Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kappa B ligand (RANKL)-induced JNK activation.
The differentiation of cells of the monocytic lineage into mature osteoclasts (OC) is specifically induced by the tumor necrosis factor-related factor, RANKL (receptor activator of NF-kappaB ligand; also known as OPGL, ODF, or TRANCE). Because inhibition of osteoclastogenesis is one of the main mechanisms by which estrogen (E2) prevents bone loss, it is likely that E2 may regulate either the production of, or the target cell responsiveness to RANKL. We found that E2 decreases the differentiation into OC of both murine bone marrow monocytes and RAW 264.7 cells, a monocytic line, by down-regulating the activation of Jun N-terminal kinase 1 (JNK1). Diminished JNK1 activity results in decreased nuclear levels of the key osteoclastogenic transcription factors, c-Fos and c-Jun, and lower binding of these transcriptional inducers to DNA. Thus, one novel mechanism by which E2 down-regulates osteoclastogenesis is by decreasing the responsiveness of OC precursors to RANKL.
Srivastava
S
S
Division of Bone and Mineral Diseases and Department of Pathology, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.
Toraldo
G
G
Weitzmann
M N
MN
Cenci
S
S
Ross
F P
FP
Pacifici
R
R
D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D015342:DNA Probes; D015536:Down-Regulation; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B
D002352:Carrier Proteins; D015342:DNA Probes; D008562:Membrane Glycoproteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D004958:Estradiol; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases