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

Normal bone remodeling involves a balance between osteoclast-mediated bone resorption and osteoblast/osteocyte-mediated bone formation and is critical for maintaining healthy bone mass. This balance is often disrupted in disease conditions, such as osteoporosis and rheumatoid arthritis (RA). The mechanisms underlying bone remodeling especially in disease settings are far from 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 previously reported that the immunoregulator Def6 is a key inhibitor of osteoclast differentiation and bone resorption in both physiological and TNFα-mediated inflammatory conditions. In this study, we identify Def6 as a novel osteoblastic regulator that suppresses osteoblast differentiation and bone formation. Def6 deficiency enhances both osteoclastic bone resorption and osteoblastic osteogenesis. The enhanced bone resorption in Def6-/- mice dominates, lead...