Oral Presentation 6th Australian Health and Medical Research Congress 2012

Sclerostin Stimulates Osteocyte Support of Osteoclast Activity by a RANKL-Dependent Pathway (#206)

Asiri R Wijenayaka 1
  1. The University Of Adelaide, Adelaide, SA, Australia

Sclerostin is a product of mature osteocytes embedded in mineralised bone and is a negative regulator of bone mass and osteoblast differentiation. Since its finding there has been huge interest in understanding more about sclerostin because of its huge therapeutic potential in treating bone diseases. The exact mechanism of sclerostin action is yet to be elucidated. While evidence suggests that sclerostin has an anti-anabolic role, the possibility also exists that sclerostin has catabolic activity. To test this we treated human primary pre-osteocyte cultures, cells we have found are exquisitely sensitive to sclerostin, or mouse osteocyte-like MLO-Y4 cells, with recombinant human sclerostin (rhSCL) and measured effects on pro-catabolic gene expression. Sclerostin dose-dependently up-regulated the expression of receptor activator of nuclear factor kappa B (RANKL) mRNA and down-regulated that of osteoprotegerin (OPG) mRNA, causing an increase in the RANKL:OPG mRNA ratio thus supporting osteoclast formation leading to bone catabolism. To examine the effects of rhSCL on resulting osteoclastic activity, MLO-Y4 cells plated onto a bone-like substrate were primed with rhSCL for 3 days and then either mouse splenocytes or human peripheral blood mononuclear cells (PBMC) were added. This resulted in cultures with elevated osteoclastic resorption (approximately 7-fold) compared to untreated co-cultures. The increased resorption was abolished by co-addition of recombinant OPG. In co-cultures of MLO-Y4 cells with PBMC, SCL also increased the number and size of the TRAP-positive multinucleated cells formed. Importantly, rhSCL had no effect on TRAP-positive cell formation from monocultures of either splenocytes or PBMC.
Together these results show for the first time that sclerostin, in addition to its anti-anabolic activity, acts on osteocytes to promote osteoclast formation and activity in a RANKL-dependent manner