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Loss of Grem1-articular cartilage progenitor cells causes osteoarthritis

Osteoarthritis (OA), which carries an enormous disease burden across the world, is characterised by irreversible degeneration of articular cartilage (AC), and subsequently bone. The cellular cause of OA is unknown. Here, using lineage tracing in mice, we show that the BMP-antagonist Gremlin 1 (Grem1...

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Autores principales: Ng, Jia Q., Jafarov, Toghrul H., Little, Christopher B., Wang, Tongtong, Ali, Abdullah, Ma, Yan, Radford, Georgette A, Vrbanac, Laura, Ichinose, Mari, Whittle, Samuel, Hunter, David, Lannagan, Tamsin RM, Suzuki, Nobumi, Goyne, Jarrad M., Kobayashi, Hiroki, Wang, Timothy C., Haynes, David, Menicanin, Danijela, Gronthos, Stan, Worthley, Daniel L., Woods, Susan L., Mukherjee, Siddhartha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10081168/
https://www.ncbi.nlm.nih.gov/pubmed/37034712
http://dx.doi.org/10.1101/2023.03.29.534651
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author Ng, Jia Q.
Jafarov, Toghrul H.
Little, Christopher B.
Wang, Tongtong
Ali, Abdullah
Ma, Yan
Radford, Georgette A
Vrbanac, Laura
Ichinose, Mari
Whittle, Samuel
Hunter, David
Lannagan, Tamsin RM
Suzuki, Nobumi
Goyne, Jarrad M.
Kobayashi, Hiroki
Wang, Timothy C.
Haynes, David
Menicanin, Danijela
Gronthos, Stan
Worthley, Daniel L.
Woods, Susan L.
Mukherjee, Siddhartha
author_facet Ng, Jia Q.
Jafarov, Toghrul H.
Little, Christopher B.
Wang, Tongtong
Ali, Abdullah
Ma, Yan
Radford, Georgette A
Vrbanac, Laura
Ichinose, Mari
Whittle, Samuel
Hunter, David
Lannagan, Tamsin RM
Suzuki, Nobumi
Goyne, Jarrad M.
Kobayashi, Hiroki
Wang, Timothy C.
Haynes, David
Menicanin, Danijela
Gronthos, Stan
Worthley, Daniel L.
Woods, Susan L.
Mukherjee, Siddhartha
author_sort Ng, Jia Q.
collection PubMed
description Osteoarthritis (OA), which carries an enormous disease burden across the world, is characterised by irreversible degeneration of articular cartilage (AC), and subsequently bone. The cellular cause of OA is unknown. Here, using lineage tracing in mice, we show that the BMP-antagonist Gremlin 1 (Grem1) marks a novel chondrogenic progenitor (CP) cell population in the articular surface that generates joint cartilage and subchondral bone during development and adulthood. Notably, this CP population is depleted in injury-induced OA, and with age. OA is also induced by toxin-mediated ablation of Grem1 CP cells in young mice. Transcriptomic analysis and functional modelling in mice revealed articular surface Grem1-lineage cells are dependent on Foxo1; ablation of Foxo1 in Grem1-lineage cells led to early OA. This analysis identified FGFR3 signalling as a therapeutic target, and injection of its activator, FGF18, caused proliferation of Grem1-lineage CP cells, increased cartilage thickness, and reduced OA pathology. We propose that OA arises from the loss of CP cells at the articular surface secondary to an imbalance in progenitor cell homeostasis and present a new progenitor population as a locus for OA therapy.
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spelling pubmed-100811682023-04-08 Loss of Grem1-articular cartilage progenitor cells causes osteoarthritis Ng, Jia Q. Jafarov, Toghrul H. Little, Christopher B. Wang, Tongtong Ali, Abdullah Ma, Yan Radford, Georgette A Vrbanac, Laura Ichinose, Mari Whittle, Samuel Hunter, David Lannagan, Tamsin RM Suzuki, Nobumi Goyne, Jarrad M. Kobayashi, Hiroki Wang, Timothy C. Haynes, David Menicanin, Danijela Gronthos, Stan Worthley, Daniel L. Woods, Susan L. Mukherjee, Siddhartha bioRxiv Article Osteoarthritis (OA), which carries an enormous disease burden across the world, is characterised by irreversible degeneration of articular cartilage (AC), and subsequently bone. The cellular cause of OA is unknown. Here, using lineage tracing in mice, we show that the BMP-antagonist Gremlin 1 (Grem1) marks a novel chondrogenic progenitor (CP) cell population in the articular surface that generates joint cartilage and subchondral bone during development and adulthood. Notably, this CP population is depleted in injury-induced OA, and with age. OA is also induced by toxin-mediated ablation of Grem1 CP cells in young mice. Transcriptomic analysis and functional modelling in mice revealed articular surface Grem1-lineage cells are dependent on Foxo1; ablation of Foxo1 in Grem1-lineage cells led to early OA. This analysis identified FGFR3 signalling as a therapeutic target, and injection of its activator, FGF18, caused proliferation of Grem1-lineage CP cells, increased cartilage thickness, and reduced OA pathology. We propose that OA arises from the loss of CP cells at the articular surface secondary to an imbalance in progenitor cell homeostasis and present a new progenitor population as a locus for OA therapy. Cold Spring Harbor Laboratory 2023-03-30 /pmc/articles/PMC10081168/ /pubmed/37034712 http://dx.doi.org/10.1101/2023.03.29.534651 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Ng, Jia Q.
Jafarov, Toghrul H.
Little, Christopher B.
Wang, Tongtong
Ali, Abdullah
Ma, Yan
Radford, Georgette A
Vrbanac, Laura
Ichinose, Mari
Whittle, Samuel
Hunter, David
Lannagan, Tamsin RM
Suzuki, Nobumi
Goyne, Jarrad M.
Kobayashi, Hiroki
Wang, Timothy C.
Haynes, David
Menicanin, Danijela
Gronthos, Stan
Worthley, Daniel L.
Woods, Susan L.
Mukherjee, Siddhartha
Loss of Grem1-articular cartilage progenitor cells causes osteoarthritis
title Loss of Grem1-articular cartilage progenitor cells causes osteoarthritis
title_full Loss of Grem1-articular cartilage progenitor cells causes osteoarthritis
title_fullStr Loss of Grem1-articular cartilage progenitor cells causes osteoarthritis
title_full_unstemmed Loss of Grem1-articular cartilage progenitor cells causes osteoarthritis
title_short Loss of Grem1-articular cartilage progenitor cells causes osteoarthritis
title_sort loss of grem1-articular cartilage progenitor cells causes osteoarthritis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10081168/
https://www.ncbi.nlm.nih.gov/pubmed/37034712
http://dx.doi.org/10.1101/2023.03.29.534651
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