Sulfate biology genes are associated with mineralization in mouse and human

Sulfate plays a critical role in bone health and development. More than 90 sulfate-related genes are highly conserved across mammalian species, but very few of these genes have been linked to adverse bone phenotypes in humans. To extend our knowledge of sulfate-related gene expression dynamics during mineralization, this study leveraged 6 publicly available transcriptomic datasets, covering human osteosarcoma cell line Saos-2 mineralization, 2 mouse calvarial osteoblast mineralization models, vascular smooth muscle cell (VSMC) calcification, and 2 neurogenic heterotopic ossification datasets. We focused on a total of 12 sulfate-related genes that were upregulated during mineralization of Saos-2 cells. Six of these genes (Slc26a11, Sgsh, Sqor, Sult1a1, Tpst1, and Ust) were also consistently upregulated during mouse osteoblast and VSMC mineralization. Additionally, 3 genes (Cth, Got1, and Sulf1) were upregulated in Saos-2 mineralization but downregulated in mouse primary osteoblasts. Cbs, Chst3, and Chst13 were unchanged in the mouse primary cell models. Cbs, Chst13, Sgsh, Sulf1, and Ust also increased in models of heterotopic ossification. We have now identified several genes (CHST13, TPST1, UST, SULF1, GOT1, SLC26A11, and SULT1A1) that have not previously been considered for adverse bone conditions in humans, suggesting that additional sulfate biology genes may be linked with human skeletal conditions. Network analysis showed large co-expression clusters of genes, including sulfate biology and bone genes, that were upregulated across the calcification time courses. Gene ontology term enrichment analysis demonstrated significant enrichment in terms associated with mineralization, including ossification, bone mineralization, cartilage development, and extracellular matrix organization for these clusters of genes. This study provides a collated list of sulfate-related genes and networks that are associated with mineralization, which will facilitate future functional studies of sulfation pathways associated with bone pathology.