A research team at High Magnetic Field Laboratory of Chinese Academy of Sciences (CHMFL), collaborating with researchers from Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, found that orchestrated regulation of Runx2/Osterix and Zn²⁺ uptake promoted citrate accumulation and apatite formation which is found to be in decline upon aging leading to degenerated bone formation.

Citrate is essential to biomineralization of the bone especially as an integral part of apatite nanocomposite. Citrate precipitate of apatite has been hypothesized to be derived from mesenchymal stem/stromal cells (MSCs) upon differentiation into mature osteoblasts.

However, the source of citrate in bone is not clearly known; in particular, how intracellular citrate metabolism and deposition is governed during apatite formation is not well defined.

Based on 13C-labeled signals identified by solid-state multinuclear magnetic resonance analysis in this study, 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. On one hand, 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. On the other hand, 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.

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.

This study entitled "Runx2/Osterix and Zinc Uptake Synergize to Orchestrate Osteogenic Differentiation and Citrate containing Bone Apatite Formation" was published on Advanced Science.