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Bone remodeling involves a balance between bone resorption and formation. The mechanisms underlying bone remodeling are not well understood. DEF6 is recently identified as a novel loci associated with bone mineral density. However, it is unclear how Def6 impacts bone remodeling. We identify Def6 as a novel osteoblastic regulator that suppresses osteoblastogenesis and bone formation. Def6 deficiency enhances both bone resorption and osteogenesis. The enhanced bone resorption in Def6 -/-  mice dominates, leading to osteoporosis. Mechanistically, Def6 inhibits the differentiation of both osteoclasts and osteoblasts via a common mechanism through endogenous type-I IFN-mediated feedback inhibition. RNAseq analysis shows expression of a group of IFN stimulated genes (ISGs) during osteoblastogenesis. Furthermore, we found that Def6 is a key upstream regulator of IFNβ and ISG expression in osteoblasts. Collectively, our results identify a novel immunoregulatory function of Def6 in bone remodeling, and shed insights into the interaction between immune system and bone.

Def6 regulates endogenous type-I interferon responses in osteoblasts and suppresses osteogenesis