bechtold S, Ripperger P, Dalla Pozza R, Bonfig W, Hafner R, Michels H, Schwarz HP: Growth hormone increases final height in patients with juvenile idiopathic arthritis: data from a randomized controlled study. J Clin Endocrinol Metab 2007;92:3013–3018.
14.
Chrysis D, Ritzen EM, Sävendahl L: Growth retardation induced by dexamethasone is associated with increased apoptosis of the growth plate chondrocytes. J Endocrinol 2003;176:331–337.
15.
Amgen: Kineret® (Anakinra) Product Monograph, 2006.
16.
Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J: Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med 2005;201:1479–1486.
17.
Lequerre T, Quartier P, Rosellini D, Alaoui F, De Bandt M, Mejjad O, Kone-Paut I, Michel M, Dernis E, Khellaf M, Limal N, Job-Deslandre C, Fautrel B, Le Loet X, Sibilia J: Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 2008;67:302–308.
18.
Ilowite N, Porras O, Reiff A, Rudge S, Punaro M, Martin A, Allen R, Harville T, Sun YN, Bevirt T, Aras G, Appleton B: Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study. Clin Rheumatol 2009;28:129–137.
19.
Wyeth: Enbrel® (Etanercept) US Prescribing Information, 2008.
20.
Lovell DJ, Reiff A, Ilowite NT, Wallace CA, Chon Y, Lin SL, Baumgartner SW, Giannini EH: Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis. Arthritis Rheum 2008;58:1496–1504.
21.
Yim DS, Zhou H, Buckwalter M, Nestorov I, Peck CC, Lee H: Population pharmacokinetic analysis and simulation of the time-concentration profile of etanercept in pediatric patients with juvenile rheumatoid arthritis. J Clin Pharmacol 2005;45:246–256.
22.
Schmeling H, Seliger E, Horneff G: Growth reconstitution in juvenile idiopathic arthritis treated with etanercept. Clin Exp Rheumatol 2003;21:779–784.
23.
Tynjala P, Lahdenne P, Vahasalo P, Kautiainen H, Honkanen V: Impact of anti-TNF treatment on growth in severe juvenile idiopathic arthritis. Ann Rheum Dis 2006;65:1044–1049.
24.
Vojvodich PF, Hansen JB, Andersson U, Sävendahl L, Hagelberg S: Etanercept treatment improves longitudinal growth in prepubertal children with juvenile idiopathic arthritis. J Rheumatol 2007;34:2481–2485.
25.
R&D Systems I: Anti-Rat IL-1β Antibody, 2010.
26.
R&D Systems I: Anti-Rat TNF-α/TNFSF1A Antibody, 2009.
27.
Chagin AS, Karimian E, Zaman F, Takigawa M, Chrysis D, Sävendahl L: Tamoxifen induces permanent growth arrest through selective induction of apoptosis in growth plate chondrocytes in cultured rat metatarsal bones. Bone 2007;40:1415–1424.
28.
Takei S, Groh D, Bernstein B, Shaham B, Gallagher K, Reiff A: Safety and efficacy of high dose etanercept in treatment of juvenile rheumatoid arthritis. J Rheumatol 2001;28:1677–1680.
29.
Johnsen AK, Schiff MH, Mease PJ, Moreland LW, Maier AL, Coblyn JS, Helfgott SM, Leff JA, Weinblatt ME: Comparison of 2 doses of etanercept (50 vs. 100 mg) in active rheumatoid arthritis: a randomized double blind study. J Rheumatol 2006;33:659–664.
30.
Weinblatt ME, Schiff MH, Ruderman EM, Bingham CO 3rd, Li J, Louie J, Furst DE: Efficacy and safety of etanercept 50 mg twice a week in patients with rheumatoid arthritis who had a suboptimal response to etanercept 50 mg once a week: results of a multicenter, randomized, double-blind, active drug-controlled study. Arthritis Rheum 2008;58:1921–1930.
31.
Alten R, Gram H, Joosten LA, van den Berg WB, Sieper J, Wassenberg S, Burmester G, van Riel P, Diaz-Lorente M, Bruin GJ, Woodworth TG, Rordorf C, Batard Y, Wright AM, Jung T: The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis. Arthritis Res Ther 2008;10:R67.
32.
Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, Bekker P: Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 2004;50:1412–1419.
33.
Fintini D, Brufani C, Cappa M: Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency. Ther Clin Risk Manag 2009;5:553–559.
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2011
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