E proteins regulate osteoclast maturation and survival.
Osteoclasts are bone-specific polykaryons derived from myeloid precursors under the stimulation of macrophage colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). E proteins are basic helix-loop-helix (bHLH) transcription factors that modulate lymphoid versus myeloid cell fate decisions. To study the role of E proteins in osteoclasts, myeloid-specific E protein gain-of-function transgenic mice were generated. These mice have high bone mass due to decreased osteoclast numbers and increased osteoclast apoptosis leading to overall reductions in resorptive capacity. The molecular mechanism of decreased osteoclast numbers and resorption is in part a result of elevated expression of CD38, a regulator of intracellular calcium pools with known antiosteoclastogenic properties, which increases sensitivity to apoptosis. In vivo, exogenous RANKL stimulation can overcome this inhibition to drive osteoclastogenesis and bone loss. In vitro-derived ET2 osteoclasts are more spread and more numerous with increases in RANK, triggering receptor expressed on myeloid cells 2 (TREM2), and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) compared to wild type. However, their resorptive capacity does not increase accordingly. Thus, E proteins participate in osteoclast maturation and survival in homeostatic bone remodeling.
Department of Microbiology and Immunology, Graduate College, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
Courtney L
CL
Long
William L
WL
Berry
Ying
Y
Zhao
Xiao-Hong
XH
Sun
Mary Beth
MB
Humphrey
D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis; D016723:Bone Remodeling / Q000235:genetics; D001862:Bone Resorption; D001842:Bone and Bones / Q000033:anatomy & histology; D002454:Cell Differentiation / Q000187:drug effects*; D005260:Female; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D053245:RANK Ligand / Q000494:pharmacology; D058127:Transcription Factor 3 / Q000502:physiology*
D050778:NFATC Transcription Factors; D053245:RANK Ligand; D058127:Transcription Factor 3; D051997:ADP-ribosyl Cyclase 1