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Drug repurposing strategy reveals Cobimetinib as a promising disease-modifying drug for Osteoarthritis

ABSTRACT: Osteoarthritis (OA) is a common disabling disease for which no effective pharmacological therapy exists. The progression of osteoarthritis is characterized by the loss of homeostasis in the cartilage. Since in the early stages of the disease, a phenotypic switch is seen in which articular chondrocytes become hypertrophic and promote degradation of the cartilage extracellular matrix, targeting this phenomenon might be the key to developing a disease-modifying osteoarthritis drug (DMOAD). In this study, the signature reversing principle combined with a drug repurposing strategy was used to accelerate the identiﬁcation and validation of potential DMOADs. Starting from single-cell transcriptomic analysis of patient-derived cartilage, we identified 6 drugs predicted to reduce chondrocyte hypertrophy. Subsequent in vitro evaluation in human chondrocytes and cartilage explants demonstrated that Cobimetinib, a MEK1/2 inhibitor, reduced chondrocyte hypertrophy-related and catabolic gene expression, such as SPP1, COL10A1, MMP13 and ADAMTS5, while promoting collagen type 2 and aggrecan gene expression. Finally, single-cell RNA sequencing performed on osteoarthritic cartilage explants exposed to Cobimetinib ex vivo confirmed the anti-hypertrophic effect of Cobimetinib on hypertrophy-related gene expression and additionally showed a deletion of chondrocytes with a fibrotic phenotype. This study is a proof of concept that omics data together with a drug repurposing strategy accelerate drug discovery in diseases like osteoarthritis and could quickly lead to many new therapeutic roles for safe and effective drugs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290973 | GEO | 2026/01/07

REPOSITORIES: GEO

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Project description:Autologous chondrocyte transplantation (ACT) is a routine technique to regenerate focal cartilage lesions. However, patients with osteoarthritis (OA) are lacking an appropriate long-lasting treatment alternative, partly since it is not known if chondrocytes from OA patients have the same chondrogenic differentiation potential as chondrocytes from donors not affected by OA. Articular chondrocytes from patients with OA undergoing total knee replacement (Mankin Score >3, AhlbÃ¤ck Score >2) and from patients undergoing ACT, here referred to as normal donors (ND), were isolated applying protocols used for ACT. Their chondrogenic differentiation potential was evaluated both in high-density pellet and scaffold (Hyaff-11) cultures by histological proteoglycan assessment (Bern Score) and immunohistochemistry for collagen types I and II. Chondrocytes cultured in monolayer and scaffolds were subjected to gene expression profiling using genome-wide oligonucleotide microarrays. Expression data were verified by using quantitative RT-PCR. Chondrocytes from ND and OA donors demonstrated accumulation of comparable amounts of cartilage matrix components, including sulphated proteoglycans and collagen types I and II. The mRNA expression of cartilage markers (COL2A1, COMP, aggrecan, CRTL1, SOX9) and genes involved in matrix synthesis (biglycan, COL9A2, COL11A1, TIMP4, CILP2) was highly induced in 3D cultures of chondrocytes from both donor groups. Genes associated with hypertrophic or OA cartilage (COL10A1, RUNX2, periostin, ALP, PTHR1, MMP13, COL1A1, COL3A1) were not significantly regulated between the two groups of donors. The expression of 661 genes, including COMP, FN1, and SOX9, were differentially regulated between OA and ND chondrocytes cultured in monolayer. During scaffold culture, the differences diminished between the OA and ND chondrocytes, and only 184 genes were differentially regulated. Only few genes were differentially expressed between OA and ND chondrocytes in Hyaff-11 culture. The risk of differentiation into hypertrophic cartilage does not seem to be increased for OA chondrocytes. Our findings suggest that the chondrogenic capacity is not significantly affected by OA and OA chondrocytes fulfill the requirements for matrix-associated ACT. Experiment Overall Design: Gene expression profiles of monolayer cultures (ML; passage 2) and Hyaff-11 scaffold cultures (3D; 14 days in vitro) of chondrocytes from 3 normal donors (ND; underwent ACT treatment) and 3 donors suffering from Osteoarthritis (OA; underwent knee replacement surgery) were determined. Comparative analyses between 3D and ML cultures (3D vs. ML) were performed to assess differentiation capacity of ND and OA chondrocytes. Furthermore, OA-related differences were determined comparing OA and ND monolayers as well as scaffold cultures (each OA vs. ND).

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Drug repurposing strategy reveals Cobimetinib as a promising disease-modifying drug for Osteoarthritis

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