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bioRxiv · 10.64898/2026.01.07.696511

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.
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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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Zhou, P., Feng, J., Zhang, Y., Liu, Y., Ma, D., Xue, A., Wei, W., Sun, L., Yu, D., Zheng, T.. 2026-01-08. Therapeutic interleukin-2 rewires skeletal-immune circuits to reverse postmenopausal bone loss. https://doi.org/10.64898/2026.01.07.696511

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