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ResearchIn-Press PreviewBone biologyCell biology Open Access | 10.1172/jci.insight.205996

RSPO2 synergizes with BMP2 to enhance Wnt-dependent bone healing

Buchan Jiang,1 Erin B. Meymarian,1 Shije Shahin,1 Jack T. Wilkening,1 Alexander J. Knights,1 Archana Sanjay,2 Tristan Maerz,1 Yadav Wagley,1 and Kurt D. Hankenson1

1Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Orthopaedics, Musculoskeletal Institute, School of Medicine, UConn Health, Farmington, United States of America

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1Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Orthopaedics, Musculoskeletal Institute, School of Medicine, UConn Health, Farmington, United States of America

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1Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Orthopaedics, Musculoskeletal Institute, School of Medicine, UConn Health, Farmington, United States of America

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1Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Orthopaedics, Musculoskeletal Institute, School of Medicine, UConn Health, Farmington, United States of America

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1Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Orthopaedics, Musculoskeletal Institute, School of Medicine, UConn Health, Farmington, United States of America

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1Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Orthopaedics, Musculoskeletal Institute, School of Medicine, UConn Health, Farmington, United States of America

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1Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Orthopaedics, Musculoskeletal Institute, School of Medicine, UConn Health, Farmington, United States of America

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1Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Orthopaedics, Musculoskeletal Institute, School of Medicine, UConn Health, Farmington, United States of America

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1Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, United States of America

2Department of Orthopaedics, Musculoskeletal Institute, School of Medicine, UConn Health, Farmington, United States of America

Find articles by Hankenson, K. in: PubMed | Google Scholar |

Published October 20, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.205996.
Copyright © 2026, Jiang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 20, 2026 - Version history
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Abstract

Bone morphogenetic protein-2 (BMP2) is used clinically to promote bone regeneration, but dose-limiting side effects restrict its clinical utility. Canonical Wnt signaling is essential for bone formation, and R-spondin-2 (RSPO2) is a secreted Wnt agonist highly expressed by osteoprogenitors. We found that BMP2 strongly induced RSPO2 during early human mesenchymal stem cell (hMSC) osteoblast differentiation. Recombinant RSPO2 synergized with BMP2 in both hMSCs and MC3T3-E1 preosteoblasts, whereas RSPO2 silencing impaired BMP2-driven osteogenic responses. In a murine critical-size calvarial defect model, co-delivery of RSPO2 and a suboptimal dose of BMP2 yielded significantly more new bone than BMP2 alone, while RSPO2 alone was ineffective. Enhanced canonical Wnt activation with BMP2-RSPO2 co-treatment was shown with an in vivo Wnt reporter mouse. Bulk RNA sequencing of MC3T3-E1 cells revealed that BMP2-RSPO2 co-treatment differentially activated osteogenesis-related genes and pathways compared to BMP2 alone. The guanine exchange factor (GEF), Prex1, was selectively upregulated by BMP2-RSPO2 co-treatment, and was required for RSPO2-mediated enhancement of BMP2-induced osteoblastogenesis. These findings identify RSPO2 as an enhancer of BMP2-driven osteogenesis, amplifying Wnt activation and involving PREX1-dependent signaling. RSPO2 or PREX1 activation may represent a co-therapy that could enhance BMP2 efficacy while mitigating the adverse effects of high-dose BMP2.

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