Epidermal growth factor receptor signalling mediates growth hormone-induced growth of chondrocytes from sex hormone-inhibited adolescent rats

Abstract

1. Growth hormone (GH) has been demonstrated to overcome the inappropriate deceleration of growth rate in children with central precocious puberty treated with gonadotropin-releasing hormone analogue (GnRHa). However, the underlying mechanisms remain largely unclear. In the present study, we investigated the potential involvement of the epidermal growth factor receptor (EGFR) pathway in the growth promotion by GH using in vitro cultured growth plate chondrocytes isolated from adolescent rats treated with GnRHa. 2. Chondrocytes were stimulated with GH in the presence or absence of the Janus tyrosine kinase (JAK) 2 inhibitor AG490 (1, 10 and 100 nmol/L), the EGFR kinase inhibitor AG1478 (0.1, 1 and 10 nmol/L), U0126 (an inhibitor of extracellular signal-regulated kinase (Erk) activation; 10 μmol/L) or a neutralizing antibody against epidermal growth factor (EGF Ab; 0.1, 1 and 10 μg/mL). The proliferation of chondrocytes was assessed by the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay and immunostaining for proliferating cell nuclear antigen (PCNA). Phosphorylation of Erk1/2 and EGFR was detected by western-blotting. Intracellular mRNA and extracellular protein levels of EGF were detected using reverse transcription-polymerase chain reaction and ELISA, respectively. 3. Growth hormone promoted the proliferation of chondrocytes, which was correlated with increased phosphorylation of Erk1/2 and EGFR and enhanced expression of EGF. Pretreatment with AG490, AG1478, U0126 or EGF Ab completely or partially inhibited the proliferation of chondrocytes and activation of Erk1/2 and EGFR. Pretreatment with AG490, AG1478, or U0126 partially inhibited the expression of EGF. 4. The findings indicate that GH promotes chondrocyte proliferation by activating EGFR signalling.

Multiple Effects of Growth Hormone in the Body: Is it Really the Hormone for Growth?

“…330 The effects of the GH-IGF-I axis on cell turnover in the adult brain probably are not limited to neuronal progenitors, since IGF-I can promote proliferation of oligodendrocyte progenitor cells and differentiation and survival of oligodendrocytes, 331,332 an effect also induced by EGF, 333 whose expression and that of its receptor may also be induced by GH. 334 Thus, it is likely that the aging-related decline in GH/IGF-I and dependent changes in oligodendrocyte genesis and/or maturation may contribute to impaired remyelination in the CNS of aged individuals 335 and to a decline in normal cognitive function.…”

Growth Hormone and Kynesitherapy for Brain Injury Recovery

“…Given their high migratory potential and their ability to differentiate into myelin-forming cells, subventricular zone neural stem cells represent an important endogenous source of OPCs for preserving the oligodendrocyte population in the white matter and for the repair of demyelinating injuries (Gonzalez-Perez & Alvarez-Buylla, 2011). Of interest here is the fact that growth hormone induces EGF and EGFR expression in many territories (Pan et al, 2011) and activates EGFR by tyrosine phosphorilation as an essential element leading to MAP kinase activation and gene expression (Yamauchi et al, 1998). Another growth factor involved in neurogenesis is the hematopoietic growth factor erythropoietin (EPO).…”

“…These results suggest that some of the neuroprotective effects of growth hormone are mediated directly through the growth hormone receptor and do not involve IGF-I induction (Scheepens et al, 2001). The effects of the GH/IGF-I axis on cell turnover in the adult brain probably are not limited to neuronal progenitors, since IGF-I can promote proliferation of oligodendrocyte progenitor cells (OPCs) and differentiation and survival of oligodendrocytes (McMorris & McKinnon, 1996;Aberg et al, 2007;Pang et al, 2007), an effect also induced by EGF (Gonzalez-Perez & Alvarez-Buylla, 2011) whose expression and that of its receptor may also be induced by GH (Pan et al, 2011). Thus, it is likely that the agingrelated decline in GH/IGF-I and dependent changes in oligodendrocyte genesis and/or maturation may contribute to impaired remyelination in the central nervous system of aged individuals (Gilson & Blakemore, 1993;Shields et al, 1999;Franklin et al, 2002;Sim et al, 2002) and to a decline in normal cognitive function.…”

Periodic Mechanical Stress Activates PKCδ-Dependent EGFR Mitogenic Signals in Rat Chondrocytes via PI3K-Akt and ERK1/2

“…Yano et al demonstrated that mechanical stretching induced proliferative signals on human keratinocytes via EGFRextracellular signal-regulated kinase (ERK)1/2 [15,16]. EGFR has been shown to play important roles in the modulation of chondrocyte activity and functions following chemical stimuli [17,18]. Moreover, the relationship among EGFR, PKC, and PI3K has been alluded to in some studies concerning signaling transduction of other cells [19,20].…”