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It is unclear whether recombinant human growth hormone (rhGH) in inflammatory bowel disease (IBD) alters cytokine profile. The objective of this study is to evaluate changes in cytokines and systemic markers of the insulin growth factor axis following 6 months of rhGH treatment in children with IBD. In a six-month randomised control trial in children with IBD treated with rhGH at 0.067 mg/kg/day and controls (11 in each group), we measured pro-, anti-inflammatory cytokines and systemic markers of the IGF axis (total IGF-1, free IGF-1, total IGFBP-3, ALS, IGFBP-2) at baseline (T+0), and six months (T+6). Results expressed as median (range). In the rhGH group, TNFα was 3.1pg/ml (2.9, 100.6) and 3.6pg/ml (3.1, 5.3) at T+0 and T+6, respectively (p=0.85), whereas in the controls this was 3.3pg/ ml (2.7, 4.0) and 3.1pg/m l (2.7, 4.7), respectively (p=0.79). In the rhGH group, IL1β was 18.0pg/ml (5.0,716.7) and 18.0pg/ml (1.7, 52.2) at T+0 and T+6 respectively(p=0.90), whereas in the controls this was 19.8pg/ml (4.1, 27.1) and 19.1pg/ml (2.4,77.3), respectively (p=0.65). None of the twenty-eight other cytokines analysed was different at T+6 in either group. Despite increase in total IGF1 in the rhGH group (p=0.03), free IGF1, IGFBP3, ALS and IGFBP2 did not change in either group at T+6. Percentage change in IGFBP3, was significantly associated with percentage change in IL2 (r=0.77, p=0.009) and IL4 (r=0.58, p=0.01). Percentage change in ALS was significantly associated with percentage change in IL2 (r=0.90, p less than 0.0001) and IL4 (r=0.63, p=0.04). Although changes in markers of the GH/IGF-1 axis do show an association with cytokines (IL-2, IL-4) in pediatric IBD, six months of rhGH treatment was not associated with any significant changes in levels of a range of pro and anti-inflammatory cytokine. Careful evaluation of disease process is required in future trials of rhGH in paediatric IBD.

Longitudinal bone growth is a tightly regulated process that relies on complex synchronized mechanisms at the growth plate. Chronic paediatric inflammatory diseases are well accepted to lead to growth retardation and this is likely due to raised inflammatory cytokine levels and reduced growth hormone (GH)/insulin-like growth factor-1 (IGF-I) signalling. The precise cellular mechanisms responsible for this inhibition are unclear and therefore in this article, we will review the potential interactions between inflammatory cytokines and the GH/IGF-I axis in the regulation of bone growth. In particular, we will emphasis the potential contribution of the suppressors of cytokine signalling (SOCS) proteins, and in particular SOCS2, in mediating this process., (2009 John Wiley & Sons, Ltd.)

Objective: To investigate the relationship between markers of inflammation with physical growth and systemic markers of GH secretion in JIA., Design: This is a cross sectional prospective study of patients with JIA recruited during therapeutic arthrocentesis of 17 children with JIA (F,10): 8 oligoarticular (OJIA) and 9 polyarticular (PJIA)., Results: Median adjusted height (AHt) SDS was -0.3 (-2.2 to 1.6). Serum ALS SDS (median -1.3, range -2.7 to -0.6) was reduced compared with serum IGFBP-3 SDS (median -0.5, range -7.7 to 2.3) and IGF-1 SDS (median -0.2, range -0.5 to 0.5). Log serum IL5 (95% CI -3.25, -0.81) and log serum IL15 (95% CI -9.58, -4.10) were independent factors associated with AHt SDS. Inflammatory cytokines individually showed no association with IGF-1, IGFBP-1, -2, -3 and ALS., Conclusion: Children with JIA and mild degree of growth retardation show decreased ALS and IGFBP-3. Cytokines did not show an association to systemic markers of GH secretion. However, this study reports the novel, preliminary association between serum levels of IL5 and IL15 and the extent of short stature.

