Runx2/Osterix and Zinc Uptake Synergize to Orchestrate Osteogenic Differentiation and Citrate Containing Bone Apatite Formation.
Xuekun FuYunyan LiTongling HuangZhiwu YuKun MaMeng YangQingli LiuHaobo PanHuaiyu WangJunfeng WangMin GuanPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2018)
Citrate is essential to biomineralization of the bone especially as an integral part of apatite nanocomposite. Citrate precipitate of apatite is hypothesized to be derived from mesenchymal stem/stromal cells (MSCs) upon differentiation into mature osteoblasts. Based on 13C-labeled signals identified by solid-state multinuclear magnetic resonance analysis, boosted mitochondrial activity and carbon-source replenishment of tricarboxylic acid cycle intermediates coordinate to feed forward mitochondrial anabolism and deposition of citrate. Moreover, zinc (Zn2+) is identified playing dual functions: (i) Zn2+ influx is influenced by ZIP1 which is regulated by Runx2 and Osterix to form a zinc-Runx2/Osterix-ZIP1 regulation axis promoting osteogenic differentiation; (ii) Zn2+ enhances citrate accumulation and deposition in bone apatite. Furthermore, age-related bone loss is associated with Zn2+ and citrate homeostasis; whereas, restoration of Zn2+ uptake alleviates age-associated declining osteogenic capacity and amount of citrate deposition. Together, these results indicate that citrate is not only a key metabolic intermediate meeting the emerging energy demand of differentiating MSCs but also participates in extracellular matrix mineralization, providing mechanistic insight into Zn2+ homeostasis and bone formation.
Keyphrases
- mesenchymal stem cells
- bone loss
- heavy metals
- magnetic resonance
- bone marrow
- extracellular matrix
- bone mineral density
- transcription factor
- oxidative stress
- solid state
- soft tissue
- contrast enhanced
- risk assessment
- postmenopausal women
- body composition
- highly efficient
- positron emission tomography
- quantum dots
- solid phase extraction