Fas receptor is required for estrogen deficiency-induced bone loss in mice

Kovačić, Nataša and Grčević, Danka and Katavić, Vedran and Lukić, Ivan Krešimir and Grubišić, Vladimir and Mihovilović, Karlo and Cvija, Hrvoje and Croucher, Peter Ian and Marušić, Ana (2010) Fas receptor is required for estrogen deficiency-induced bone loss in mice. Laboratory Investigation, 90 (3). pp. 402-13. ISSN 0023-6837

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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.

Item Type: Article
MeSH: Animals ; Antigens, CD95/metabolism ; Apoptosis ; Cell Differentiation ; Cell Lineage ; Cells, Cultured ; Estrogens/deficiency ; Fas Ligand Protein/metabolism ; Female ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Osteoblasts/cytology ; Osteoblasts/physiology ; Osteoclasts/cytology ; Osteoclasts/physiology ; Osteoporosis/metabolism ; Ovariectomy ; Signal Transduction
Departments: Katedra za fiziologiju i imunologiju
Katedra za anatomiju i kliničku anatomiju
Depositing User: Marijan Šember
Status: Published
Kovačić, NatašaUNSPECIFIED
Katavić, VedranUNSPECIFIED
Lukić, Ivan KrešimirUNSPECIFIED
Grubišić, VladimirUNSPECIFIED
Mihovilović, KarloUNSPECIFIED
Croucher, Peter IanUNSPECIFIED
Date: March 2010
Date Deposited: 28 Oct 2010
Last Modified: 23 Sep 2011 16:11
Subjects: /
Related URLs:
    URI: http://medlib.mef.hr/id/eprint/872

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