The importance of the role of iron regulatory proteins (IRPs) in mitochondrial iron homeostasis and function has been raised. To understand how an IRP affects mitochondrial function, we used globally Irp2-depleted mouse embryonic fibroblasts (MEFs) and found that Irp2 ablation significantly induced the expression of both hypoxia-inducible factor subunits, Hif1α and Hif2α. The increase of Hif1α up-regulated its targeted genes, enhancing glycolysis, and the increase of Hif2α down-regulated the expression of iron–sulfur cluster (Fe–S) biogenesis-related and electron transport chain (ETC)-related genes, weakening mitochondrial respiration. Inhibition of Hif1α by genetic knockdown or a specific inhibitor prevented Hif1α-targeted gene expression, leading to decreased aerobic glycolysis. Inhibition of Hif2α by genetic knockdown or selective disruption of the heterodimerization of Hif2α and Hif1β restored the mitochondrial ETC and coupled oxidative phosphorylation (OXPHOS) by enhancing Fe–S biogenesis and increasing ETC-related gene expression. Our results indicate that Irp2 modulates the metabolic switch from aerobic glycolysis to OXPHOS that is mediated by Hif1α and Hif2α in MEFs.
Diffuse idiopathic skeletal hyperostosis (DISH) is a noninflammatory skeletal disease characterized by the progressive ectopic ossification and calcification of ligaments and enthuses. However, specific pathogenesis remains unknown. Bone marrow mesenchymal stem cells (BMSCs) are a major source of osteoblasts and play vital roles in bone metabolism and ectopic osteogenesis. However, it is unclear whether BMSCs are involved in ectopic calcification and ossification in DISH. The current study aimed to explore the osteogenic differentiation abilities of BMSCs from DISH patients (DISH-BMSCs). Our results showed that DISH-BMSCs exhibited stronger osteogenic differentiation abilities than normal control (NC)-BMSCs. Human cytokine array kit analysis showed significantly increased secretion of Galectin-3 in DISH-BMSCs. Furthermore, Galectin-3 downregulation inhibited the increased osteogenic differentiation ability of DISH-BMSCs, whereas exogenous Galectin-3 significantly enhanced the osteogenic differentiation ability of NC-BMSCs. Notably, the increased Galectin-3 in DISH-BMSCs enhanced the expression of β-catenin as well as TCF-4, whereas attenuation of Wnt/β-catenin signaling partially alleviated Galectin-3-induced osteogenic differentiation and activity in DISH-BMSCs. In addition, our results noted that Galectin-3 interacted with β-catenin and enhanced its nuclear accumulation. Further in vivo studies showed that exogenous Galectin-3 enhanced ectopic bone formation in the Achilles tendon in trauma-induced rats by activating Wnt/βcatenin signaling. The current study indicated that enhanced osteogenic differentiation of DISH-BMSCs was mainly attributed to the increased secretion of Galectin-3 by DISH-BMSCs, which enhanced β-catenin expression and its nuclear accumulation. Our study helps illuminate the mechanisms of pathological osteogenesis and sheds light on the possible development of potential therapeutic strategies for DISH treatment.
Objective
Junctional kyphosis is a common complication after corrective long spinal fusion for adult spinal deformity. Whereas there is still a paucity of data on junctional kyphosis, specifically among late posttraumatic thoracolumbar kyphosis (LPTK) patients. Thus, the aim of this study was to investigate the characteristics and risk factors of junctional kyphosis in LPTK patients receiving long segmental instrumented fusion.
Methods
We retrospectively reviewed a cohort of LPTK patients who had received long segmental instrumented fusion (>4 segments) in our center between January 2012 and January 2019. Radiographic assessments included the sagittal alignment, pelvic parameters, bone quality on CT images, and measurements of the cross‐sectional area (CSA, cross‐sectional area of muscle‐vertebral body ratio × 100) and fat saturation fraction (FSF, cross‐sectional area of fat‐muscle body ratio × 100) of paraspinal muscles. Patients in this study were divided into those with junctional kyphosis or failure (Group J) and those without (Group NJ) during follow‐up. Group J included patients with junctional kyphosis (Group JK) and patients with junctional failure (Group JF).
Results
A total of 65 patients (16 males and 49 females, average age 56.5 ± 23.4 years) were enrolled in this study. After (32.7 ± 8.5) months follow‐up, 15 patients (23.1%) experienced junctional kyphosis, and four of them deteriorated into junctional failure. Eighty percent (12/15) of junctional kyphosis was identified within 6 months after surgery. In comparison with Group NJ, Group J were older (P = 0.026), longer fusion levels (P < 0.001), greater thoracic kyphosis (P = 0.01), greater global kyphosis (P = 0.023), lower bone quality (P < 0.001), less CSA (P = 0.005) and higher FSF (P <0.001) of paraspinal muscles. Preoperative global kyphosis more than 48.5° (P = 0.001, odds ratio 1.793) and FSF more than 48.4 (P = 0.010, odds ratio 2.916) were identified as independent risk factors of junctional kyphosis. Based on the statistical differences among Group NJ, Group JK and Group JF (P < 0.001), Group JF had lower bone quality than Group NJ (P < 0.001) and Group JK (P = 0.015). In terms of patient‐reported outcomes, patients in Group JF had worse outcomes in ODI and VAS scores, and PCS and MCS of SF‐36 than Group NJ and group JK
Conclusion
The prevalence of junctional kyphosis was 23.1% in LPTK patients after long segmental instrumented fusion. Preoperative hyperkyphosis and advanced fatty degeneration of paraspinal muscles were independent risk factors of junctional kyphosis. Patients with lower bone quality were more likely to develop junctional failure.
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