Osteoporosis with increased osteoclastogenesis in hematopoietic cell-specific STAT3-deficient mice.
Hematopoietic cell-specific disruption of the STAT3 gene induces hyperproliferation of cells of the myeloid lineage. Osteoclasts (OC), the bone-resorbing cells, are generated from the same precursors as monocyte/macrophages. STAT3 mutant mice exhibit decreased bone density, bone volume, and increased numbers of TRAP-positive OC. In vitro generation of OC showed significantly greater numbers of OC in mutant mice. The increased numbers of Mac1+ cells and c-kit+ cells were detected by FACS analysis, suggesting an increased number of OC precursors. Treatment of splenocytes with CSF-1 and RANKL significantly increased the Mac-1+RANK+ cells, with much higher levels observed in cells from mutant mice compared with littermate controls. Besides enhanced number of Mac1+ OC precursors, we also identified an OC-generating Mac1- c-kit+ population in mutant mice which was absent in littermate controls. The Mac1- c-kit- cells did not generate OC. Finally, we determined that protein expression and mRNA level of c-fos, a transcription factor which is essential for OC differentiation, were enhanced in OC precursors of mutant mice, which may contribute to the osteopenic phenotype.
Zhang
Zhiyuan
Z
Sections of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Welte
Thomas
T
Troiano
Nancy
N
Maher
Stephen E
SE
Fu
Xin-Yuan
XY
Bothwell
Alfred L M
AL
D000818:Animals; D016723:Bone Remodeling; D001862:Bone Resorption / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency*; D006412:Hematopoietic Stem Cells; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000473:pathology*; D010024:Osteoporosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000172:deficiency*
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D015534:Trans-Activators