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Original Article | Open Access

Mobilization of monocytic myeloid-derived suppressor cells is regulated by PTH1R activation in bone marrow stromal cells

Eun Jung Lee1,2,, Kyoung Jin Lee1,2,, Seungpil Jung3, Kyong Hwa Park4, Serk In Park1,2,5 ( )
Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea
The BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
Division of Breast and Endocrine Surgery, Department of Surgery, Korea University Anam Hospital, Seoul, Republic of Korea
Division of Oncology and Hematology, Department of Internal Medicine, Korea University Anam Hospital, Seoul, Republic of Korea
Vanderbilt Center for Bone Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

These authors contributed equally: Eun Jung Lee, Kyoung Jin Lee.

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Abstract

Myeloid-derived suppressor cells (MDSCs) are bone marrow (BM)-derived immunosuppressive cells in the tumor microenvironment, but the mechanism of MDSC mobilization from the BM remains unclear. We investigated how BM stromal cell activation by PTH1R contributes to MDSC mobilization. PTH1R activation by parathyroid hormone (PTH) or PTH-related peptide (PTHrP), a tumor-derived counterpart, mobilized monocytic (M-) MDSCs from murine BM without increasing immunosuppressive activity. In vitro cell-binding assays demonstrated that α4β1 integrin and vascular cell adhesion molecule (VCAM)-1, expressed on M-MDSCs and osteoblasts, respectively, are key to M-MDSC binding to osteoblasts. Upon PTH1R activation, osteoblasts express VEGF-A and IL6, leading to Src family kinase phosphorylation in M-MDSCs. Src inhibitors suppressed PTHrP-induced MDSC mobilization, and Src activation in M-MDSCs upregulated two proteases, ADAM-17 and MMP7, leading to VCAM1 shedding and subsequent disruption of M-MDSC tethering to osteoblasts. Collectively, our data provide the molecular mechanism of M-MDSC mobilization in the bones of tumor hosts.

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Bone Research
Volume 11,
December 2023
Article number: 22
DOI: 10.1038/s41413-023-00255-y
Cite this article:
Lee EJ, Lee KJ, Jung S, et al. Mobilization of monocytic myeloid-derived suppressor cells is regulated by PTH1R activation in bone marrow stromal cells. Bone Research, 2023, 11: 22. https://doi.org/10.1038/s41413-023-00255-y

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Received: 21 June 2022
Revised: 23 January 2023
Accepted: 01 March 2023
Published: 21 April 2023
© The Author(s) 2023

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