Fas receptor is required for estrogen deficiency-induced bone loss in mice.
Bone mass is determined by bone cell differentiation, activity, and death, which mainly occur through apoptosis. Apoptosis can be triggered by death receptor Fas (CD95), expressed on osteoblasts and osteoclasts and may be regulated by estrogen. We have previously shown that signaling through Fas inhibits osteoblast differentiation. In this study we analyzed Fas as a possible mediator of bone loss induced by estrogen withdrawal. At 4 weeks after ovariectomy (OVX), Fas gene expression was greater in osteoblasts and lower in osteoclasts in ovariectomized C57BL/6J (wild type (wt)) mice compared with sham-operated animals. OVX was unable to induce bone loss in mice with a gene knockout for Fas (Fas -/- mice). The number of osteoclasts increased in wt mice after OVX, whereas it remained unchanged in Fas -/- mice. OVX induced greater stimulation of osteoblastogenesis in Fas -/- than in wt mice, with higher expression of osteoblast-specific genes. Direct effects on bone cell differentiation and apoptosis in vivo were confirmed in vitro, in which addition of estradiol decreased Fas expression and partially abrogated the apoptotic and differentiation-inhibitory effect of Fas in osteoblast lineage cells, while having no effect on Fas-induced apoptosis in osteoclast lineage cells. In conclusion, the Fas receptor has an important role in the pathogenesis of postmenopausal osteoporosis by mediating apoptosis and inhibiting differentiation of osteoblast lineage cells. Modulation of Fas effects on bone cells may be used as a therapeutic target in the treatment of osteoresorptive disorders.
Kovacic
Natasa
N
Department of Anatomy, University of Zagreb, School of Medicine, Zagreb, Croatia. natasa@mef.hr
Grcevic
Danka
D
Katavic
Vedran
V
Lukic
Ivan Kresimir
IK
Grubisic
Vladimir
V
Mihovilovic
Karlo
K
Cvija
Hrvoje
H
Croucher
Peter Ian
PI
Marusic
Ana
A
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004967:Estrogens / Q000172:deficiency*; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology* / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology* / Q000502:physiology; D010024:Osteoporosis / Q000378:metabolism*; D010052:Ovariectomy; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism*
D004967:Estrogens; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D019014:fas Receptor