Therapeutic interleukin-2 rewires skeletal-immune circuits to reverse postmenopausal bone loss

Zhou, P., Feng, J., Zhang, Y., Liu, Y., Ma, D., Xue, A., Wei, W., Sun, L., Yu, D., Zheng, T.

The Division of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia · biorxiv

Paper

Abstract

Postmenopausal osteoporosis results from excessive osteoclast activity, but the immune circuits that limit osteoclastogenesis in the bone marrow remain poorly understood. Here, we tested a clinically accessible immunotherapy low-dose interleukin-2 (IL-2) as a therapeutic intervention in mice with established ovariectomy-induced bone loss, integrating microcomputed tomography imaging, single-cell transcriptomics, genetic perturbation, and human monocyte-osteoclast assays. Therapeutic administration of IL-2 reversed trabecular bone loss, expanded CXCR3 regulatory T cells in bone marrow, and promoted IL-10- and CGRP-producing ILC2s that were required for protection. IL-2 also acted directly on the osteoclast lineage, suppressing mouse and human osteoclastogenesis through activation of a STAT1-IRF1-dependent IFN program in RANKL-stimulated monocytes. Together, these data define an IL-2-responsive skeletal-immune network that can be therapeutically engaged to suppress osteoclastogenesis, which opens new avenues for cytokine-based immunotherapies in postmenopausal osteoporosis and related bone disorders.

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Research summary

Therapeutic administration of low-dose interleukin-2 can reverse postmenopausal bone loss by modulating immune circuits that regulate osteoclastogenesis. This paper is relevant as it addresses a mechanism underlying bone loss associated with aging, specifically postmenopausal osteoporosis, and explores a potential therapeutic intervention that could impact age-related bone disorders.

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