Transforming growth factor-beta enables NFATc1 expression during osteoclastogenesis.
Osteoclastogenesis is dependent on distinct stimuli that prime and activate osteoclast differentiation. One cytokine needed to prime monocytes for osteoclastogenesis is TGF-beta, which enables and augments RANKL and TNF-alpha-induced osteoclast differentiation. However, the precise time-period during which this occurs and the molecular mechanism mediating this action are unknown. We report here TGF-beta prime monocytes for osteoclast formation within 24h by regulating expression of NFATc1, a key osteoclastic transcription factor. TGF-beta directly induces cytoplasmic NFATc1 expression within 24h, but is unable to stimulate NFATc1 nuclear translocation. Furthermore, RANKL-induced NFATc1 expression is dependent on the presence of TGF-beta during the early stages of osteoclastogenesis. Similarly, TNF-alpha activates osteoclastogenesis by stimulating translocation of TGF-beta-induced NFATc1. In light of these findings, it is apparent that osteoclast formation is dependent on coordinated interactions between TGF-beta and RANKL/TNF-alpha that regulate the expression and intracellular distribution of NFATc1 during early stages of osteoclast differentiation.
School of Biological Science, Ecotoxicology and Stress Biology Group, Room 404 Davy, University of Plymouth, PL4 8AA, UK.
S W
SW
Fox
K E
KE
Evans
A C
AC
Lovibond
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051379:Mice; D009000:Monocytes / Q000166:cytology* / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D016212:Transforming Growth Factor beta