BoneKEy Reports | BoneKEy Watch

DNA methylation and its role in bone formation and resorption

---

DOI:10.1038/bonekey.2012.45

Sclerostin is a potent Wnt signaling inhibitor that decreases bone formation and so is a potential therapeutic target in osteoporosis. The SOST gene that encodes it remains unexpressed in mature osteoblasts but is expressed in osteocytes. This first of two linked studies from the same research group shows that SOST expression is upregulated dramatically by AzadC, a potent demethylating agent, indicating that regulation of SOST expression during the transition from osteoblast to osteocyte may be regulated by DNA methylation.

The authors also investigated the effect of DNA methylation on the transcriptional levels of RANKL and osteoprotegerin (OPG), both critical regulators of osteoclastogenesis. They discovered that DNA methylation within the regulatory regions of the genes encoding these factors repressed their expression, but low levels of methylation led to active transcription. This was confirmed when human cells that were not expressing RANKL or OPG at baseline were stimulated to do so by exposure to AzadC.

Editor's comment: These studies provide a novel insight into the mechanisms by which methylation of the promoter region of crucial genes regulates bone formation and resorption. Demethylation of the SOST promoter region may explain why osteocytes, but not lining osteoblasts, express sclerostin. Similarly, methylation/demethylation could control the transition from RANKL to OPG expression as osteoblasts undergo terminal differentiation.

---

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.