sclerostin stimulates osteocyte support of osteoclast activity by a rankl-dependent pathwayrankl-dependent sclerostin刺激破骨细胞的骨细胞支持活动的途径.pdfVIP

Sclerostin Stimulates Osteocyte Support of Osteoclast Activity by a RANKL-Dependent Pathway 1 1 1 2 1 Asiri R. Wijenayaka , Masakazu Kogawa , Hui Peng Lim , Lynda F. Bonewald , David M. Findlay , Gerald J. Atkins1* 1 Bone Cell Biology Group, Discipline of Orthopaedics and Trauma, University of Adelaide, and the Hanson Institute, Adelaide, Australia, 2 University of Missouri - Kansas City School of Dentistry, Department of Oral Biology, Kansas City, Missouri, United States of America 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 o