Recent research on the growth plate: Impact of inflammatory cytokines on longitudinal bone growth.

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. However, recent studies have also shown evidence of a direct effect of these factors at the growth plate level. In conditions of chronic inflammation, pro-inflammatory cytokines are upregulated and released into the circulation. The most abundant of these, tumor necrosis factor α, interleukin 1ß (IL1ß), and IL6, are all known to directly act on growth plate cartilage to induce apoptosis and thereby suppress bone growth. Both clinical and experimental studies have shown that growth retardation can partly be rescued when these cytokines are blocked. Therefore, therapy modulating the local actions of these cytokines may be effective for preventing growth failure in patients with chronic inflammatory disorders. In this review, we report the current knowledge of inflammatory cytokines and their role in regulating bone growth.

Pro-inflammatory cytokines produced by growth plate chondrocytes may act locally to modulate longitudinal bone growth.

INTRODUCTION: Interleukin-1ß (IL-1ß) and tumour necrosis factor-α (TNF-α), both cytokines upregulated during chronic inflammation, are known to suppress bone growth. So far no role of these cytokines in modulation of normal bone growth has been established. METHODOLOGY: Applying RT-PCR and immunohistochemistry, expression of IL-1ß and TNF-α was studied in cultured fetal (E20) rat metatarsal bones. Anakinra (500 µg/ml; IL-1 receptor antagonist) and/or etanercept (500 µg/ml; soluble TNF-α receptor) were used to block cytokine actions. RESULTS: The local expression of IL-1ß and TNF-α was confirmed in the rat metatarsal growth plate. When cultured for 12 days and compared to control, the length of bones exposed to anakinra, etanercept, or anakinra plus etanercept increased by 7.7 ± 2.0 (p < 0.05), 11.7 ± 2.8 (p < 0.01) and 20.3 ± 1.9% (p < 0.001), respectively, while the height of the hypertrophic growth plate zone (collagen X staining) increased by 11.0 ± 6.7, 17.4 ± 7.1 and 43.1 ± 5.0% (p < 0.01), respectively. Moreover, etanercept increased chondrocyte proliferation (BrdU incorporation). CONCLUSION: Our findings that IL-1ß and TNF-α are produced by growth plate chondrocytes and that their antagonists improve growth of cultured metatarsal bones suggest that these cytokines play a physiological role in the normal regulation of longitudinal bone growth.

The biologics anakinra and etanercept prevent cytokine-induced growth retardation in cultured fetal rat metatarsal bones.

BACKGROUND/AIMS: Chronic inflammation during childhood often leads to impaired bone growth and reduced adult height. Proinflammatory cytokines interleukin (IL)-1ß 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-1ß 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-1ß 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-1ß 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.