The phenotype gap is a challenge for genetically dissecting redundant endocrine signaling pathways, such as the six isoforms in the insulin-like growth factor binding protein (IGFBP) family. Although overexpressed IGFBPs can inhibit or potentiate IGF actions or have IGF-independent actions, mutant mice lacking IGFBP-encoding genes do not exhibit major phenotypes. We found that although zebrafish deficient in did not show overt phenotypes when raised in Ca-rich solutions, they died prematurely in low Ca conditions. A group of epithelial cells expressing take up Ca and proliferate under low Ca conditions because of activation of IGF signaling. Deletion of blunted low Ca stress-induced IGF signaling and impaired adaptive proliferation. Reintroducing zebrafish Igfbp5a, but not its ligand binding-deficient mutant, restored adaptive proliferation. Similarly, adaptive proliferation was restored in zebrafish lacking by expression of human IGFBP5, but not two cancer-associated IGFBP5 mutants. Knockdown of IGFBP5 in human colon carcinoma cells resulted in reduced IGF-stimulated cell proliferation. These results reveal a conserved mechanism by which a locally expressed Igfbp regulates organismal Ca homeostasis and survival by activating IGF signaling in epithelial cells and promoting their proliferation in Ca-deficient states. These findings underscore the importance of physiological context when analyzing loss-of-function phenotypes of endocrine factors.

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INTRODUCTION: Distraction osteogenesis using internal distraction devices is commonly used to treat patients with congenital micrognathia. One main disadvantage of this treatment is the requirement for device and screw removal after a consolidation period. The conventional internal distraction devices utilize titanium screws for fixation. The removal of titanium screws can pose a challenge in some instances and may require the use of transbuccal approach with a trocar system.Biodegradable poly-L-lactide (PLLA) materials have been used for maxillofacial osteosynthesis in pediatric patient population. These materials do not need to be removed and are strong enough to provide bony fixation. Previous in vivo studies have found that the average force produced by mandibular distraction is 35.6N, with the maximal force reaching 69.4N. 1 We hypothesize that PLLA screws are strong enough to support the compressive force encountered during active mandibular distraction.

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