Stress-induced IL-6 dysregulation impairs pediatric bone growth and increases fragility
Background
During childhood, linear growth and peak bone mass acquisition are critical, tightly regulated processes. However, various stressors can trigger systemic inflammation, potentially compromising skeletal development. Interleukin-6 (IL-6), a key pro-inflammatory cytokine, is known to be upregulated by stress, yet its specific impact on pediatric bone health has lacked a comprehensive review. Understanding this link is crucial for addressing bone growth disorders in children.
Study Design
This comprehensive review synthesized current evidence on stress-induced IL-6 upregulation and its detrimental effects on pediatric bone health. Researchers examined findings from diverse sources, including animal models, gene knockout studies, and clinical data from pediatric inflammatory disorders such as juvenile idiopathic arthritis, pediatric systemic lupus erythematosus, and inflammatory bowel disease. The review also incorporated insights from models of metabolic stress to collectively demonstrate how stress triggers IL-6, leading to impaired skeletal growth and increased fragility in children.
Results
Persistent IL-6 upregulation significantly disrupts the normal functioning of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, a critical regulator of linear growth. Furthermore, elevated IL-6 levels enhance receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis, leading to increased bone resorption. The review also highlighted that stress-induced IL-6 promotes bone marrow adiposity, further compromising bone quality. Systemic or local IL-6 directly impairs stem cell differentiation and inhibits the proliferation and maturation of growth plate chondrocytes, ultimately restricting longitudinal bone growth. Elevated IL-6 also adversely affects muscle health and the crucial crosstalk between muscle and bone, thereby compromising skeletal integrity.
Stress-induced high levels of IL-6 adversely affect the skeletal, immune, and endocrine systems, compromising skeletal development and bone growth in children.
Key Findings
- Stress-induced IL-6 upregulation impairs pediatric skeletal growth and increases bone fragility.
- Elevated IL-6 disrupts the
GH/IGF-1axis, a key regulator of linear bone growth. - Persistent IL-6 enhances
RANKL-mediated osteoclastogenesis and promotes bone marrow adiposity. - High IL-6 levels directly inhibit growth plate chondrocyte proliferation and maturation, restricting longitudinal growth.
- IL-6 also negatively impacts muscle-bone crosstalk, further compromising skeletal integrity.
Why It Matters
This review underscores the urgent need for integrative therapeutic strategies that target inflammation and redox imbalance in children experiencing stress-induced IL-6 dysregulation. Early intervention to mitigate stress and inflammation could be crucial for preserving optimal bone health and preventing long-term skeletal fragility in pediatric populations. For clinicians, this highlights the importance of considering inflammatory markers like IL-6 in children with unexplained growth delays or bone density issues. While not a direct protocol, it emphasizes a mechanistic target for future drug development, potentially involving anti-inflammatory or IL-6 pathway inhibitors to support healthy bone development.
il-6
pediatric-health
bone-growth
inflammation
osteoclastogenesis
gh-igf-1-axis