CCN3: lactational bone booster.

Mammalian reproduction requires that nursing mothers transfer large amounts of calcium to their offspring through milk. Meeting this demand requires the activation of a brain-breast-bone circuit during lactation that coordinates changes in systemic hormones, dietary calcium intake, skeletal turnover, and calcium transport into milk. Classically, increased bone resorption via increased parathyroid hormone-related protein and low estrogen levels is the main source of calcium for milk production during lactation. Over the past few decades, investigators have described many aspects of this brain-breast-bone axis during lactation, yet many unanswered questions remain. Using a comprehensive set of parabiosis coupled with in vivo µCT, bone transplant studies, cell culturing and differentiation assays, mouse genetic models, pharmacologic interventions, hepatic viral transduction, and sequencing analysis, a recent study discovered that cellular communication network factor 3 (CCN3), derived from ARH neurons, functions as an osteogenic hormone to sustain bone formation and progeny survival during lactation. Compelling evidence has been presented to show that (1) CCN3 expression in ARH neurons fluctuates, almost exclusively appearing during lactation; (2) CCN3 stimulates mouse and human skeletal stem cell activity, increases bone remodeling and fracture repair in young and old mice of both sexes; (3) knockdown Ccn3 transcripts in the ARH neurons in lactating dams causes devastating bone loss and failure to sustain progeny survival. These findings suggested that the stage-specific expression of CCN3 in female ARH neurons during lactation is a newly identified brain-bone axis evolved to sustain the skeleton in mammalian mothers and offspring.