Objective: Growth retardation in children with chronic inflammatory disease may be partly due to direct effects of pro-inflammatory cytokines on the growth plate and requires further investigation., Design: This study assessed the cytokine concentrations in serum and synovial fluid (SF) in juvenile idiopathic arthritis (JIA), and determined the effect of the biological fluid on cultured murine metatarsal growth., Patients: Serum and SF were obtained from four children attending for arthrocentesis (child A, systemic; children B, C and D, oligoarticular). In addition, serum samples were obtained from four more children (children E and F, polyarticular; child G, oligoarticular)., Measurements: Anthropometry, cytokine levels and longitudinal bone growth were assessed., Results: Cytokines were elevated to a variable extent in the samples. Although all serum samples were associated with reduced metatarsal growth, only SF from child A and child B reduced metatarsal growth. Metatarsals treated with child A's SF showed reduced proliferation, reduced proliferative and mineralizing zone width, and increased hypertrophic zone width. Tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 concentrations were elevated in child A's SF. However, SF exposure with neutralizing antibodies to these cytokines or IGF-1 did not improve metatarsal growth., Conclusion: SF and serum JIA samples can impair bone growth at the growth plate. In synovial fluid, the effect is variable but resistant to treatment with IL-1beta, IL-6 and TNF-alpha specific antibodies and IGF-1, suggesting that other factors in this biological fluid may also have an effect on longitudinal growth through IGF-1-independent mechanisms.

Growth disorders are commonly observed in children suffering from chronic inflammatory diseases such as Juvenile Idiopathic Arthritis (JIA) and Inflammatory Bowel Disease (IBD). These disorders range from general growth retardation to local acceleration of growth in the affected limb and are associated with the increased production of pro-inflammatory cytokines. In this article, we review how cytokines influence child growth by exerting a local effect at the level of the growth plate, and through systemic effects throughout the whole body.

Childhood inflammatory bowel disease (IBD) especially those with Crohn disease is commonly complicated by faltering growth and pubertal delay. Pro-inflammatory cytokines are often elevated in IBD and may affect linear growth and puberty either systemically or at the level of the growth plate. Further study of the underlying mechanisms of the deleterious effects of cytokines on the growth plate may improve management of faltering growth in childhood IBD. Well-controlled clinical studies of the respective effect of nutritional support, immunomodulatory therapy, biological agents and growth and puberty promoting agents on managing faltering growth also require further attention.

Childhood chronic inflammatory disease can be associated with transient and permanent growth retardation. This study examined the potential for spontaneous growth recovery following pro-inflammatory cytokine exposure. Murine ATDC5 chondrogenic cells and postnatal metatarsals were exposed to interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNFalpha), and their growth and proliferative capacity were determined following recovery. TNFalpha and IL-1beta reduced chondrocyte proliferation and aggrecan and collagen types II and X expression at minimum concentrations of 10 ng/ml and 0.1 ng/ml respectively. TNFalpha but not IL-1beta exposure led to increased caspase-3 activity and altered cellular morphology, consistent with reduced viability. Cytokine exposure particularly inhibited proteoglycan synthesis. This effect was dose and duration dependent. Compared with the control, IL-1beta and TNFalpha led to a 71% and 45% reduction in metatarsal growth after 8 days of exposure respectively (P < 0.05). An additive effect of IL-1beta combined with TNFalpha was observed (110% decrease; P < 0.05). Metatarsals exposed to IL-1beta or TNFalpha individually for a 2-day period, and allowed to recover spontaneously in the absence of cytokines for a further 6 days, showed normal growth trajectories. In combination, growth was 59% lower (P < 0.01) compared with control metatarsals at the end of the recovery period. Exposure to the combination for 4 days followed by a 4-day recovery period resulted in 87% decrement compared with controls (P < 0.05). IL-6 did not alter any parameter studied. IL-1beta and TNFalpha exert diverse inhibitory effects on ATDC5 chondrocyte dynamics and metatarsal growth. The extent of recovery following cytokine exposure depends on the duration of exposure, and may be incomplete following longer periods of exposure.

