Article
- The EMBO Journal (2008) 27, 535 - 545
- doi:10.1038/sj.emboj.7601984
Published online: 24 January 2008
Subject Categories:
Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival
Susan A Krum1, Gustavo A Miranda-Carboni2, Peter V Hauschka3, Jason S Carroll1,5, Timothy F Lane2, Leonard P Freedman4 and Myles Brown1
- Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Departments of Ob-Gyn and Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Department of Orthopaedic Surgery, Children's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Women's Health and Musculoskeletal Biology, Wyeth Research, Collegeville, PA, USA
Correspondence to:
Myles Brown, Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, D730, Boston, MA 02115, USA. Tel.: +1 617 632 3948; Fax: +1 617 632 5417; E-mail: myles_brown@dfci.harvard.edu
5Present address: Cancer Research UK, Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE, UK
Received 24 October 2007; Accepted 19 December 2007
Abstract
Estrogen deficiency in menopause is a major cause of osteoporosis in women. Estrogen acts to maintain the appropriate ratio between bone-forming osteoblasts and bone-resorbing osteoclasts in part through the induction of osteoclast apoptosis. Recent studies have suggested a role for Fas ligand (FasL) in estrogen-induced osteoclast apoptosis by an autocrine mechanism involving osteoclasts alone. In contrast, we describe a paracrine mechanism in which estrogen affects osteoclast survival through the upregulation of FasL in osteoblasts (and not osteoclasts) leading to the apoptosis of pre-osteoclasts. We have characterized a cell-type-specific hormone-inducible enhancer located 86 kb downstream of the FasL gene as the target of estrogen receptor-alpha induction of FasL expression in osteoblasts. In addition, tamoxifen and raloxifene, two selective estrogen receptor modulators that have protective effects in bone, induce apoptosis in pre-osteoclasts by the same osteoblast-dependent mechanism. These results demonstrate that estrogen protects bone by inducing a paracrine signal originating in osteoblasts leading to the death of pre-osteoclasts and offer an important new target for the prevention and treatment of osteoporosis.
Keywords:
- bone,
- estrogen,
- Fas ligand,
- osteoblast,
- osteoclast
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
NEWS AND VIEWS
Bad bones, grey hair, one mutation
Nature Medicine News and Views (01 Apr 2003)
Osteoclasts, no longer osteoblast slaves
Nature Medicine News and Views (01 Dec 2006)
RESEARCH
Coordination of PGC-1β and iron uptake in mitochondrial biogenesis and osteoclast activation
Nature Medicine Article (01 Mar 2009)
Nature Medicine Article (01 Apr 2009)
