Targeting growth hormone function: strategies and therapeutic applications

Lu, Man; Flanagan, Jack U.; Langley, Ries J.; Hay, Michael P.; Perry, Jo K.

doi:10.1038/s41392-019-0036-y

Cited by 86 publications

(90 citation statements)

References 150 publications

(166 reference statements)

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“…I t is known that growth hormone (GH) exerts several diverse actions in addition to somatic growth stimulation, which involve metabolic regulation as well as modulation of immune, reproductive, and neural functions, including behavior, among others. 1,2 Regarding the neural effects of GH, it has been shown recently that its clinical application has revealed promising results as a treatment for stroke, spinal cord injury, brain trauma, and neurodegenerative diseases. 3,4 Also, important neurotrophic actions of GH in the neuroretina are related with the modulation of developmental apoptosis and neuroprotection, 5,6 because it has been observed that exogenous GH administration protects against experimental excitotoxic damage.…”

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confidence: 99%

Growth Hormone Neuroprotection Against Kainate Excitotoxicity in the Retina is Mediated by Notch/PTEN/Akt Signaling

Fleming

Balderas-Márquez

Epardo

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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In the retina, growth hormone (GH) promotes axonal growth, synaptic restoration, and protective actions against excitotoxicity. Notch signaling pathway is critical for neural development and participates in the retinal neuroregenerative process. We investigated the interaction of GH with Notch signaling pathway during its neuroprotective effect against excitotoxic damage in the chicken retina. METHODS. Kainate (KA) was used as excitotoxic agent and changes in the mRNA expression of several signaling markers were determined by qPCR. Also, changes in phosphorylation and immunoreactivity were determined by Western blotting. Histology and immunohistochemistry were performed for morphometric analysis. Overexpression of GH was performed in the quail neuroretinal-derived immortalized cell line (QNR/D) cell line. Exogenous GH was administered to retinal primary cell cultures to study the activation of signaling pathways. RESULTS. KA disrupted the retinal cytoarchitecture and induced significant cell loss in several retinal layers, but the coaddition of GH effectively prevented these adverse effects. We showed that GH upregulates the Notch signaling pathway during neuroprotection leading to phosphorylation of the PI3K/Akt signaling pathways through downregulation of PTEN. In contrast, cotreatment of GH with the Notch signaling inhibitor, DAPT, prevented its neuroprotective effect against KA. We identified binding sites in Notch1 and Notch2 genes for STAT5. Also, GH prevented Müller cell transdifferentiation and downregulated Sox2, FGF2, and PCNA after cotreatment with KA. Additionally, GH modified TNF receptors immunoreactivity suggesting anti-inflammatory actions. CONCLUSIONS. Our data indicate that the neuroprotective effects of GH against KA injury in the retina are mediated through the regulation of Notch signaling. Additionally, anti-inflammatory and antiproliferative effects were observed.

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confidence: 99%

Growth Hormone Neuroprotection Against Kainate Excitotoxicity in the Retina is Mediated by Notch/PTEN/Akt Signaling

Fleming

Balderas-Márquez

Epardo

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Human GH is a classical pituitary endocrine hormone essential for normal postnatal growth that has pleiotropic effects across multiple physiological systems, while its overproduction has been linked to cancer. The hormone is also expressed in extra-pituitary tissues and shows localized autocrine/paracrine effects at those sites [10]. Although the theoretical concern of increased tumor growth for patients taking GH has been addressed by numerous studies, a meta-analysis by Shen et al included 4 studies and actually found that GH was associated with a decreased risk of craniopharyngioma recurrence in adults [11].…”

Section: Discussionmentioning

confidence: 99%

Malignant Transformation of Craniopharyngioma after Growth Hormone Replacement Therapy

