Cytokine profiling and <i>in vitro</i> studies of murine bone growth using biological fluids from children with juvenile idiopathic arthritis

Background: Growth disorders are commonly observed in children with chronic inflammatory disease. It is likely that these disorders are mediated by a combination of factors, including the disease process and its treatment (with drugs such as glucocorticoids [GCs]). These factors affect the growth hormone-insulin-like growth factor I (IGF-I) axis, which is crucial for promoting linear growth at the level of the growth plate. Recent advances in our knowledge of the effects of GCs and proinflammatory cytokines on the growth plate have led to an improved understanding of the biological rationale for the use of growth-promoting therapy in children with chronic inflammatory disease and concurrent growth retardation. Conclusions: Both GCs and proinflammatory cytokines can adversely affect a number of components of growth plate chondrogenesis, and these effects can be ameliorated by raising local IGF-I exposure. However, this intervention does not lead to complete normalization of the growth plate. In children with chronic inflammation, the cornerstone of improving growth remains the judicious use of GCs while ensuring effective control of the disease process.

Section: Addressing the Cytokine Insult As A Means Of Promoting Growthmentioning

confidence: 99%

Section: Cytokine Effects On Growthmentioning

confidence: 99%

Promoting Growth in Chronic Inflammatory Disease: Lessons from Studies of the Growth Plate

Ahmed

Sävendahl

2009

“…Recent studies of in vitro longitudinal growth and growth plate chondrogenesis have led to a better understanding of the direct inhibitory effects of individual cytokines, as well as biological fluid from children with inflammation, on growth plate chondrogenesis [8,9,10]. Proinflammatory cytokines may also directly affect sex-steroid synthesis at the level of the gonads or through inhibiting gonadotrophin secretion and, thus, affect entry into and progress through puberty [11, 12].…”

Section: Inflammatory Cytokines In Ibdmentioning

confidence: 99%

“…Interleukin-1-β (IL-1β), tumour necrosis factor-α (TNF-α) and IL-6 remain the main proinflammatory cytokines that are studied in children with IBD [13, 14]. However, the inflammatory cytokine cascade is a complex balance between a number of pro- and anti-inflammatory cytokines, and the respective levels of these cytokines may vary between children with the same group of conditions [10, 15, 16]. This variability in the inflammatory milieu may explain some of the differences that are observed in the end-organ effects in patients, as well as the differences between in vitro studies and those in patients.…”

Section: Inflammatory Cytokines In Ibdmentioning

confidence: 99%

Improving Growth in Children with Inflammatory Bowel Disease

Ahmed

Wong²,

McGrogan³

2007

Background: Growth in children with inflammatory bowel disease (IBD) is affected through a number of mechanisms; controlling disease activity and supporting poor nutritional status are paramount in these patients. Further understanding of the basic mechanisms by which cytokines influence growth will facilitate the development of therapeutic modalities to improve growth. Conclusions: Clinical management that addresses growth and puberty in children with IBD should be a partnership between paediatric gastroenterologists and endocrinologists. Well-designed studies of growth-promoting hormonal treatment may answer questions regarding the efficacy and safety of treating growth retardation in the subgroup of patients who continue to fail to grow despite optimal management of their IBD.

“…The major upregulated proinflammatory cytokines found in tissues or biological fluids from inflammatory bowel disease [5] or JIA [6,7,8] patients are interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α. They affect longitudinal bone growth by disrupting the growth hormone (GH)/insulin-like growth factor (IGF)-I axis [9,10].…”

Section: Introductionmentioning

confidence: 99%

The Biologics Anakinra and Etanercept Prevent Cytokine-Induced Growth Retardation in Cultured Fetal Rat Metatarsal Bones

Fernandez-Vojvodich

Karimian

Sävendahl³

2011

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.