Sodium/myo-inositol cotransporter 1 and myo-inositol are essential for osteogenesis and bone formation.
myo-Inositol (MI) plays an essential role in several important processes of cell physiology, is involved in the neural system, and provides an effective treatment for some psychiatric disorders. Its role in osteogenesis and bone formation nonetheless is unclear. Sodium/MI cotransporter 1 (SMIT1, the major cotransporter of MI) knockout (SMIT1(-/-)) mice with markedly reduced tissue MI levels were used to characterize the essential roles of MI and SMIT1 in osteogenesis. SMIT1(-/-) embryos had a dramatic delay in prenatal mineralization and died soon after birth owing to respiratory failure, but this could be rescued by maternal MI supplementation. The rescued SMIT1(-/-) mice had shorter limbs, decreased bone density, and abnormal bone architecture in adulthood. Deletion of SMIT1 resulted in retarded postnatal osteoblastic differentiation and bone formation in vivo and in vitro. Continuous MI supplementation partially restored the abnormal bone phenotypes in adult SMIT1(-/-) mice and strengthened bone structure in SMIT1(+/+) mice. Although MI content was much lower in SMIT1(-/-) mesenchymal cells (MSCs), the I(1,4,5)P(3) signaling pathway was excluded as the means by which SMIT1 and MI affected osteogenesis. PCR expression array revealed Fgf4, leptin, Sele, Selp, and Nos2 as novel target genes of SMIT1 and MI. SMIT1 was constitutively expressed in multipotential C3H10T1/2 and preosteoblastic MC3T3-E1 cells and could be upregulated during bone morphogenetic protein 2 (BMP-2)-induced osteogenesis. Collectively, this study demonstrated that deficiency in SMIT1 and MI has a detrimental impact on prenatal skeletal development and postnatal bone remodeling and confirmed their essential roles in osteogenesis, bone formation, and bone mineral density (BMD) determination.
Dai
Zhijie
Z
Departments of Medicine,Anatomy, Hong Kong, China.
Chung
Sookja K
SK
Miao
Dengshun
D
Lau
Kam S
KS
Chan
Alfred W H
AW
Kung
Annie W C
AW
D000375:Aging / Q000378:metabolism; D000818:Animals; D001842:Bone and Bones / Q000196:embryology / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation; D002460:Cell Line; D004622:Embryo, Mammalian / Q000378:metabolism; D017353:Gene Deletion; D007294:Inositol / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis; D010024:Osteoporosis / Q000378:metabolism / Q000473:pathology; D027981:Symporters / Q000172:deficiency / Q000378:metabolism*; D014158:Transcription, Genetic
C508355:SLC5A3 protein, mouse; D027981:Symporters; D007294:Inositol; D015544:Inositol 1,4,5-Trisphosphate