Nishimura¹,

Nakase²,

Nakagawa³

et al. 2020

CRSS

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Background: We present a rare case of malignant transformation of a craniopharyngioma in a patient who received growth hormone replacement therapy. Case Description: A 43-year-old male came to our department with a headache and visual disturbance and was admitted. Brain magnetic resonance imaging (MRI) revealed a giant tumor in the intra- and suprasellar region compressing the optic chiasma. Using a transcranial pterional approach, the tumor was removed as much as possible, with the residual mass removed later with a trans-sphenoidal approach. The initial histopathological diagnosis was adamantinomatous craniopharyngioma. Decompression of the optic chiasma was achieved and visual function improved, though residual tumor tissue remained in the parasellar region, without regrowth seen for more than 24 years. At the age of 67 years, the patient received growth hormone replacement therapy because of a deficiency, then 2 years later the residual tumor began to grow gradually. Trans-sphenoidal surgery was again performed to remove the growing tumor and histopathology results revealed an adamantinomatous craniopharyngioma with malignant transformation. Stereotactic radiation therapy was performed for the residual mass with a total dose of 60 Gy. Presently, 1 year later the patient has a stable condition, and the tumor remains controlled, while follow-up examinations are continuing. Conclusion: A craniopharyngioma may undergo malignant transformation with continuous exposure to administered growth hormone. Close follow-up and imaging examinations are necessary to detect a change, including tumor growth in such cases.

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“…Under normal physiological conditions, GH is secreted from the anterior pituitary lobe into the circulation and transported primarily to the liver where it binds the GHR [8]. Ligand binding to the transmembrane homodimeric receptor complex induces a conformational change and concomitant phosphorylation of the tyrosine kinase, Janus kinase 2 (JAK2), which in turn lead to activation of downstream signal transducer and activator of transcription 1 (STAT1), STAT3 and STAT5 [8,9]. Ligand binding and GHR activation also results in direct activation of Src family kinases (SFKs), independent of JAK2, and leads to activation of mitogen-activated protein (MAP) kinase.…”

Section: Introductionmentioning

confidence: 99%

“…The STAT transcriptional regulators dimerize and bind to GH-responsive elements in promoter regions of target genes and activate transcription. STAT5 is the major mediator and predominant transcription factor that mediates GH-induced cell proliferation through the upregulation of IGF-1 [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…The molecular mechanisms for GHR activation and signaling have been extensively studied in cellular models with exogenously over-expression of the GHR [9] and have provided a good understanding of the plethora of roles played by GH in physiology and disease [8,9]. GH deficiency has been studied postnatally in the surgical hypophysectomy model, and in several gene knockout (KO) and mutant GHR models, which have provided extensive insight to the role of GH in postnatal growth and development [12,13].…”

Section: Introductionmentioning

confidence: 99%

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Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative

Petersen

Gandhi

Buchardt

et al. 2020

IJMS

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Somapacitan is a long-acting, once-weekly, albumin-binding growth hormone (GH) derivative. The reversible albumin-binding properties leads to prolonged circulation half-life. Here, we investigated and compared somapacitan with human GH on downstream receptor signaling in primary hepatocytes and hepatocellular models and using isothermal titration calorimetry to characterize receptor binding of somapacitan in the presence or absence of human serum albumin (HSA). With non-invasive fluorescence imaging we quantitatively visualize and compare the temporal distribution and examine the tissue-specific growth hormone receptor (GHR) activation at distribution sites. We found that signaling kinetics were slightly more rapid and intense for GH compared with somapacitan. Receptor binding isotherms were characterized by a high and a low affinity interaction site with or without HSA. Using in vivo optical imaging we found prolonged systemically biodistribution of somapacitan compared with GH, which correlated with plasma pharmacokinetics. Ex vivo mouse organ analysis revealed that the temporal fluorescent intensity in livers dosed with somapacitan was significantly increased compared with GH-dosed livers and correlated with the degree of downstream GHR activation. Finally, we show that fluorescent-labeled analogs distributed to the hypertrophic zone in the epiphysis of proximal tibia of hypophysectomized rats and that somapacitan and GH activate the GHR signaling in epiphyseal tissues.

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Targeting growth hormone function: strategies and therapeutic applications

Cited by 86 publications

References 150 publications

Growth Hormone Neuroprotection Against Kainate Excitotoxicity in the Retina is Mediated by Notch/PTEN/Akt Signaling

Growth Hormone Neuroprotection Against Kainate Excitotoxicity in the Retina is Mediated by Notch/PTEN/Akt Signaling

Malignant Transformation of Craniopharyngioma after Growth Hormone Replacement Therapy

Tissue Distribution and Receptor Activation by Somapacitan, a Long Acting Growth Hormone Derivative

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