Studies in transgenic mice showed that overexpression of IGFBP-2 resulted in mice that were resistant to diet induced obesity, suggesting it might be affecting fat cell differentiation. Addition of IGFBP-2 to fat cells in culture showed that the whole protein inhibited their differentiation. When IGFBP-2 gene expression was deleted, mice had markedly reduced bone turnover, reduced bone mineral density, a reduced number of bone trabeculi, and reduced trabecular and cortical thickness. This and other data lead to the conclusion that IGFBP-2 is functioning during stem cell allocation to allocate cells into the osteoblast and away from the adipocyte lineage. As such, IGFBP-2 could be expected to reduce fat mass and increase bone mass if administered to humans.
This 13 amino acid peptide discovered within IGFBP-2 confers these effects. First, this means a small peptide can be utilized to design a nonpeptide molecule which could then be orally active; second, the amino acid peptide modulates the effects IGFBP-2 independent of its ability to bind the IGFs; finally, administration of the peptide to subjects deficient in IGFBP-2 reconstituted the effect of intact IGFBP-2.
This peptide structure could be extremely useful for the development of a drug to treat obesity and/or to increase bone mineral density. The drug would be predicted to be particularly effective in states of low bone turnover or in patients with obesity who have polymorphisms that result in low serum IGFBP-2.
For the treatment of postmenopausal osteoporosis in women and in senile osteoporosis in men. Also obese patients with low serum IGFBP-2 should respond with weight loss. Based on the peptide structure an orally active drug could be developed that would make long term treatment possible. If not a pegylation of the peptide which prolongs its halflife would make chronic subcutaneous injection treatment feasible. The major advantage is that a 13 amino acid peptide contains all the biologic activity of the parent protein. Therefore it is amenable to tertiary structure development of a small molecule that mimics the effect of the native peptide. This gives one a major competitive advantage for developing a drug around this target.
Name: Research Tool Manager