Carbonic anhydrase III protects osteocytes from oxidative stress

Abstract

Osteocytes aremaster orchestrators of bone remodeling; they control osteoblast and osteoclast activitiesboth directly via cell-to-cell communication and indirectly via secreted factors, and they are the main postnatal source of sclerostin and RANKL(receptor activator of NF-kB ligand), tworegulators of osteoblastandosteoclast function.Despite progress in understanding osteocyte biology and function, much remains to be elucidated. Recently developed osteocytic cell lines-together with new genome editing tools-has allowed a closer look at the biology and molecular makeup of these cells. By using single-cell cloning, we identified genes that are associated with high Sost/sclerostin expression and analyzed their regulation and function. Unbiased transcriptome analysis of high-vs. low-Sost/sclerostin-expressing cells identified known and novel genes.Dmp1 (dentinmatrix protein 1), Dkk1 (DickkopfWNT signaling pathway inhibitor 1), and Phexwere among themost up-regulated known genes, whereas Srpx2, Cd200, and carbonic anhydrase III (CAIII) were identified as novelmarkers of differentiated osteocytes.Aspn, Enpp2, Robo2, Nov, and Serpina3g were among the transcripts thatweremost significantly suppressed in high-Sost cells. Considering that CAII was recently identified as being regulated by Sost/sclerostin and capable of controllingmineral homeostasis, we focused our attention onCAIII. Here, we report that CAIII is highly expressed in osteocytes, is regulated byparathyroid hormone both in vitro and in vivo, and protects osteocytes from oxidative stress.