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The direct impact of pegvisomant on osteoblast functions and bone development

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Abstract

Purpose

Acromegaly is a chronic disease characterized by growth hormone (GH) hypersecretion, usually caused by a pituitary adenoma, resulting in elevated circulating levels of insulin-like growth factor type I (IGF-I). Pegvisomant (PEG), the GH-receptor (GHR) antagonist, is used in treating acromegaly to normalize IGF-I hypersecretion. Exposure to increased levels of GH and IGF-I can cause profound alterations in bone structure that are not completely reverted by treatment of GH hypersecretion. Indeed, there is evidence that drugs used for the treatment of acromegaly might induce direct effects on skeletal health regardless of biochemical control of acromegaly.

Methods

We investigated, for the first time, the effect of PEG on cell proliferation, differentiation, and mineralization in the osteoblast cell lines MC3T3-E1 and hFOB 1.19 and its potential impact on bone development in zebrafish larvae.

Results

We observed that PEG did not affect osteoblast proliferation, apoptosis, alkaline phosphatase (ALP) activity, and mineralization. After PEG treatment, the analysis of genes related to osteoblast differentiation showed no difference in Alp, Runx2, or Opg mRNA levels in MC3T3-E1 cells. GH significantly decreased cell apoptosis (− 30 ± 11%, p < 0.001) and increased STAT3 phosphorylation; these effects were suppressed by the addition of PEG in MC3T3-E1 cells. GH and PEG did not affect Igf-I, Igfbp2, and Igfbp4 mRNA levels in MC3T3-E1 cells. Finally, PEG did not affect bone development in zebrafish larvae at 5 days post-fertilization.

Conclusion

This study provides a first evidence of the impact of PEG on osteoblast functions both in vitro and in vivo. These findings may have clinically relevant implications for the management of skeletal health in subjects with acromegaly.

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Data availability

The data that support the findings of this study are available upon reasonable request in the Zenodo repository.

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Funding

The present study was supported by an investigator-sponsored research (ISR) grant, to Humanitas from Pfizer Srl. Pfizer Srl had no role in the study design, data analysis, and results interpretation of the study.

Author information

Author notes

  1. A. Grasso and M. L. Schiavone contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Cellular and Molecular Endocrinology, IRCCS Humanitas Research Hospital, Rozzano, MI, Italy

    E. Vitali, A. Grasso & G. Trivellin

  2. IRCCS Humanitas Research Hospital, Rozzano, MI, Italy

    M. L. Schiavone

  3. Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090, Pieve Emanuele, MI, Italy

    G. Trivellin, G. Mazziotti & A. Lania

  4. National Research Council, Institute of Genetic and Biomedical Research (CNR-IRGB), Milan, Italy

    C. Sobacchi

  5. Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Trento, Italy

    M. Mione

  6. Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, Rozzano, MI, Italy

    G. Mazziotti & A. Lania

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  1. E. Vitali
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Correspondence to G. Mazziotti.

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Vitali, E., Grasso, A., Schiavone, M.L. et al. The direct impact of pegvisomant on osteoblast functions and bone development. J Endocrinol Invest (2023). https://doi.org/10.1007/s40618-023-02281-3

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