Abstract
The formation of hydroxyapatite crystals and their insertion into collagen fibrils of the matrix are essential steps for bone mineralization. As phosphate is a main structural component of apatite crystals, its uptake by skeletal cells is critical and must be controlled by specialized membrane proteins. In mammals, in vitro studies have suggested that the high-affinity sodium-phosphate cotransporter PiT1 could play this role. In vivo, PiT1 expression was detected in hypertrophic chondrocytes of murine metatarsals, but its implication in bone physiology is not yet deciphered. As the complete deletion of PiT1 results in embryonic lethality at E12.5, we took advantage of a mouse model bearing two copies of PiT1 hypomorphic alleles to study the effect of a low expression of PiT1 on bone mineralization in vivo. In this report, we show that a 85% down-regulation of PiT1 in long bones resulted in a slight (6%) but significant reduction of femur length in young mice (15- and 30-day-old). However, despite a defect in alcian blue / alizarin red S and Von Kossa staining of hypomorphic 1-day-old mice, using X-rays micro-computed tomography, energy dispersive X-ray spectroscopy and histological staining techniques we could not detect differences between hypomorphic and wild-type mice of 15- to 300-days old. Interestingly, the expression of PiT2, the paralog of PiT1, was increased 2-fold in bone of PiT1 hypomorphic mice accounting for a normal phosphate uptake in mutant cells. Whether this may contribute to the absence of bone mineralization defects remains to be further deciphered.
Highlights
Bone mineralization is mainly orchestrated by osteoblasts through a complex and spatially regulated process initiated by the synthesis of type I collagen rich extracellular matrix (MEC) that will be the place of carbonated hydroxyapatite deposition
We took advantage of a mouse model bearing two copies of PiT1 hypomorphic alleles to explore the physiological relevance of PiT1 in bone mineralization
It must be stressed that PiT1 hypomorphic mice display a mild anemia at birth, which is not compensated over time [25]
Summary
Bone mineralization is mainly orchestrated by osteoblasts through a complex and spatially regulated process initiated by the synthesis of type I collagen rich extracellular matrix (MEC) that will be the place of carbonated hydroxyapatite deposition. Three different modes have been described to explain mineral deposition into collagen matrices: (i) crystals deposition can occur without intervention of intracellular processes from solution by charged noncollagenous proteins in the collagen spaces [4]; (ii) matrix vesicles (MV) may bud from the plasma membrane, accumulate ions extracellularly and serve as primary nucleation sites [5,6]; and (iii) crystallization of hydroxyapatite may arise from a transient amorphous mineral precursor deposited within the collagen gap zones [1,7,8]. Due to its structural role in the apatite crystal, Pi is considered as a major factor regulating the mineralization process [9]. Its uptake by the osteoblasts lining the bone surface, or by the mineralizing growth plate chondrocytes is usually considered as a pre-requirement to the mineralization process that must be tightly controlled by specialized membrane proteins [10]
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