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. 2022 Dec 1;28(12):2633–2645. doi: 10.1038/s41591-022-02059-9

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Extended Data Fig. 5 — a, Log₂[FC] (log2FC) of genes significantly regulated at either 2 h, 7 or 21 d after LNA043 treatment in damaged OA cartilage compared to placebo (Limma moderated t-test, Bejamini and Hochberg, P ≤ 0.05). Most-significantly regulated genes are shown in bold; fold upregulation is visualized by red color intensity, fold downregulation by blue color intensity, adjusted P-values (adj. P) ≤ 0.05 are shaded in yellow b, Temporal counter-regulation of RAAK OA signatures by LNA043. Signatures were generated from the RAAK study published by Ramos et al.³⁸. The enrichment significance for each geneset, defined as the negative log₁₀ of the False Discovery Rate (-log10(FDR)), is plotted over time. Signs depict the direction of enrichment (positive for geneset upregulation and negative for geneset downregulation). Heatmap of the expression profiles of individual genes in the RAAK signatures. OA-associated changes in damaged versus undamaged OA cartilage are reverted by LNA043 treatment across all three timepoints in the FIH study. Downregulated genes, besides FN1 and OPN, encode TNFRSF11B/OPG (a subchondral bone remodeling regulator in OA^39,40), inflammatory mediators like cytokine receptor-like factor 1 (CRLF1)⁸⁴ and the middle zone articular cartilage marker C-X-C motif chemokine ligand 14 (CXCL14)⁸⁵, as well as nerve growth factor (NGF) the key mediator of pain in OA (reviewed by Dietz et al.⁶³). Upregulated genes encode cartilage development pathway members whose expression correlates negatively with OA, besides CHRDL2, FRZB and COL9A1, the adipokine chemerin (RARRES2)⁸⁶. Data are expressed as log ₂[FC](log2FC). c, Temporal expression profiles of selected members of the RAAK signatures in damaged and undamaged cartilage upon LNA043 treatment. Expression levels are expressed as log₂[CPM] (log2CPM). Data is represented as mean ± s.d.