IGF-1 c.258 A > G synonymous mutation ameliorates senile osteoporosis

Abstract

Senile osteoporosis SOP is a multifactorial, age-related progressive phenomenon that leads to an increased susceptibility to fragility fractures. IGF-1 is an important regulator of bone reconstruction and metabolism. Nevertheless, we unexpectedly found IGF-1 c.258A>G synonymous mutation did not alter bone growth at sexual maturation under expression change of IGF-1. Considering the RNA-seq results that c.258A>G involved in cellular senescence, we suspected c.258A>G may participate in SOP. Therefore, the effect of IGF-1 c.258A>G on SOP was firstly detected by in vivo assays, the changes of BMD, bone formation and resorption index as well as the expression of related genes in Gal-induced SOP mice with two genotypes indicated it resisted SOP. Then, the in vitro study of H2O2-induced primary osteoblasts and MC3T3-E1 cells confirmed the IGF-1 c.258A>G ameliorates SOP by promoting the proliferation, migration, differentiation and mineralization. At last, co-culture system of two genotypes osteoblast and osteoclast further verified the mutation prevents SOP by increasing the bone formation capacity. Collectively, this study illuminated the role of IGF-1 c.258A>G in ameliorating SOP, which may be identified as an adjuvant therapy target for SOP. To our knowledge, this is one of the few studies that have been done in animals on the function of synonymous mutations.