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Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway.
PLoS One. 2011; 6(10):e25900.Plos

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 RANK: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.

Authors+Show Affiliations

Bone Cell Biology Group, Discipline of Orthopaedics and Trauma, University of Adelaide, and the Hanson Institute, Adelaide, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21991382

Citation

Wijenayaka, Asiri R., et al. "Sclerostin Stimulates Osteocyte Support of Osteoclast Activity By a RANKL-dependent Pathway." PloS One, vol. 6, no. 10, 2011, pp. e25900.
Wijenayaka AR, Kogawa M, Lim HP, et al. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS ONE. 2011;6(10):e25900.
Wijenayaka, A. R., Kogawa, M., Lim, H. P., Bonewald, L. F., Findlay, D. M., & Atkins, G. J. (2011). Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PloS One, 6(10), e25900. https://doi.org/10.1371/journal.pone.0025900
Wijenayaka AR, et al. Sclerostin Stimulates Osteocyte Support of Osteoclast Activity By a RANKL-dependent Pathway. PLoS ONE. 2011;6(10):e25900. PubMed PMID: 21991382.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. AU - Wijenayaka,Asiri R, AU - Kogawa,Masakazu, AU - Lim,Hui Peng, AU - Bonewald,Lynda F, AU - Findlay,David M, AU - Atkins,Gerald J, Y1 - 2011/10/04/ PY - 2011/05/04/received PY - 2011/09/13/accepted PY - 2011/10/13/entrez PY - 2011/10/13/pubmed PY - 2012/2/7/medline SP - e25900 EP - e25900 JF - PloS one JO - PLoS ONE VL - 6 IS - 10 N2 - 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 RANK: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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/21991382/Sclerostin_stimulates_osteocyte_support_of_osteoclast_activity_by_a_RANKL_dependent_pathway_ L2 - http://dx.plos.org/10.1371/journal.pone.0025900 DB - PRIME DP - Unbound Medicine ER -