IDH2 deficiency increases bone mass with reduced osteoclastogenesis by limiting RANKL expression in osteoblasts.

Mitochondria are not only responsible for cellular energy production but are also involved in signaling, cellular differentiation, cell death, and aging. Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) catalyzes the decarboxylation of isocitrate to α-ketoglutarate, accompanied by NADPH production. IDH2 plays a central role in mitochondrial function in multiple cell types and various organs, including the heart, kidneys, and brain. However, the function of IDH2 in bone tissue is yet to be elucidated. Here, we report that disruption of IDH2 in mice results in high bone mass due to decreased osteoclast number and resorption activity. Although IDH2 played no cell-intrinsic role in osteoclasts, IDH2-deficient animals showed decreased serum markers of osteoclast activity and bone resorption. Bone marrow stromal cells/osteoblasts from Idh2 knockout mice were defective in promoting osteoclastogenesis due to a reduced expression of a key osteoclastogenic factor, receptor activator of nuclear factor-κB ligand (RANKL), in osteoblasts in vivo and in vitro through the attenuation of ATF4-NFATc1 signaling. Our findings suggest that IDH2 is a novel regulator of osteoblast-to-osteoclast communication and bone metabolism, acting via the ATF4-NFATc1-RANKL signaling axis in osteoblasts, and they provide a rationale for further study of IDH2 as a potential therapeutic target for the prevention of bone loss.