Loss of PiT-2 results in abnormal bone development and decreased bone mineral density and length in mice

Abstract

Normal bone mineralization requires phosphate oversaturation in bone matrix vesicles, as well as normal regulation of phosphate metabolism via the interplay among bone, intestine, and kidney. In turn, derangement of phosphate metabolism greatly affects bone function and structure. The type III sodium-dependent phosphate transporters, PiT-1 and PiT-2, are believed to be important in tissue phosphate metabolism and physiological bone formation, but their requirement and molecular roles in bone remain poorly investigated. In order to decipher the role of PiT-2 in bone, we examined normal bone development, growth, and mineralization in global PiT-2 homozygous knockout mice. PiT-2 deficiency resulted in reduced vertebral column, femur, and tibia length as well as mandibular dimensions. Micro-computed tomography analysis revealed that bone mineral density in the mandible, femur, and tibia were decreased, indicating that maintenance of bone function and structure is impaired in both craniofacial and long bones of PiT-2 deficient mice. Both cortical and trabecular thickness and mineral density were reduced in PiT-2 homozygous knockout mice compared with wild-type mice. These results suggest that PiT-2 is involved in normal bone development and growth and plays roles in cortical and trabecular bone metabolism feasibly by regulating local phosphate transport and mineralization processes in the bone. Further studies that evaluate bone cell-specific loss of PiT-2 are now warranted and may yield insight into complex mechanisms of bone development and growth, leading to identification of new therapeutic options for patients with bone diseases.

Slc20a2, Encoding the Phosphate Transporter PiT2, Is an Important Genetic Determinant of Bone Quality and Strength

“…Extraskeletal abnormalities in Slc20a2 knockout mice recapitulate the autosomal dominant human condition of PFBC characterized by symmetric calcification in the basal ganglia and other brain regions in affected heterozygous individuals. However, the major dental, skeletal, and ocular abnormalities reported here were not recognized previously and result from complete SLC20A2 deficiency. Thus, SLC20A2 deficiency causes abnormalities of endochondral and intramembranous ossification that affect skeletal development, linear growth, and mineral accrual, resulting in profound and discordant decreases in bone strength and stiffness.…”

“…This phenotype is recapitulated in SLC20A2‐deficient mice, in which a local increase in Pi concentrations in the cerebrospinal fluid (CSF) has been suggested to contribute to Ca‐Pi deposition in CSF‐producing tissues and microvessels . Preliminary histomorphometric analysis of SLC20A2‐deficient mice also suggested a role for SLC20A2 in skeletal mineralization, whereas SLC20A2 expression in vascular smooth muscle has been proposed to inhibit vascular calcification …”

EOS789, a novel pan-phosphate transporter inhibitor, is effective for the treatment of chronic kidney disease–mineral bone disorder

“…18,19 It is recently reported that PiT-2 may play a role in bone development and its deletion leads to decreased MBD. 20 However, in fact, no toxicological effects in lung, brain, or bone were observed in rats and dogs on EOS789 in repeated oral dose toxicity studies lasting up to 13 weeks (data not shown). Even though the systemic inhibition of NaPi-IIb and PiT-2 has a potential risk of ectopic calcification and decreased bone mineral density, EOS789 is expected to avoid these safety risks due to its very low fractional absorption.…”

The Need of a Paradigm Shift to Better Understand PiT1 and PiT2 Biology: Response to “Why Is There No PiT1/SLC20A1 Pathogenic Variants Yet Linked to Primary Familial Brain Calcification?”

“…(2)(3)(4) In contrast, we and others have rather shown the involvement of PiT2 in these phenomena in vivo. (5,6) Therefore, when considering the recent in vivo studies rather than early in vitro observations, the absence of identified mutations in the PiT1 gene in PFBC patients does not appear surprising.…”