BoneKEy Reports | BoneKEy Watch
The link between sclerostin, carbonic anhydrase 2 and osteocyte activity
DOI:10.1038/bonekey.2013.209
When human osteocyte-like cells or mouse MLO-Y4 cells were treated with recombinant human sclerostin (rhSCL), the genes encoding carbonic anhydrase 2 (CA2/Car2), tartrate resistant acid phosphatase (ACP5/Acp5) and cathepsin K (CTSK/Ctsk) were upregulated.
Co-culture with a pH-sensitive dye revealed that rhSCL treatment significantly lowered intracellular and extracellular pH and led to the release and loss of calcium ions from a mineralized cell layer. These effects were blocked by acetazolamide, a carbonic anhydrase inhibitor. Kogawa et al. concluded that osteocytes are able to regulate calcium deposition by altering carbonic anhydrase expression.
RNA interference was then used to knock down expression of Car2 in mouse cells. Cells with an 81% reduction in Car2 expression showed no reduction in extracellular pH when treated with rhSCL, and the addition of acetazolamide had no impact. rhSCL treatment of mouse cells in which the sclerostin receptors had been knocked down did not induce expression of Car2, Acp5 or Ctsk, and there were no changes in pH or calcium release. When rhSCL was used to treated ex vivo human trabecular bone samples, an increase in osteocyte lacunar area was noted; this was prevented by co-culture with acetazolamide.
Editor’s comment: In vitro experiments in an osteocyte-like cell line provide new insights into an autocrine loop involving sclerostin and LRP4/5/6 receptors that triggers bone resorption by these cells. Whether these mechanisms contribute to explain the reduction in bone turnover observed with a sclerostin-neutralizing antibody remains to be investigated.
This work is licensed under a
Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.