Loss of Grem1-lineage chondrogenic progenitor cells causes osteoarthritis

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.

Transforming growth factor beta signaling and craniofacial development: modeling human diseases in zebrafish

“…Interestingly, many variants associated with OA risk are frequently found in non-coding regulatory elements rather than the open reading frames of coding genes, suggesting that slight alterations to the expression of genes, rather than the activity/function of the gene itself, are responsible for increased OA risk ( Aubourg et al, 2022 ). Moreover, loss of Grem1- expressing chondrogenic progenitor cells in mouse joints results in an OA phenotype, further implicating altered BMP signaling in the progression of this disease ( Ng et al, 2023 ). Additionally, it has been hypothesized that slight variations to the way the joint develops during embryogenesis (via modulating GDF5 expression/activity) can influence how a joint functions in adulthood, which may influence the likelihood of developing OA later in life ( Kiapour et al, 2018 ; Pregizer et al, 2018 ; Richard et al, 2020 ).…”

Prg4-Expressing Chondroprogenitor Cells in the Superficial Zone of Articular Cartilage

“…A recent study identified that the bone morphogenetic protein (BMP) antagonist Gremlin 1 (Grem1), a secreted protein, marked the SFZ progenitor cell population in adult mice’s AC and confirmed the loss of Grem1-lineage articular cells with age [ 38 ]. Employing the Grem1-CreERt2 mouse strain, tamoxifen was administered at postnatal days 4–6 (P4–6), and Grem1-lineage chondroprogenitor cells were immediately observed within the cartilaginous epiphysis and meniscus (about 39% of chondrocytes).…”

“…Employing the Grem1-CreERt2 mouse strain, tamoxifen was administered at postnatal days 4–6 (P4–6), and Grem1-lineage chondroprogenitor cells were immediately observed within the cartilaginous epiphysis and meniscus (about 39% of chondrocytes). In later stages of joint development, the Grem1-lineage progeny cells transdifferentiated to osteoblasts of subchondral bone during secondary ossification center formation, and by one month they populated the entire joint, including the third part of the AC [ 38 ]. However, tamoxifen injected at 6 weeks of age revealed Grem1-positive cells in the SFZ of articular cartilage only [ 38 ].…”

“…In later stages of joint development, the Grem1-lineage progeny cells transdifferentiated to osteoblasts of subchondral bone during secondary ossification center formation, and by one month they populated the entire joint, including the third part of the AC [ 38 ]. However, tamoxifen injected at 6 weeks of age revealed Grem1-positive cells in the SFZ of articular cartilage only [ 38 ]. Immunofluorescence staining of tissue samples showed overlap between articular Grem1-lineage cells and Prg4-expressing progenitors (12% of the AC double positive), but the Grem1-lineage cells were largely distinct from collagen type II (Col2)-expressing chondrocytes [ 38 ].…”

“…However, tamoxifen injected at 6 weeks of age revealed Grem1-positive cells in the SFZ of articular cartilage only [ 38 ]. Immunofluorescence staining of tissue samples showed overlap between articular Grem1-lineage cells and Prg4-expressing progenitors (12% of the AC double positive), but the Grem1-lineage cells were largely distinct from collagen type II (Col2)-expressing chondrocytes [ 38 ]. Clustering of scRNAseq data for the Grem1 lineage revealed five distinct cell clusters [ 38 ].…”