• Xiao-Wen Gao, Xiao-Tao Su, Zheng-Hao Lu, and Jun Ou.
• Department of Spinal Surgery, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan, China.
• Spine. 2020 Mar 1; 45 (5): 292-299.

Study DesignIn vitro studies of the role of 17β-estradiol (E2) and its possible targets in intervertebral disc degeneration (IDD).ObjectiveTo define the regulatory role of E2 in IDD and the potential mechanisms.Summary Of Background DataIDD has intricate etiology that is influenced by multiple risk factors. However, the underlying molecular mechanisms of occurrence and progression of IDD are not well elucidated. The degradation of extracellular matrix (ECM) has been extensively observed in IDD. E2 was found to inhibit ECM degradation in human nuleus pulposus cells (HNPCs), but the molecular mechanism remained to be determined.MethodsWestern blot and qPCR was performed to quantify the expression of target proteins in HNPCs. Luciferase reporter gene assay was applied to detect the effects of E2 and forkhead box O-3 (FOXO3) on matrix metalloproteinases (MMP)-3 promoter activity. Chromatin immunoprecipitation assay analyzed the binding of FOXO3 to MMP-3 and the effect of E2 on this process.ResultsWe identified the upregulation of collagen II and aggrecan by E2 independent of time and concentration. And E2 downregulated MMP-3 expression in human nucleus pulposus cells. The phosphorylation of FOXO3 led to the reduction of MMP-3 promoter activity. Furthermore, 17β-estradiol-induced the activation of PI3K/Akt pathway is required for FOXO3 phosphorylated.ConclusionE2 prevents the degradation of ECM by upregulating collagen II and aggrecan expression via reducing MMP-3 expression in HNPCs, and PI3K/Akt/FOXO3 pathway is dispensable for MMP-3 downregulated. Therefore, E2 protects against IDD by preventing ECM degradation.Level Of Evidence3.

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