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Analysis of circulating osteoclast and osteogenic precursors in patients with Gorham-Stout disease

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Abstract

Purpose

Gorham-Stout disease is a very rare disorder characterized by progressive bone erosion and angiomatous proliferation; its etiopathogenesis is still unknown, and diagnosis is still performed by exclusion criteria. The alteration of bone remodeling activity has been reported in patients; in this study, we characterized circulating osteoclast and osteogenic precursors that could be important to better understand the osteolysis observed in patients.

Methods

Flow cytometry analysis of PBMC (Peripheral Blood Mononuclear Cells) was performed to characterize circulating osteoclast and osteogenic precursors in GSD patients (n = 9) compared to healthy donors (n = 55). Moreover, ELISA assays were assessed to evaluate serum levels of bone markers including RANK-L (Receptor activator of NF-κB ligand), OPG (Osteoprotegerin), BALP (Bone Alkaline Phosphatase) and OCN (Osteocalcin).

Results

We found an increase of CD16−/CD14+CD11b+ and CD115+/CD14+CD11b+ osteoclast precursors in GSD patients, with high levels of serum RANK-L that could reflect the increase of bone resorption activity observed in patients. Moreover, no significant alterations were found regarding osteogenic precursors and serum levels of BALP and OCN.

Conclusion

The analysis of circulating bone cell precursors, as well as of RANK-L, could be relevant as an additional diagnostic tool for these patients and could be exploited for therapeutic purposes.

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Acknowledgements

This work was supported by research grants (#MDBR-19-116-LGDA/LMI and #MDBR-21-111-LGDA/LMI) from the University of Pennsylvania Orphan Disease Center in partnership with Lymphangiomatosis & Gorham’s Disease Alliance and the Lymphatic Malformation Institute to ADF, by the Ricerca Finalizzata Ministero della Salute (GR-2019-12370244) to ADF, and by the Italian Ministry of Health (Current Research funds). MR, ST and JDG were supported by Fondazione Umberto Veronesi.

Funding

This work was supported by research grants (#MDBR-19-116-LGDA/LMI and #MDBR-21-111-LGDA/LMI) from the University of Pennsylvania Orphan Disease Center in partnership with Lymphangiomatosis & Gorham’s Disease Alliance and the Lymphatic Malformation Institute to ADF, by the Ricerca Finalizzata Ministero della Salute (GR-2019-12370244) to ADF, and by the Italian Ministry of Health (Current Research funds). MR, ST and JDG were supported by Fondazione Umberto Veronesi.

Author information

Authors and Affiliations

  1. Bone Physiopathology Research Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children’s Hospital, IRCCS, Viale San Paolo 15, 00146, Rome, Italy

    M. Rossi, S. Terreri, G. Battafarano & A. Del Fattore

  2. Rare Diseases and Medical Genetic Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    I. Rana, P. S. Buonuomo, M. V. Gonfiantini & A. Bartuli

  3. Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University, Rome, Italy

    L. Di Giuseppe & Cristiana Cipriani

  4. Clinical Laboratory, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    M. D’Agostini & O. Porzio

  5. Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy

    O. Porzio

  6. Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy

    J. Di Gregorio

  7. Pediatric Palliative Care Center, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    A. Jenkner

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  1. M. Rossi
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Contributions

MR, ST, GB, LDG, MDA, OP and JDG performed analysis of bone cells precursors and contributed to the discussion of the results. IR, PSB, MVG, CC and AJ recruited the patients and performed the ELISA assays. ADF and AB designed and supervised the work and wrote the paper. All authors reviewed the manuscript and approved the final version. ADF is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding author

Correspondence to A. Del Fattore.

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Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Ethical approval

All the procedures performed in this study involving human participants were in accordance with the ethical standards as laid down in the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Both patients and parents were required to sign the informed consent form to participate in the study.

Study approval statement

The study was approved by Bambino Gesù Children’s Hospital's ethics committee (Protocol No. GR-2019-12370244, 01/02/2021).

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Supplementary Information

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40618_2024_2365_MOESM1_ESM.tif

Supplementary file1 FACS negative staining controls. A Representative FACS plots of Fluorescence Minus One (FMO) control for A CD115-BV605 and B CD34-BV650 staining. Left panels: FMO control; right panels: fully stained (TIF 1208 KB)

40618_2024_2365_MOESM2_ESM.tif

Supplementary file2 Correlations of serum markers with osteoclast precursor populations. A Correlations of RANK-L and CD16− (left panel) or CD16+ (right panel) cell percentage in the gate of CD14+CD11b+ cells. B Correlation of OPG and CD115+ cell percentage in the gate of CD14+CD11b+ cells. The p values are obtained from linear regression analysis (TIF 904 KB)

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Rossi, M., Terreri, S., Battafarano, G. et al. Analysis of circulating osteoclast and osteogenic precursors in patients with Gorham-Stout disease. J Endocrinol Invest (2024). https://doi.org/10.1007/s40618-024-02365-8

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