Effects of insulin and insulin‐like growth factor 1 on osteoblast proliferation and differentiation: differential signalling via Akt and ERK

Abstract

Insulin and insulin-like growth factor 1 (IGF-1) are evolutionarily conserved hormonal signalling molecules, which influence a wide array of physiological functions including metabolism, growth and development. Using genetic mouse studies, both insulin and IGF-1 have been shown to be anabolic agents in osteoblasts and bone development primarily through the activation of Akt and ERK signalling pathways. In this study, we examined the temporal signalling actions of insulin and IGF-1 on primary calvarial osteoblast growth and differentiation. First, we observed that the IGF-1 receptor expression decreases whereas insulin receptor expression increases during osteoblast differentiation. Subsequently, we show that although both insulin and IGF-1 promote osteoblast differentiation and mineralization in vitro, IGF-1, but not insulin, can induce osteoblast proliferation. The IGF-1-induced osteoblast proliferation was mediated via both MAPK and Akt pathways because the IGF-1-mediated cell proliferation was blocked by U0126, an MEK/MAPK inhibitor, or LY294002, a PI3-kinase inhibitor. Osteocalcin, an osteoblast-specific protein whose expression corresponds with osteoblast differentiation, was increased in a dose- and time-dependent manner after insulin treatment, whereas it was decreased with IGF-1 treatment. Moreover, insulin treatment dramatically induced osteocalcin promoter activity, whereas IGF-1 treatment significantly inhibited it, indicating direct effect of insulin on osteocalcin synthesis.

Amino Acid Intakes Are Associated With Bone Mineral Density and Prevalence of Low Bone Mass in Women: Evidence From Discordant Monozygotic Twins

“…Higher protein intake is thought to beneficially affect bone health through a number of mechanisms, including its role in maintaining bone structure and increasing insulin‐like growth factor 1 (IGF‐1), an important mediator of osteoblastic activity 1, 2. Conversely, dietary protein is a source of metabolic acid that may lower the pH of urine and increase urinary calcium excretion, which could lower bone mass,3 although a meta‐analyses of randomized trials reported that higher protein intakes are not detrimental to calcium retention or bone mineral loss 4.…”

Mesenchyme‐specific overexpression of nucleolar protein 66 in mice inhibits skeletal growth and bone formation

“…7A, C; P , 0.05). These results suggested that mesenchymal overexpression of NO66 in mice may inhibit the IGF1/IGF1R/Akt signaling pathway, an important signal in the control of chondrocyte and osteoblast proliferation (14,15). Previous in vitro studies reported that NO66 has a histone demethylase activity that is specific for H3K4me3 and H3K36me3.…”

“…18). Expression of these factors is differentially regulated by a broad signaling network including IGF1, BMP2, and Wnt/b-catenin signaling pathways (11,(13)(14)(15). To determine changes in mRNA expression of these factors, we performed qPCR assays using total RNA from limbs of E13.5 mouse embryos.…”

“…In Osx-null (Osx 2/2 ) mice, expression of bone formation markers, such as type I collagen (Col1), alkaline phosphatase (Alp), bone sialoprotein (Bsp), and Osteocalcin (Oc), was inhibited, and formation of both endochondral and intramembranous bones was abolished (9). Bone formation and growth are also controlled by a broad signaling network including IGF, bone morphogenetic protein (BMP), and members of the Wnt family (11)(12)(13)(14)(15). Previous studies showed that dysregulation of these signaling molecules results in abnormal bone growth (16)(17)(18)(19).…”

The roles of the exoribonucleases DIS3L2 and XRN1 in human disease

“…Alternatively, downregulation of XRN1 may lead to increased expression of specific miRNAs and/or protein-coding RNAs which then promote the cancerous phenotype. Possible candidates are IGF-1, which is known to induce proliferation of osteoblasts [38][39][40] and/or pro-inflammatory RNAs such as FOS and MYC which are widely known to be involved in cancer progression.…”