Genetic insights into serum cathepsins as diagnostic and therapeutic targets in knee and hip osteoarthritis

Abstract

Osteoarthritis (OA) is a chronic disease due to the deterioration of cartilage structure and function, involving the progressive degradation of the cartilage extracellular matrix. Cathepsins, lysosomal cysteine proteases, play pivotal roles in various biological and pathological processes, particularly in protein degradation. Excess cathepsins levels are reported to contribute to the development of OA. However, the causal relationship between the cathepsin family and knee and hip OA remains uncertain. Therefore, this study utilized bidirectional Mendelian Randomization (MR) analyses to explore this causal association. Our results indicated that elevated serum levels of cathepsin O increase the overall risk of knee OA, while increased serum levels of cathepsin H enhance the risk of hip OA. Conversely, the reverse MR analyses did not reveal a reverse causal relationship between them. In summary, OA in different anatomical locations may genetically result from pathological elevations in different serum cathepsin isoforms, which could be utilized as diagnostic and therapeutic targets in clinical practice.

Keywords: Cathepsins; Extracellular matrix degradation; Hip osteoarthritis; Knee osteoarthritis; Mendelian randomization analyses.

Figure 1

MR design for causal analysis of serum cathepsins and knee/hip OA on genetic predisposition.

Figure 2

(A) The forest plot of the causal effect of cathepsins on Knee OA; (B) The forest plot of the causal effect of Knee OA on cathepsins.

Figure 3

The MR results of cathepsin O on knee OA. (A) Scatter plot showing the causal effect of cathepsin O on knee OA. (B) Forest plot for the overall causal effects of cathepsin O on knee OA. (C) Leave-one-out plot for the causal effect of cathepsin O on knee OA. (D) Funnel plot of SNPs related to cathepsin O and knee OA.

Figure 4

(A) The forest plot of the causal effect of cathepsins on Hip OA; (B) The forest plot of the causal effect of Hip OA on cathepsins.

Figure 5

The MR results of cathepsin H on hip OA. (A) Scatter plot showing the causal effect of cathepsin H on hip OA. (B) Forest plot for the overall causal effects of cathepsin H on hip OA. (C) Leave-one-out plot for the causal effect of cathepsin H on hip OA. (D) Funnel plot of SNPs related to cathepsin H and hip OA.