BoneKEy Reports | BoneKEy Watch

Sclerostin regulates RANKL expression in osteocytes

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DOI:10.1038/bonekey.2012.20

It is becoming clear that osteocytes are an important source of the RANK ligand (RANKL), osteoprotegerin (OPG) and sclerostin. This study demonstrated that sclerostin upregulated RANKL receptor mRNA in cultured human primary pre-osteocytes and in murine osteocyte-like MLO-Y4 cells. Simultaneous down-regulation of OPG was observed. This combination of events led to a significant increase in the ratio of RANKL:OPG mRNA.

MLO-Y4 cells held within a bone-like substrate, primed with recombinant human sclerostin and then treated with mouse splenocytes or human peripheral mononuclear cells, showed a 7-fold increase in osteoclastic bone resorption compared to untreated cultures. This effect was reversed by adding OPG.

Sclerostin did not cause apoptosis of MLO-Y4 cells, indicating that the increase in osteoclast activity was driven by viable, not dying, osteocytes. The authors conclude that sclerostin promotes osteoclast formation and osteocyte activity by increasing RANKL expression, a pathway that may be worthy of further exploration in the search for new treatment options for osteoporosis.

Editor's comment: Since ablation of beta-catenin signalling in osteocytes results in increased bone resorption, osteocytes have become a plausible target for molecules that regulate Wnt-beta-catenin signalling. These in vitro results indicate that sclerostin regulates RANKL expression in osteocytes, suggesting that these cells may regulate bone resorption via an autocrine loop.

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