Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China.
J Cell Mol Med. 2024 Jul;28(14):e18551. doi: 10.1111/jcmm.18551.
Despite numerous investigations on the influence of fibroblast growth factor 23 (FGF23), α-Klotho and FGF receptor-1 (FGFR1) on osteoporosis (OP), there is no clear consensus. Mendelian randomization (MR) analysis was conducted on genome-wide association studies (GWASs)-based datasets to evaluate the causal relationship between FGF23, α-Klotho, FGFR1 and OP. The primary endpoint was the odds ratio (OR) of the inverse-variance weighted (IVW) approach. Furthermore, we stably transfected FGF23-mimic or siRNA-FGF23 into human bone marrow mesenchymal stem cells (hBMSCs) in culture and determined its cell proliferation and the effects on osteogenic differentiation. Using MR analysis, we demonstrated a strong correlation between serum FGF23 levels and Heel- and femoral neck-BMDs, with subsequent ORs of 0.919 (95% CI: 0.860-0.983, p = 0.014) and 0.751 (95% CI: 0.587-0.962; p = 0.023), respectively. The expression levels of FGF23 were significantly increased in femoral neck of patients with OP than in the control cohort (p < 0.0001). Based on our in vitro investigation, after overexpression of FGF23, compared to the control group, the BMSC's proliferation ability decreased, the expression level of key osteogenic differentiation genes (RUNX2, OCN and OSX) significantly reduced, mineralized nodules and ALP activity significantly decreased. After silencing FGF23, it showed a completely opposite trend. Augmented FGF23 levels are causally associated with increased risk of OP. Similarly, FGF23 overexpression strongly inhibits the osteogenic differentiation of hBMSCs, thereby potentially aggravating the pathological process of OP.
尽管已经对成纤维细胞生长因子 23（FGF23）、α-klotho 和 FGF 受体-1（FGFR1）对骨质疏松症（OP）的影响进行了大量研究，但仍没有明确的共识。我们基于全基因组关联研究（GWAS）数据集进行了孟德尔随机化（MR）分析，以评估 FGF23、α-klotho、FGFR1 和 OP 之间的因果关系。主要终点是逆方差加权（IVW）方法的比值比（OR）。此外，我们在培养的人骨髓间充质干细胞（hBMSCs）中稳定转染了 FGF23 模拟物或 siRNA-FGF23，并测定了其细胞增殖和对成骨分化的影响。通过 MR 分析，我们证明了血清 FGF23 水平与跟骨和股骨颈骨密度之间存在很强的相关性，随后的 OR 分别为 0.919（95%CI：0.860-0.983，p=0.014）和 0.751（95%CI：0.587-0.962；p=0.023）。OP 患者股骨颈处的 FGF23 表达水平明显高于对照组（p<0.0001）。基于我们的体外研究，与对照组相比，FGF23 过表达后，BMSC 的增殖能力降低，关键成骨分化基因（RUNX2、OCN 和 OSX）的表达水平明显降低，矿化结节和 ALP 活性明显降低。沉默 FGF23 后，其表现出完全相反的趋势。FGF23 水平的升高与 OP 风险的增加有关。同样，FGF23 的过表达强烈抑制了 hBMSC 的成骨分化，从而可能加重 OP 的病理过程。
