Pro-Inflammatory Cytokines Produced by Growth Plate Chondrocytes May Act Locally to Modulate Longitudinal Bone Growth

Introduction: Interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha), 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-1 beta and TNF-alpha was studied in cultured fetal (E20) rat metatarsal bones. Anakinra (500 mu g/ml; IL-1 receptor antagonist) and/or etanercept (500 mu g/ml; soluble TNF-alpha receptor) were used to block cytokine actions. Results: The local expression of IL-1 beta and TNF-alpha 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-1 beta and TNF-alpha 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. Copyright (C) 2012 S. Karger AG, Basel