Courtney L. Long, William L. Berry, Ying Zhao, Xiao-Hong Sun, Mary Beth Humphrey
Osteoclasts are bone specific polykarons derived from myeloid precursors under the stimulation of MCSF and 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 due, in part, to elevated expression of CD38, a regulator of intracellular calcium pools with known anti-osteoclastogenic 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, TREM2, and 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.