Perturbations in Insulin/IGF-1 signaling resulting in diminished skeletogenesis Gene(s) modifed1 Genetic approach2 Phenotype Ref. Dwarf Trabecular Bone Cortical Bone BMD Bone Strength Gab1 C (OC-Cre) NR3 ↓ ↓ NR ↓ 24 IRS1 G Yes ↓ ↓ ↓ NR 26 IRS2 G No ↓ ↓ ↓ NR 25 Akt1 G Yes ↓ ↓ ↓ NR 29 Akt1 & Akt2 G Yes NR NR NR NR 28 FoxO1 C (Col1a1-Cre) No ↓ ↓ ↓ NR 32 FoxO1, 3 & 4 MT (Mx-Cre) No ↓ ↓ ↓ NR 33 IGF1R C (OC-Cre) No ↓ ↔ ↓ NR 44 IGF1R C (Osx-Cre) Yes ↓ NR NR NR 45 IR C (Col1a1-Cre) NR NR NR ↓ NR 59 IR C (OC-Cre) NR ↓ NR NR NR 57 MEK1 TG (dominant/negative) Yes NR NR ↓ NR 38 Perturbations in Insulin/IGF-1 signaling resulting in enhanced skeletogenesis MEK1 TG (active ) No (large) NR NR ↑ NR 38 PTEN C (OC-Cre) NR ↑ ↑ ↑ NR 30 FoxO1, 3 & 4 C (Osx-Cre) NR NR ↑ ↑ NR 34 1 Pathways presented in Figure 1. 2Genetic Approach: C= conditional knockout; G=global knockout; MT = multiple tissue knockout; TG = transgenic over-expression. 3NR = Not reported

Table 1: Various mouse models in which components of insulin and/or IGF-I signaling have been independently assessed in skeletogenesis.