SREBP2 restricts osteoclast differentiation and activity by regulating IRF7 and limits inflammatory bone erosion.

Osteoclasts are multinucleated bone resorbing cells, and their dysregulation leads to pathological bone destruction. Osteoclast formation must be tightly regulated to prevent excessive bone loss and to minimize bone damage. SREBP2 is a key transcription factor for cholesterol biosynthesis and a sensor for intracellular lipids. However, how the crosstalk between SREBP2 and lipid metabolism contributes to osteoclasts has not been determined. Here, we reveal that SREBP2 is a negative regulator of osteoclastogenesis. Targeted deletion of SREBP2 in myeloid cells result in low bone mass and accelerates inflammatory bone destruction. SREBP2-mediated regulation of osteoclastogenesis is independent of its canonical function in cholesterol biosynthesis but is mediated, in part, by its downstream target, interferon regulatory factor (IRF)7. Taken together, our study highlights the SREBP2-IRF7 regulatory circuit forms as a negative feedback inhibitory loop in osteoclast differentiation that represents a novel mechanism to restrain deleterious pathological bone destruction.