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, 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, highlighting
an immunoregulatory function of Def6 in bone cells. The presence of IFN
stimulated gene (ISG) expression in osteoblast differentiation is a recent
topic of interest. Our genome-wide RNAseq analysis shows expression of a
group of ISGs during osteoblast differentiation and demonstrates that Def6
is a key upstream regulator of ISG expression in osteoblasts.
Collectively, our results identify novel immunoregulatory function of Def6
in both osteoclastic bone resorption and osteoblastic bone formation in
bone remodeling, and shed insights into the interaction between immune
system and bone turn over. In TNFα-mediated inflammatory bone loss, TNFα
decreases Def6 expression in osteoclasts but does not impact Def6
expression in osteoblasts. This differential regulation of Def6 expression
by TNFα leads to enhanced osteoclast differentiation and reduced
osteoblast differentiation, leading to drastically enhanced bone
resorption with limited new bone formation in response to TNFα. These
results revealed an important mechanism by which TNFα disrupts normal bone
remodeling, and suggest that differential modulation of Def6 expression in
different bone cells may represent novel therapeutic strategies to treat
inflammatory bone loss.