Background: Children with inflammatory diseases usually display abnormal growth patterns as well as delayed puberty. This is a result of several factors related to the disease itself, such as malnutrition, hypercortisolism, and elevated levels of pro-inflammatory cytokines. These factors in combination with glucocorticoid treatment contribute to growth retardation during chronic inflammation by systemically affecting the major regulator of growth, the GH/IGF1 axis. In conditions of chronic inflammation, pro-inflammatory cytokines are up-regulated and released into circulation. The most abundant of these, tumor necrosis factor-α (TNF-α), interleukin-1β (IL1β) and interleukin-6 (IL6). Recent studies show evidence of a direct effect of these factors at the growth plate level.
Objective and hypotheses: To study the molecular response of the growth plate to inflammatory cytokines.
Method: Cytokine actions in growth plate cartilage was studied in ex vivo cultures of fetal rat metatarsal bones. Molecular mechanisms were studied focusing on chondrocyte proliferation, differentiation and cell death. Furthermore, a retrospective clinical study was performed to investigate the potential for anti-cytokine treatment to rescue bone growth in children and adolescents with chronic juvenile rheumatoid arthritis.
Results: TNF-α, IL1β, and IL6 were all found to directly act on growth plate cartilage to induce apoptosis and thereby suppress bone growth. Moreover, TNF-α and IL1β were found to act in synergy to suppress chondrocyte proliferation and differentiation as well as increase apoptosis. Clinical and experimental studies showed that growth retardation can partly be rescued when these cytokines are blocked.
Conclusion: Therapy modulating the local actions of pro-inflammatory cytokines may be effective for preventing growth failure in patients with chronic inflammatory disorders. The current knowledge of inflammatory cytokines and their role in regulating bone growth will be reviewed in this presentation.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology