Defective enamel and bone development in sodium-dependent citrate transporter (NaCT) Slc13a5 deficient mice

Abstract

There has been growing recognition of the essential roles of citrate in biomechanical properties of mineralized tissues, including teeth and bone. However, the sources of citrate in these tissues have not been well defined, and the contribution of citrate to the regulation of odontogenesis and osteogenesis has not been examined. Here, tooth and bone phenotypes were examined in sodium-dependent citrate transporter (NaCT) Slc13a5 deficient C57BL/6 mice at 13 and 32 weeks of age. Slc13a5 deficiency led to defective tooth development, characterized by absence of mature enamel, formation of aberrant enamel matrix, and dysplasia and hyperplasia of the enamel organ epithelium that progressed with age. These abnormalities were associated with fragile teeth with a possible predisposition to tooth abscesses. The lack of mature enamel was consistent with amelogenesis imperfecta. Furthermore, Slc13a5 deficiency led to decreased bone mineral density and impaired bone formation in 13-week-old mice but not in older mice. The findings revealed the potentially important role of citrate and Slc13a5 in the development and function of teeth and bone.

Citrate-based materials fuel human stem cells by metabonegenic regulation

“…We demonstrated the expression of SLC13a5 in hMSCs, further showing that citrate-elevated ALP expression was dependent on SLC13a5. These findings have significant implications in bone stem cell biology, providing a biological mechanism underlying the reported contribution of exogenous citrate in teeth and bone showing that SLC13a5 deficiency in mice leads to impaired bone formation and defective tooth development (35). Similarly, consumption of extracellular citrate has been found in cancer cells that are known to be metabolically active to meet their high energetic and synthetic needs.…”

Analysis of naturally occurring mutations in the human uptake transporter NaCT important for bone and brain development and energy metabolism

“…These analyses showed that the absence of NaCT in mice promotes longevity and protects from insulin resistance and adiposity 10 . Furthermore, NaCT deficiency led to defective tooth and bone development characterized by the absence of mature enamel, decreased bone mineral density and impaired bone formation 11 . In contrast to the human “knock-out” phenotype, it has not been reported that knock-out animals show evidence of epileptic activity of other neurological signs, which may be due to species differences of transporter expression or other compensatory mechanisms.…”

“…Studies with NaCT [INDY (−/−)]-knock out mice demonstrated that deletion of this transporter mimics aspects of dietary restriction and protects these mice against insulin resistance and adiposity 10 . Furthermore, the absence of this transporter led to defective tooth and bone development 11 .…”

Citrate chemistry and biology for biomaterials design

“…However, SLC13a5 gene expression is found to be upregulated significantly in newly formed rat bone [131] and also at the early stage of osteointegration [132], which is in agreement with the sharply increased accumulation of intraperitoneally injected 14 C labeled citrate in the soft callus after bone fracture [133], pointing out a potential link between citrate biology and bone formation. Moreover, SLC13a5 deficiency could lead to impaired bone formation and defective tooth enamel development [134]. Excitingly, soluble citrate released from citrate-based materials during degradation, after supplemented in osteogenic medium, has been found to elevate the alkaline phosphatase (ALP) of osteoblast-like MG63 cells [72] and to increase the calcium nodule formation of human mesenchymal stem cells (hMSCs) [135].…”