Causal Associations of Inflammatory Cytokines With Osteosarcopenia: Insights From Mendelian Randomization and Single Cell Analysis

<b>Background:</b> Osteosarcopenia, the coexistence of osteoporosis and sarcopenia, poses significant challenges in aging populations due to its dual impact on bone and muscle health. Inflammation, mediated by specific cytokines, is thought to play a crucial role in the development of osteosarcopenia, though the underlying mechanisms are not fully understood. <b>Objective:</b> This study aimed to clarify the causal role of circulating cytokines in the pathogenesis of osteosarcopenia by employing mendelian randomization (MR) and single-cell RNA sequencing (scRNA-seq) to identify cell-specific cytokine expression patterns. The ultimate objective was to uncover potential pathological mechanisms and therapeutic targets for treating osteosarcopenia. <b>Methods:</b> A two-sample MR approach was employed, leveraging publicly available genome-wide association study (GWAS) data from multiple cohorts. A total of 91 circulating cytokines were examined using genetic instruments, and their causal effects on traits related to osteoporosis and sarcopenia were evaluated. Various complementary and sensitivity analyses were performed to ensure robust findings. Additionally, scRNA-seq datasets from human muscle and bone marrow were analyzed to validate the single-cell expression profiles of candidate cytokines. <b>Results:</b> MR analysis identified several cytokines with causal effects on osteosarcopenia traits, including LTA, CD40, CXCL6, CXCL10, DNER (delta and notch-like epidermal growth factor-related receptor), and VEGFA (vascular endothelial growth factor A). LTA and CD40 were protective for both bone and muscle, while VEGFA posed a risk. Other cytokines demonstrated opposite effects on bone and muscle. Single cell analysis revealed distinct expression patterns, with LTA highly expressed in lymphocytes, CD40 in immune cells, and VEGFA in various musculoskeletal cell types. Age-related differences in cytokine expression were also noted, with LTA more highly expressed in younger individuals, and VEGFA in older individuals. <b>Conclusion:</b> This study offers preliminary insights into the inflammatory mechanisms potentially driving osteosarcopenia, identifying key cytokines that may be involved in its pathogenesis. By integrating MR and scRNA-seq data, we highlight potential therapeutic targets, though further research is needed to confirm these findings and their implications for musculoskeletal health.