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

Abstract

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.

40 YEARS OF IGF1: Insulin-like growth factors: actions on the skeleton

“…Haploinsufficient IGF-IR mice (IGF-IR +/− ) are viable, but show reductions in serum IGF-I levels and reduced body size (Castilla-Cortazar et al, 2014; Holzenberger et al, 2001). Femurs of the IGF-IR +/− mice are shorter and have decreased mineral density due to lifelong deficits in bone formation and impaired osteoblast activity (Yeh et al, 2015). To avoid the developmental lethality seen in the IGF-IRKO mice, investigators used the Cre-loxP technology.…”

Osteopenia in a Mouse Model of Spinal Cord Injury: Effects of Age, Sex and Motor Function

“…There appears to be a decline in the sensitivity of bone to mechanical loading with aging. In fact, aging is also associated with declines in the number and function of bone forming osteoblasts, and the differentiation of these cells from multipotent mesenchymal stem cells [ 77 , 78 , 79 , 80 , 81 , 82 ].…”

Molecular Basis of Bone Aging

“…These changes of the GH-IGF axis, along with the reduced osteoblast response to GH and IGF-1, contributes to the age-related bone loss. IGF-1 stimulation of cultured osteoblasts obtained from subjects of different ages enhanced cell proliferation and increased the expression of various extra-cellular matrix proteins such as type I collagen, biglycan, fibronectin and decorin in an age-dependent manner, with osteoblasts derived from younger subjects showing a better response [34,35]. Osteoblastic cells derived from aged human donors exhibit decreased proliferative responses to GH and to the platelet-derived growth factor compared with younger donor cells [36].…”