Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, UK.
Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, Japan.
FASEB J. 2024 Sep 15;38(17):e23892. doi: 10.1096/fj.202400602R.
Mesenchymal stromal stem cells (MSCs) or skeletal stem cells (SSCs) play a major role in tissue repair due to their robust ability to differentiate into osteoblasts, chondrocytes, and adipocytes. Complex cell signaling cascades tightly regulate this differentiation. In osteogenic differentiation, Runt-related transcription factor 2 (RUNX2) and ALP activity are essential. Furthermore, during the latter stages of osteogenic differentiation, mineral formation mediated by the osteoblast occurs with the secretion of a collagenous extracellular matrix and calcium deposition. Activation of nuclear factor erythroid 2-related factor 2 (NRF2), an important transcription factor against oxidative stress, inhibits osteogenic differentiation and mineralization via modulation of RUNX2 function; however, the exact role of NRF2 in osteoblastogenesis remains unclear. Here, we demonstrate that NRF2 activation in human bone marrow-derived stromal cells (HBMSCs) suppressed osteogenic differentiation. NRF2 activation increased the expression of STRO-1 and KITLG (stem cell markers), indicating NRF2 protects HBMSCs stemness against osteogenic differentiation. In contrast, NRF2 activation enhanced mineralization, which is typically linked to osteogenic differentiation. We determined that these divergent results were due in part to the modulation of cellular calcium flux genes by NRF2 activation. The current findings demonstrate a dual role for NRF2 as a HBMSC maintenance factor as well as a central factor in mineralization, with implications therein for elucidation of bone formation and cellular Ca kinetics, dystrophic calcification and, potentially, application in the modulation of bone formation.
间充质基质干细胞（MSCs）或骨骼基质干细胞（SSCs）由于其强大的分化为成骨细胞、软骨细胞和脂肪细胞的能力，在组织修复中起着重要作用。复杂的细胞信号级联反应严格调节着这种分化。在成骨分化中， runt 相关转录因子 2（RUNX2）和碱性磷酸酶（ALP）活性是必不可少的。此外，在成骨分化的后期阶段，成骨细胞通过分泌胶原细胞外基质和钙沉积来介导矿化。核因子红细胞 2 相关因子 2（NRF2）的激活，一种对抗氧化应激的重要转录因子，通过调节 RUNX2 的功能抑制成骨分化和矿化；然而，NRF2 在成骨细胞形成中的确切作用尚不清楚。在这里，我们证明 NRF2 在人骨髓基质细胞（HBMSCs）中的激活抑制了成骨分化。NRF2 的激活增加了 STRO-1 和 KITLG（干细胞标志物）的表达，表明 NRF2 保护 HBMSCs 的干性以抵抗成骨分化。相比之下，NRF2 的激活增强了矿化，这通常与成骨分化有关。我们确定，这些不同的结果部分归因于 NRF2 激活对细胞钙通量基因的调节。目前的研究结果表明，NRF2 作为 HBMSC 维持因子以及矿化的核心因子具有双重作用，这对阐明骨形成和细胞 Ca 动力学、营养不良性钙化以及潜在的骨形成调节应用具有重要意义。
