Growth and the Growth Hormone-Insulin Like Growth Factor 1 Axis in Children With Chronic Inflammation: Current Evidence, Gaps in Knowledge, and Future Directions

Abstract

Growth failure is frequently encountered in children with chronic inflammatory conditions like juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis. Delayed puberty and attenuated pubertal growth spurt are often seen during adolescence. The underlying inflammatory state mediated by proinflammatory cytokines, prolonged use of glucocorticoid, and suboptimal nutrition contribute to growth failure and pubertal abnormalities. These factors can impair growth by their effects on the GH-IGF axis and also directly at the level of the growth plate via alterations in chondrogenesis and local growth factor signaling. Recent studies on the impact of cytokines and glucocorticoid on the growth plate further advanced our understanding of growth failure in chronic disease and provided a biological rationale of growth promotion. Targeting cytokines using biological therapy may lead to improvement of growth in some of these children, but approximately one-third continue to grow slowly. There is increasing evidence that the use of relatively high-dose recombinant human GH may lead to partial catch-up growth in chronic inflammatory conditions, although long-term follow-up data are currently limited. In this review, we comprehensively review the growth abnormalities in children with juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis, systemic abnormalities of the GH-IGF axis, and growth plate perturbations. We also systematically reviewed all the current published studies of recombinant human GH in these conditions and discussed the role of recombinant human IGF-1.

Long-Term Skeletal Disproportion in Childhood-Onset Crohn’s Disease

“…Poor growth and an abnormality of the growth hormone/insulin-like growth factor 1 axis are evident during periods of active disease and may be related to multiple factors, including malnutrition and an elevation in pro-inflammatory cytokines [4]. In accordance with previous research [1], the current study suggests that short stature in CO-CD may persist into adulthood.…”

Skeletal Fragility in Children with Chronic Disease

“…1). Cytokines and GC impair systemic endocrine factors which regulate longitudinal bone growth via a reduction in secretion and sensitivity of the growth hormone (GH)/insulin like growth factor-1 (IGF-1) axis and gonadal function [8,9]. A critical contributor to bone accrual is sex steroid, as bone mass increases by approximately 30-50% during pubertal development [10].…”

Animal models to explore the effects of glucocorticoids on skeletal growth and structure

“…The GH/IGF-1 axis is the main determinant of postnatal longitudinal growth, and GH and IGF-1 have interdependent roles in growth regulation. The rate of longitudinal bone growth is principally controlled through the regulation of chondrocyte proliferation, differentiation and hypertrophy at the growth plate (Wong et al 2016). GH promotes chondrocyte differentiation, the secretion of IGF-1 by liver cells and the amplification of local IGF-1 synthesis by chondrocytes, which induces clonal expansion of chondrocyte columns within the growth plate (Zezulak & Green 1986).…”

“…Different mechanisms of GC-induced apoptosis have been proposed such as activation of caspase 3 and suppression of Bcl-2 (Chrysis et al 2003, Espina et al 2008. GCs block the activation of GH and IGF-1 receptors in chondrocytes as well as reducing IGF-1 and GH receptor expression by chondrocytes (Wong et al 2016). Glucocorticoids also impair IGF-1 signalling, mainly via the phosphoinositide 3-kinase pathway within the growth plate.…”