Brn3 transcription factors control terminal osteoclastogenesis.
Osteoclastic bone resorption is a central mechanism in skeletal development, remodeling and pathology. RANKL is a mandatory factor controlling osteoclastogenesis; however, the underlying signaling pathways are only partially characterized. Using a screening array for the investigation of differential transcription factor activation, we identified activation of the Brn3 transcription factor family as a downstream event of RANKL signaling during terminal osteoclastogenesis. RANKL stimulation induces expression of Brn3a and b and maximal transcriptional activity of Brn3 family members concurrent with osteoclastic giant cell formation. Immunohistochemical analysis revealed both nuclear and cytoplasmic localization of Brn3a and b in mature osteoclasts. Functional inhibition of Brn3 transcription factors resulted in inhibition of pre-osteoclast fusion and reduction in bone resorbing activity of mature osteoclasts. Furthermore, we identified synaptotagmin-1, a regulator of membrane and vesicular fusion, as downstream target of Brn3 with a role in osteoclast function. We conclude that Brn-3 represents a novel molecular differentiation factor that controls osteoclast maturation and function, suggesting an important role in bone metabolism.
Department of Cytokine Biology, The Forsyth Institute, Boston, Massachusetts 02115, USA.
Ulrike
U
Schulze-Späte
Ricardo
R
Battaglino
Jia
J
Fu
Anupriya
A
Sharma
Martha
M
Vokes
Philip
P
Stashenko
D000818:Animals; D001483:Base Sequence; D001862:Bone Resorption; D002454:Cell Differentiation; D002478:Cells, Cultured; D016384:Consensus Sequence; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009841:Oligonucleotides / Q000737:chemistry; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D050863:Synaptotagmin I / Q000502:physiology; D050819:Transcription Factor Brn-3A / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D050820:Transcription Factor Brn-3B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation
D018398:Homeodomain Proteins; D009841:Oligonucleotides; C494189:Pou4f1 protein, mouse; C085559:Pou4f2 protein, mouse; D050863:Synaptotagmin I; C494311:Syt1 protein, mouse; D050819:Transcription Factor Brn-3A; D050820:Transcription Factor Brn-3B