Citrate is presented in vertebrate bone universally as an integral part of apatite nanocomposite which is important for bone structure and its stability. However, the source of the citrate in bone still remains unclear, in particular, how the intracellular citrate metabolism and its deposition is governed during apatite formation is not well defined.

A research team led by Prof. GUAN Min from Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences (CAS) and Prof. WANG Junfeng from High Magnetic Field Laboratory of CAS reported that during osteoblast genesis of mesenchymal stem cells (MSC), the citrate was produced as a key intermediate in mitochondrial tricarboxylic acid cycle, and further deposited in bone apatite. 

Researchers found that the citrate of bone apatite was produced by mineralized MSC through tracing stable isotopically labeled carbon. Moreover, they demonstrated that zinc-Runx2/Osterix-ZIP1 regulation axis promoted osteoblast differentiation and apatite formation, and uncovered mitochondrial citrate metabolism as well as its relationship with zinc homeostasis during bone remodeling.

Their findings highlight the mitochondrial and the metabolic changes not only meet higher amounts of energy demand during osteogenic differentiation of MSC, but also provide metabolic intermediates directly participating in bone formation. 

The paper entitled "Runx2/Osterix and Zinc Uptake Synergize to Orchestrate Osteogenic Differentiation and Citrate containing Bone Apatite Formation" was published in Advanced Science.

This work was supported by the National Natural Science Foundation of China Grant, Ministry of Science and Technology of China, Youth Innovation Promotion Association of Chinese Academy of Sciences, Shenzhen Science and Technology Research Funding and Shenzhen Peacock Program.

Diagram of Zn²⁺ induced osteoblast differentiation of MSCs and citrate deposition during bone remodeling. (Image by GUAN Min)