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Brn3 transcription factors control terminal osteoclastogenesis
Author(s) -
SchulzeSpäte Ulrike,
Battaglino Ricardo,
Fu Jia,
Sharma Anupriya,
Vokes Martha,
Stashenko Philip
Publication year - 2007
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21257
Subject(s) - rankl , osteoclast , microbiology and biotechnology , transcription factor , bone resorption , bone remodeling , chemistry , activator (genetics) , biology , endocrinology , receptor , gene , biochemistry
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. J. Cell. Biochem. 102: 1–12, 2007. © 2007 Wiley‐Liss, Inc.