Children with chronic inflammatory diseases, such as juvenile idiopathic arthritis (JIA), suffer from a variety of growth disorders. These range from general growth retardation to local acceleration of growth in the affected limb. These disorders are associated with the increased production of proinflammatory cytokines, which may influence growth through a local effect in the growth plates of long bones and/or systemic effects throughout the whole body. In this article we review these aspects and also discuss the evidence for interaction between the inflammatory cytokine and growth-signalling pathways.

The suppressor of cytokine signalling (Socs2-/-)-knockout mouse is characterised by an overgrowth phenotype due to enhanced GH signalling. The objective of this study was to define the Socs2-/- bone phenotype and determine whether GH promotes bone mass via IGF1-dependent mechanisms. Despite no elevation in systemic IGF1 levels, increased body weight in 4-week-old Socs2-/- mice following GH treatment was associated with increased cortical bone area (Ct.Ar) (P<0.01). Furthermore, detailed bone analysis of male and female juvenile and adult Socs2-/- mice revealed an altered cortical and trabecular phenotype consistent with the known anabolic effects of GH. Indeed, male Socs2-/- mice had increased Ct.Ar (P<0.05) and thickness associated with increased strength. Despite this, there was no elevation in hepatic Igfl expression, suggesting that the anabolic bone phenotype was the result of increased local GH action. Mechanistic studies showed that in osteoblasts and bone of Socs2-/- mice, STAT5 phosphorylation was significantly increased in response to GH. Conversely, overexpression of SOCS2 decreased GH-induced STAT5 signalling. Although an increase in Igfl expression was observed in Socs2-/- osteoblasts following GH, it was not evident in vivo. Igfl expression levels were not elevated in response to GH in 4-week-old mice and no alterations in expression was observed in bone samples of 6-week-old Socs2-/- mice. These studies emphasise the critical role of SOCS2 in controlling the local GH anabolic bone effects. We provide compelling evidence implicating SOCS2 in the regulation of GH osteoblast signalling and ultimately bone accrual, which maybe via mechanisms that are independent of IGF1 production in vivo. [ABSTRACT FROM AUTHOR]

Suppressor of cytokine signalling-2 (SOCS2) negatively regulates the signal transduction of several cytokines. Socs2-/- mice show increased longitudinal skeletal growth associated with deregulated GH/IGF-1 signalling. The present study examined the role of SOCS2 in endochondral ossification and trabecular and cortical bone formation, and investigated whether pro-inflammatory cytokines associated with pediatric chronic inflammatory disorders mediate their effects through SOCS2. Seven-week-old Socs2-/- mice were heavier (27%; P < 0.001) and longer (6%; P < 0.001) than wild-type mice. Socs2-/- tibiae were longer (8%; P < 0.001) and broader (18%; P < 0.001) than that of wild-type mice, and the Socs2-/- mice had wider growth plates (24%; P < 0.001) with wider proliferative and hypertrophic zones (10% (P < 0.05) and 14% (P < 0.001) respectively). Socs2-/- mice showed increased total cross-sectional bone area (16%: P < 0.001), coupled to increased total tissue area (17%; P < 0.05) compared to tibia from wild-type mice. Socs2-/- mice showed increased percent bone volume (101%; P < 0.001), trabecular number (82%; P < 0.001) and trabecular thickness (11%; P < 0.001), with associated decreases in trabecular separation (19%; P < 0.001). TNFα exposure to growth plate chondrocytes for 48 h increased SOCS2 protein expression. Growth of metatarsals from 1-day-old Socs2-/- and Socs2+/+ mice, as well as expression of Aggrecan, Collagen Type II and Collagen Type X, were inhibited by TNFα, with no effect of genotype. Our data indicate that physiological levels of SOCS2 negatively regulate bone formation and endochondral growth. Our results further suggest that pro-inflammatory cytokines mediate their inhibitory effects on longitudinal bone growth through a mechanism that is independent of SOCS2. J. Cell. Physiol. 218: 276–284, 2009. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]