Some osteoblasts embed within bone matrix, change shape, and become dendrite-bearing osteocytes. The circuitry that drives dendrite formation during “osteocytogenesis” is poorly understood. Here we show that deletion of Sp7 in osteoblasts and osteocytes causes defects in osteocyte dendrites. Profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation. Osteocrin is a Sp7 target gene that promotes osteocyte dendrite formation and rescues defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates defects in osteocyte maturation in the absence of Sp7. Sp7-dependent osteocyte gene networks are associated with human skeletal diseases. Moreover, humans with a SP7R316C mutation show defective osteocyte morphology. Sp7-dependent genes that mark osteocytes are enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. These findings reveal a role for Sp7 and its target gene Osteocrin in osteocytogenesis, revealing that pathways that control osteocyte development influence human bone diseases.

Vitamin D and calcium are important nutrients for skeletal growth and bone health. Children and pregnant women are particularly vulnerable to 25-hydroxy vitamin D deficiency (VDD). VDD, with or without dietary calcium deficiency, can lead to nutritional rickets (NR), osteomalacia, and disturbances in calcium homeostasis. Multiple studies have linked VDD to adverse health outcomes in both children and pregnant women that extend beyond bone health. VDD remains an important global public health concern, and an important differentiation must be made between the impact of VDD on children and adults. Reports of increased incidence of NR continue to emerge. NR is an entirely preventable condition, which could be eradicated in infants and children worldwide with adequate vitamin D and calcium supplementation. The desire and necessity to put in place systems for preventing this potentially devastating pediatric disease should not elicit dispute. VDD and NR are global public health issues that require a collaborative, multi-level approach for the implementation of feasible preventative strategies. This review highlights the history, risk factors, and controversies related to VDD during pregnancy and childhood with a particular focus on global NR prevention.

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Osteocytes use an elaborate network of dendritic connections to control bone remodeling. Some osteoblasts embed within mineralized bone matrix, change shape, and become osteocytes. The molecular circuitry that drives dendrite formation during "osteocytogenesis" is poorly understood. Here we show that deletion of Sp7, a gene linked to rare and common skeletal disease, in mature osteoblasts and osteocytes causes severe defects in osteocyte dendrites. Unbiased profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation. Osteocrin is a Sp7 target gene that promotes osteocyte dendrite formation and rescues phenotypic and molecular defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates overt defects in osteocyte maturation in vivo in the absence of Sp7. Sp7-dependent gene networks enriched in developing osteocytes are associated with rare and common human skeletal traits. Moreover, humans homozygous for the osteogenesis imperfecta-causing SP7R316C mutation show dramatic defects in osteocyte morphology. Genes that mark osteocytes in vivo and that are regulated by Sp7 in vitro are highly enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. Taken together, these findings reveal a crucial role for Sp7 and its target gene Osteocrin in osteocytogenesis, demonstrating that pathways that control osteocyte development influence human bone diseases.

Background/Aims: Glucose-galactose malabsorption (GGM) is a rare and potentially fatal disorder. The autosomal recessive mutation of the SGLT1 gene interferes with the active glucose transport in the gut resulting in osmotic diarrhea and failure to thrive (FTT). Two nonrelated infants with GGM are presented as well as a novel mutation in SGLT1. Case Presentation: The first case consulted for FTT and presented with hypercalcemia and hypercalciuria. His mother had self-medicated with high doses of vitamin D. The second case consulted for macroscopic hematuria, and presented with dehydration and secondary acute kidney injury. In both cases, the profuse diarrhea, initially mistaken for polyuria, promptly resolved after the introduction of glucose-galactose-free milk. Investigations showed bilateral nephrocalcinosis and high levels of 1,25(OH)₂D₃ in both patients. We hypothesize that the upregulation of epithelial calcium channels (TRPV6) and 1,25(OH)₂D₃ are possible factors involved in the pathophysiology of nephrocalcinosis sometimes seen in GGM. Furthermore, a novel intronic SGLT1 mutation (c.207+2dup) is described. Conclusion: These 2 cases demonstrate that a malabsorption disorder such as GGM can present with nephrocalcinosis and/or hypercalcemia, with increased 1,25(OH)₂D₃ levels in infants. Prompt recognition of GGM is sometimes difficult but crucial.