EGFR controls bone development by negatively regulating mTOR-signaling during osteoblast differentiation

Abstract

Mice deficient in epidermal growth factor receptor (Egfr−/− mice) are growth retarded and exhibit severe bone defects that are poorly understood. Here we show that EGFR-deficient mice are osteopenic and display impaired endochondral and intramembranous ossification resulting in irregular mineralization of their bones. This phenotype is recapitulated in mice lacking EGFR exclusively in osteoblasts, but not in mice lacking EGFR in osteoclasts indicating that osteoblasts are responsible for the bone phenotype. Experiments are presented demonstrating that signaling via EGFR stimulates osteoblast proliferation and inhibits their differentiation by suppression of the IGF-1R/mTOR-pathway via ERK1/2-dependent up-regulation of IGFBP-3. Osteoblasts from Egfr−/− mice show increased levels of IGF-1R and hyperactivation of mTOR-pathway proteins, including enhanced phosphorylation of 4E-BP1 and S6. The same changes are also seen in Egfr−/− bones. Importantly, pharmacological inhibition of mTOR with rapamycin decreases osteoblasts differentiation as well as rescues the low bone mass phenotype of Egfr−/− fetuses. Our results demonstrate that suppression of the IGF-1R/mTOR-pathway by EGFR/ERK/IGFBP-3 signaling is necessary for balanced osteoblast maturation providing a mechanism for the skeletal phenotype observed in EGFR-deficient mice.

Hydroxylapatite-collagen hybrid scaffold induces human adipose-derived mesenchymal stem cells to osteogenic differentiation in vitro and bone regrowth in patients

“…EGFR signaling pathway is an important bone regulator, whereas it primarily plays an anabolic role in bone metabolism. The suppression of the IGF‐1R/mTOR‐pathway by the EGFR/ERK/IGFBP‐3 signaling is necessary to balance the osteoblast differentiation/maturation providing a mechanism for the skeletal phenotype observed in EGFR‐deficient mice . EGFR signaling is important for maintaining osteoprogenitor population at an undifferentiated stage reducing the expression of two major osteoblastic transcription factors, Runx2 and SP7/Osterix, in osteoblast differentiating cells .…”

“…The suppression of the IGF-1R/mTORpathway by the EGFR/ERK/IGFBP-3 signaling is necessary to balance the osteoblast differentiation/maturation providing a mechanism for the skeletal phenotype observed in EGFR-deficient mice. 35 EGFR signaling is important for maintaining osteoprogenitor population at an undifferentiated stage reducing the expression of two major osteoblastic transcription factors, Runx2 and SP7/Osterix, in osteoblast differentiating cells. 36 Runx2 and SP7 are transcription factors necessary for bone formation and responsible for controlling the differentiation of MSCs in osteoblasts.…”

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

“…Similarly, in myocardial ischaemia reperfusion injury, AMPK activates OPA‐required mitochondrial fusion and the latter inhibits mitochondrial apoptosis. Furthermore, in liver cancer, the AMPK pathway modulates mitochondrial homeostasis via upregulating PGC1 expression . In addition to Mfn1, several research studies have established the role of Mfn1 in mitochondrial damage.…”

“…Furthermore, in liver cancer, the AMPK pathway modulates mitochondrial homeostasis via upregulating PGC1 expression. 72,73 In addition to Mfn1, several research studies have established the role of Mfn1 in mitochondrial damage. For example, Mfn1 activation is associated with mitochondrial autophagy activation.…”

Psoralen accelerates bone fracture healing by activating both osteoclasts and osteoblasts

“…The above results suggest that psoralen promotes osteoclast differentiation by activating the ERK signaling, and this pathway accelerates osteoblast differentiation (39). To determine whether psoralen promotes the MAPK signaling pathway during osteoblastogenesis, MC3T3‐E1 cells were or were not treated with psoralen for 0, 5, 10, 20, 30, and 60 min.…”