Johns Hopkins University, Baltimore, MD.
Structural Role for Osteoblast Derived Citrate in Bone
Naomi Dirckx, Qian Zhang, Robert Tower, Zhu Li, Ryan Riddle, Rafael deCabo, Anne Le, Thomas Clemens
Bone stiffness and ability to resist fractures is offered by its unique structure consisting of crystals of carbonated apatite embedded in a collagenous matrix. Approximately 80% of total body citrate is stored in the skeleton where it is strongly bound to calcium crystals and defines the mechanical properties of the bone. Despite the enormous potential of citrate in controlling bone quality, the source of citrate and the mechanism of citrate incorporation in the bone minerals remain elusive.
The citrate transporter Slc13a5 is highly expressed in bone by late mineralizing osteoblasts. Indeed, radioactive C-Citrate uptake shows a 4-fold increase in the later stages of osteogenic differentiation. Culturing osteoblasts in the presence of the SLC13A5 inhibitor PF-06761281 or genetic deletion of Slc13a5 abolishes C-Citrate uptake but causes a compensational increase in citrate production from glucose by the TCA cycle in the mitochondria and release in the mineral matrix.
Both inhibitor treated and Slc13a5-/- osteoblasts fail to perform proper “nucleation” of the minerals causing a diffuse appearance of the mineral matrix, attributed to increased mineral citrate content. A mouse model with global deletion of Slc13a5 shows defective tooth enamel and bone development, similar to what has been described in patients with SLC13A5 mutations. Moreover, conditional deletion of Slc13a5 in mature osteoblasts specifically causes significantly weaker bones.
We here expose an entirely new metabolic pathway that controls the deposition of citrate into bone, and identify SLC13A5-mediated citrate uptake as a valid mechanism to further investigate for improving bone strength in low bone mass disorders.