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Type: Journal article
Title: Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway
Author: Wijenayaka, A.
Kogawa, M.
Lim, H.
Bonewald, L.
Findlay, D.
Atkins, G.
Citation: PLoS One, 2011; 6(10):e25900-1-e25900-9
Publisher: Public Library of Science
Issue Date: 2011
ISSN: 1932-6203
Statement of
Asiri R. Wijenayaka, Masakazu Kogawa, Hui Peng Lim, Lynda F. Bonewald, David M. Findlay and Gerald J. Atkins
Abstract: Sclerostin is a product of mature osteocytes embedded in mineralised bone and is a negative regulator of bone mass and osteoblast differentiation. 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. 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. Further, rhSCL did not induce apoptosis of MLO-Y4 cells, as determined by caspase activity assays, demonstrating that the osteoclastic response was not driven by dying osteocytes. Together, these results suggest that sclerostin may have a catabolic action through promotion of osteoclast formation and activity by osteocytes, in a RANKL-dependent manner.
Keywords: Cells, Cultured; Osteoclasts; Osteoblasts; Osteocytes; Animals; Humans; Mice; Acid Phosphatase; Isoenzymes; Bone Morphogenetic Proteins; Recombinant Proteins; Genetic Markers; Signal Transduction; Apoptosis; Cell Differentiation; Cell Survival; Gene Expression Regulation; Calcification, Physiologic; Osteogenesis; Adult; RANK Ligand; Tartrate-Resistant Acid Phosphatase
Description: Extent: 9p.
Rights: Copyright: © 2011 Wijenayaka et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
RMID: 0020113595
DOI: 10.1371/journal.pone.0025900
Appears in Collections:Orthopaedics and Trauma publications

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