A Mendelian randomization study: Association of Cathepsin with Osteoarticular Muscle Diseases

Objective: The cathepsin present in lysosomal cells may be closely related to bone, muscle & joint diseases (BMJD)including osteoporosis and osteoarthritis, but its specific mechanism of action still needs further research and exploration. The aim of this study is to use a two-sample Mendelian randomization (MR) comprehensive analysis to explore the causal relationship between cathepsin and the risk of BMJD. Method: Based on the published genetic data, this study used a two-sample Mendelian randomization (MR) comprehensive analysis method to explore the causality of morbidity risk between 9 cathepsins with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, peripheral arthritis(Crohn's disease, ulcerative colitis, and postdysentery joint disease), psoriatic joint disease, lower back pain, spinal stenosis, osteoporosis, bone necrosis, and connective tissue disease, cartilage diseases, benign tumors, myositis, synovitis and tenosynovitis (radial styloid tenosynovitis), shoulder periarthritis, neuromuscular junction diseases, and muscle atrophy. Meanwhile, in order to further reveal the possibility of reverse causality, we conducted a reverse Mendelian randomization analysis,using Cochran's Q test and MR Egger intercept test to evaluate the heterogeneity, horizontal pleiotropy,and stability of SNPs. Result: The study found that cathepsin B may be negatively correlated with ulcerative colitis arthritis, cathepsin E may be positively correlated with osteoarthritis, cathepsin E may be negatively correlated with musculoskeletal connective tissue diseases, cathepsin G may be positively correlated with ankylosing spondylitis, and cathepsin L2 may be positively correlated with cartilage diseases, Cathepsin S may be positively correlated with rheumatoid arthritis; through reverse MR analysis, we found that osteoporosis may lead to an increase in cathepsin B. In addition, we did not find any relationship between synovitis, tenosynovitis, shoulder periarthritis, bone necrosis, neuritis, osteoporosis,Crohn's arthritis,dysentery arthritis, psoriatic arthritis, low back pain,and cathepsin. Conclusion: Based on large-scale population studies of GWAS data, we conducted MR analysis and demonstrated a close relationship between cathepsins and BMJD from a genetic perspective, which may provide a basis for the pathogenesis of BMJD and provide new directions for future treatment strategies.