Abstract
Osteoarthritis (OA), characterised by cartilage destruction, is the most common degenerative joint disease. However, no effective disease-modifying OA therapy is currently available. Herein, we report orphan nuclear receptor small heterodimer partner (SHP, NR0B2) as a novel catabolic regulator of OA pathogenesis. NR0B2 expression was markedly downregulated in cartilage from patients with OA. Global or chondrocyte-specific Nr0b2 deletion in male mice exacerbated OA-related pain and structural changes following surgical destabilization of the medial meniscus, accompanied by increased matrix metalloproteinase (MMP)-3 and MMP-13 expression in chondrocytes. Conversely, adeno-associated virus-mediated Nr0b2 overexpression in knee joints of male mice protected against accelerated knee OA caused by Nr0b2 deficiency. Mechanistically, NR0B2 inhibited IKKβ kinase activity via IKK complex interaction, downregulating NF-κB signalling. Our results demonstrate that NR0B2 has a chondroprotective role in OA progression by regulating matrix-degrading enzymes in an IKKβ/NF-κB-dependent manner, and gene therapy targeting Nr0b2 may be a promising therapeutic strategy for OA.
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All data generated and/or analyzed during this study are included in this published article and its Supplementary Information/Source Data files and are available from the corresponding author on reasonable request. Source data are provided with this paper.
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Acknowledgements
This work was supported by the Basic Science Research Program (2023R1A2C3005244 to C.-H.L.), (RS-2024-00450466 to Y.-H.K.) of the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT, and by the KRIBB Research Initiative Program (KGM1312612).
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J.K., Y.-H.K., and C.-H.L. conceived and supervised the study. E.-J.K., J.K., Y.-H.K., and C.-H.L. designed all the experiments. E.-J.K. conducted all animal, cell biological, and molecular biological experiments, with assistance from J.-R.N. and J.-H.K., and analyzed and interpreted the relevant data under the supervision of Y.-H.K. and C.-H.L. J.-P.A., M.-C.K., J.H.C., Y.-K.C., I.-B.L., D.-H.C., and Y.-J.S. provided technical support for the animal experiments. E.-J.K. and J.A.P. performed human studies and analyzed and interpreted the relevant data under the supervision of B.J.K., J.-O.J., and J.K. Y.S.J. and H.-S.C. provided the materials and technical support for the adenovirus-related experiments. K.-S.K., J.H.H., Y.-B.K., J.-S.L., J.K., Y.-H.K., and C.-H.L. provided assistance with data interpretation and critical scientific discussion. E.-J.K. drafted the manuscript, and J.K., Y.-H.K., and C.-H.L. edited the manuscript. All authors have read and approved the final manuscript.
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Kang, EJ., Noh, JR., Kim, JH. et al. Small heterodimer partner protects against osteoarthritis by inhibiting IKKβ/NF-κB-mediated matrix-degrading enzymes in chondrocytes. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69864-5
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DOI: https://doi.org/10.1038/s41467-026-69864-5
