S100A12 as a Shared Inflammatory Driver of Intervertebral Disc Degeneration and Osteoporosis: A Mendelian Randomization and Experimental Study

Zexin Wang,1,* Bin Chen,1,* Zhenchuan Liu,1 Yuanqiang Zhang,1 Leixiang Han2 1Department of Orthopedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 2Department of Spine Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, 266035, People’s Republic of China*These authors contributed equally to this workCorrespondence: Leixiang Han, Email [email protected]: S100A12 as an indispensable molecular components inflammatory cytokines in human physiology. Notably, similar pathological mechanisms involving chronic low-grade inflammation are also observed in intervertebral disc degeneration (IVDD) and osteoporosis (OP), making the interplay between these diseases and inflammatory cytokines indisputable. Nevertheless, the precise identity of cytokines that concurrently fuel IVDD and OP remains elusive, hindering targeted therapeutic strategies.Methods: We employed genome-wide significant SNPs as instrumental variables (IVs) to assess causality between circulating inflammatory cytokines, IVDD, and OP using Mendelian randomization (MR). Data on cytokines came from Zhao et al, while IVDD and OP data were from the FinnGen database, predominantly European participants. The inverse-variance weighted (IVW) method was employed, with validation from MR-Egger, weighted median, weighted mode, and simple mode. In later experimental studies, one-way ANOVA was used to analyze differences among multiple groups, followed by Dunnett’s t-test for post-hoc comparisons. Finally, cell and human samples were utilized to validate our findings.Results: In our study, positive correlations were found between CXCL10, CXCL6, S100A12, NT-3, uPA, IL7, FLT3L, Caspase 8, TNF, and IL18 levels with IVDD/OP. While, negative correlations were observed with DNER, IL10, SIRT2, OPG, MCP-3, CCL19, SCF, GDNF, MCP-2, CCL25, and CD40L receptor levels. Reverse MR analysis showed no significant associations, indicating unidirectional causal relationships. Notably, S100A12 was identified as a shared positive risk factor influencing both IVDD and OP pathogenesis. Also, the S100A12 was significantly increased in IVDD and OP patients/cells than normal samples.Conclusion: Our study indicates a potential causal relationship that S100A12 exhibiting positive correlations with both IVDD and OP. The results strengthen the understanding of the pathogenesis of IVDD and OP, as well as, provide new treatment strategies for IVDD and OP.Keywords: intervertebral disc degeneration, osteoporosis, inflammatory cytokines, mendelian randomization, S100A12