Enhancing GFPT1 expression with glutamine protects chondrocytes in osteoarthritis

Objective: Osteoarthritis (OA) is the leading joint disease without currently available disease-modified drugs. The current study aimed to identify potential drug targets that could decelerate the progression of OA.

Methods: We employed Mendelian Randomization (MR) and colocalization analysis to identify therapeutic targets linked to 12 OA traits within 2645 targets. Bulk and single-cell RNA-seq analyses of cartilage samples were conducted to pinpoint GFPT1 and determine the specific cell types in which GFPT1 is expressed. Overexpression and knockdown experiments further explored the expression and potential OA-associated functions of GFPT1.

Results: GFPT1 has been identified as a cross-OA therapeutic candidate gene by MR analysis. We observed a significant reduction in GFPT1 expression in OA cartilage compared to normal cartilage from public transcriptomic data of both humans and mice. In vitro experiments confirmed these findings at both mRNA and protein levels in OA chondrocytes. IL-1β stimulation leads to downregulation of GFPT1. We confirmed that supplementary glutamine can reverse the suppression of GFPT1 more effectively than glucosamine in the OA in vitro model. GFPT1 upregulation with glutamine, in turn, further increases the expression of COL2A1 and decreases the expression of MMP13.

Conclusions: Our findings demonstrate that GFPT1 is downregulated in OA, and overexpressing GFPT1 can restore the anabolic metabolism of cartilage. Compared to glucosamine, enhancing GFPT1 expression with glutamine to influence the hexosamine biosynthetic pathway may offer a more effective therapeutic strategy for OA.

Anabolic metabolism; GFPT1; HBP; Mendelian randomization; Osteoarthritis; scRNA-seq.