IGF-1 Receptor Insufficiency Leads to Age-Dependent Attenuation of Osteoblast Differentiation.

In the current study, we determined the effects of IGF-1 receptor haploinsufficiency on osteoblast differentiation and bone formation throughout the lifespan. Bone mineral density was significantly decreased in femurs of male and female Igf1r(+/-) mice compared with wild-type mice. mRNA expression of osteoblast differentiation markers was significantly decreased in femurs and calvariae from Igf1r(+/-) mice compared with cells from wild-type mice. Bone morphogenetic protein-7-induced ectopic bone in Igf1r(+/-) mice was significantly smaller with fewer osteoblasts but more lipid droplets and had reduced expression of osteoblast differentiation markers compared with wild-type mice. In bone marrow cells from middle-aged and old wild-type and Igf1r(+/-) male mice, palmitate inhibited osteoblast markers expression. In cells from young wild-type male mice, palmitate did not inhibit marker expression, but in cells from young male Igf1r(+/-) mice, palmitate inhibited bone sialoprotein and osterix but not osteocalcin or type I collagen (TIC). In female wild-type mice, palmitate inhibited osteoblast markers expression in cells from young, middle-aged, and old mice except TIC in cells from middle-aged mice. Palmitate inhibited bone sialoprotein expression in cells from middle-aged and old female Igf1r(+/-) mice and osteocalcin, osterix, and TIC expression in young and middle-aged female Igf1r(+/-) mice but stimulated expression in cells from old female Igf1r(+/-) mice. We conclude that IGF-1 receptor haploinsufficiency results in a prolipid accrual phenotype in bone in association with inhibition of growth factor-induced osteoblast differentiation, a situation which may phenocopy age-related decreases in bone formation.