Brain-Derived CCN3 Is An Osteoanabolic Hormone That Sustains Bone in Lactating Females [ARC]

During lactation, mothers initiate cycles of bone formation followed by significant bone loss to meet the high calcium (Ca2+) demand by progeny. While estrogen functions typically as an anabolic driver of bone remodeling, this sex steroid is absent in postpartum females. Here, we report that a brain-derived secreted from neurons of the arcuate nucleus (ARC) fills this void and functions as a potent osteogenic factor to promote bone mass in lactating females. We previously reported an extraordinarily sex-specific high bone mass phenotype in female mice that persists with aging and is central in origin after eliminating estrogen receptor alpha signaling in ARCKISS1 neurons. Parabiosis and bone transplant studies established that a humoral factor in mutant females accounts for this unusual skeletal phenotype. High bone mass in mutant females could be traced back to the skeletal stem cell (SSC) level, reflected by their increased frequency and osteochondrogenic potential. Based on ex-vivo, in vivo, and in vitro assays, one protein emerged as the most promising secreted pro-osteogenic factor from the ARC, acting in mice and human SSCs at low concentrations (<nM) independent of age and sex. The role of this brain-derived factor in bone formation was confirmed by in vivo gain and loss of function studies. Unexpectedly, in wild-type females, a transient spike of this protein appears in ARCKISS1 neurons coincident with lactation when bone remodeling and high calcium demand intensify in estrogen-depleted mothers. Our findings establish a potentially new therapeutic anabolic bone hormone that functions in a novel female-specific brain-bone axis to ensure mammalian species survival.