An Anabolic Hormone to Promote Skeletal Stem Cell Bone Formation

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 (