Loss of Grem1-lineage chondrogenic progenitor cells causes osteoarthritis

Jia Q. Ng, Toghrul H. Jafarov, Christopher B. Little, Tongtong Wang, Abdullah M. Ali, Yan Ma, Georgette A. Radford, Laura Vrbanac, Mari Ichinose, Samuel Whittle, David J. Hunter, Tamsin R. M. Lannagan, Nobumi Suzuki, Jarrad M. Goyne, Hiroki Kobayashi, Timothy C. Wang, David R. Haynes, Danijela Menicanin, Stan Gronthos, Daniel L. Worthley (), Susan L. Woods () and Siddhartha Mukherjee ()
Additional contact information
Jia Q. Ng: Faculty of Health and Medical Sciences, University of Adelaide
Toghrul H. Jafarov: Columbia University Medical Center
Christopher B. Little: Raymond Purves Bone & Joint Research Laboratories, Kolling Institute, University of Sydney Faculty of Medicine and Health, Royal North Shore Hospital
Tongtong Wang: Faculty of Health and Medical Sciences, University of Adelaide
Abdullah M. Ali: Columbia University Medical Center
Yan Ma: Columbia University Medical Center
Georgette A. Radford: Faculty of Health and Medical Sciences, University of Adelaide
Laura Vrbanac: Faculty of Health and Medical Sciences, University of Adelaide
Mari Ichinose: Faculty of Health and Medical Sciences, University of Adelaide
Samuel Whittle: Faculty of Health and Medical Sciences, University of Adelaide
David J. Hunter: University of Sydney
Tamsin R. M. Lannagan: Faculty of Health and Medical Sciences, University of Adelaide
Nobumi Suzuki: Faculty of Health and Medical Sciences, University of Adelaide
Jarrad M. Goyne: Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute
Hiroki Kobayashi: Faculty of Health and Medical Sciences, University of Adelaide
Timothy C. Wang: Columbia University
David R. Haynes: Faculty of Health and Medical Sciences, University of Adelaide
Danijela Menicanin: Faculty of Health and Medical Sciences, University of Adelaide
Stan Gronthos: Faculty of Health and Medical Sciences, University of Adelaide
Daniel L. Worthley: Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute
Susan L. Woods: Faculty of Health and Medical Sciences, University of Adelaide
Siddhartha Mukherjee: Columbia University Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Osteoarthritis (OA) is characterised by an irreversible degeneration of articular cartilage. Here we show that the BMP-antagonist Gremlin 1 (Grem1) marks a bipotent chondrogenic and osteogenic progenitor cell population within the articular surface. Notably, these progenitors are depleted by injury-induced OA and increasing age. OA is also caused by ablation of Grem1 cells in mice. Transcriptomic and functional analysis in mice found that articular surface Grem1-lineage cells are dependent on Foxo1 and ablation of Foxo1 in Grem1-lineage cells caused OA. FGFR3 signalling was confirmed as a promising therapeutic pathway by administration of pathway activator, FGF18, resulting in Grem1-lineage chondrocyte progenitor cell proliferation, increased cartilage thickness and reduced OA. These findings suggest that OA, in part, is caused by mechanical, developmental or age-related attrition of Grem1 expressing articular cartilage progenitor cells. These cells, and the FGFR3 signalling pathway that sustains them, may be effective future targets for biological management of OA.

Date: 2023
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DOI: 10.1038/s41467-023-42199-1

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