Childhood obesity can be devastating to the growing skeleton because it can accelerate bone elongation and contribute to the development of painful conditions such as limb bowing, joint instability, fractures, and slipped epiphyses. The primary obstacle to successful clinical intervention is lack of knowledge of the underlying cause of obesity-induced growth acceleration. Paradoxically, obese children have low to normal levels of growth hormone and IGF-I, the two major hormones that stimulate growth. IGF binding proteins (IGFBPs), which restrict growth by sequestering free IGF-I, are reduced in obesity. Preliminary data suggest that local binding proteins may regulate bone elongation by entrapping IGF-I and limiting its transport into the skeleton. The long- term goal is to elucidate the role of local IGFBPs in regulating bone elongation in skeletal growth plates. The overall objective is to determine how IGFBP reduction leads to growth acceleration in obesity. The central hypothesis, based on strong preliminary data and tested under two specific aims using dynamic in vivo multiphoton microscopy and a mouse model of human obesity, is that a decrease in local IGFBPs promotes bone lengthening by allowing more IGF-I transport into growth plates.
Specific Aim 1 uses in vivo cartilage imaging and ex vivo protein assays to determine bone elongation rate, IGFBP levels, and amount of IGF-I transport into growth plates of obese and non-obese mice.
Specific Aim 2 uses local injections to deliver IGFBPs into one limb of young mice to show if local IGFBPs limit IGF-I transport and elongation rate. The rationale for demonstrating a causative link between local IGFBPs in the skeleton and IGF-I transport into growth plates is to facilitate design of IGFBP-based therapies to regulate skeletal growth and improve bone quality in obese children. This project is innovative by using multiphoton imaging to dynamically assess growth plate transport at the cellular level in vivo. This contribution is significant because it can yield transformative findings that mechanistically link IGFBPs to IGF-I uptake in cartilage and bone elongation rate. Such results could aid the development of IGFBPs as a therapeutic strategy for normalizing bone maturation rate in obese children, thus reducing chronic adult disability.