Persistent postnatal IGF2 expression alters adult skeletal architecture in <i>Igf2</i> ^<i>G/A</i> mice.

Abstract

IGF2 is an imprinted growth factor essential for fetal development. A single nucleotide variation at a conserved ZBED6 binding site within <i>Igf2</i> intron 3 induces post-natal IGF2 expression and resulted in increased lean mass in multiple species. While the role of IGF2 in muscle growth is established, its impact on the adult skeleton remains incompletely defined. We studied 13-week-old male and female <i>Igf2</i> ^<i>G/A</i> knock-in mice carrying the pig-derived G ➔ A substitution that prevents ZBED6 binding. We quantified <i>Igf2</i> expression in bone and visceral tissues, measured body and organ size, assessed femoral geometry and microarchitecture by micro-CT, examined growth plate morphology, evaluated bone turnover markers (P1NP, CTX1), and tested whole-bone mechanical properties. <i>Igf2</i> ^<i>G/A</i> mice exhibited increased size, body weight, length, and kidney mass, while liver mass trended higher. <i>Igf2</i> mRNA levels were elevated in kidney, liver, and bone tissues. Femurs demonstrated greater length and larger periosteal perimeter, with increased cortical area in both sexes but no changes in cortical thickness or bone mineral density. Trabecular parameters remained unchanged in males but improved in females, characterized by higher BV/TV, increased trabecular thickness and number, and reduced spacing. Growth plate metrics were predominantly unaffected, except for a modest increase in mean thickness observed in <i>Igf2</i> ^<i>G/A</i> females. Serum P1NP and CTX1 levels showed no genotype-dependent differences. Mechanical testing revealed reduced elastic modulus in both sexes of the <i>Igf2</i> ^<i>G/A</i> compared to wildtype and lower ultimate stress in females, while other mechanical properties remained unchanged. Circulating IGF1 and IGFBP3 levels as well as bone expression of <i>Igf1/Igf1r/Igfbp3</i> were unchanged, suggesting small if any impact of the greater GH-IGF axis on the phenotype. Post-natal IGF2 expression alters the adult murine skeleton by augmenting longitudinal growth and cortical accrual and inducing female-specific trabecular gains, with selective decrements in material properties. These data establish IGF2 as a regulator of postnatal bone architecture and mechanics and extend the functional scope of the conserved ZBED6-IGF2 regulatory axis to the skeleton.