Loss of Grem1-lineage chondrogenic progenitor cells causes osteoarthritis

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. This study reveals an important chondrocytic progenitor population for maintenance of adult articular cartilage marked by Gremlin 1. Loss of these progenitors causes osteoarthritis and suggests methods to sustain them may be effective future targets for management of osteoarthritis.