A maternal brain hormone that builds bone.

In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.

Brain-Derived CCN3 Is An Osteoanabolic Hormone That Sustains Bone in Lactating Females.

In lactating mothers, the high calcium (Ca 2+ ) demand for milk production triggers significant bone resorption. While estrogen would normally counteract excessive bone loss and maintain sufficient bone formation during this postpartum period, this sex steroid drops precipitously after giving birth. Here, we report that brain-derived CCN3 (Cellular Communication Network factor 3) secreted from KISS1 neurons of the arcuate nucleus (ARC KISS1 ) fills this void and functions as a potent osteoanabolic factor to promote bone mass in lactating females. Using parabiosis and bone transplant methods, we first established that a humoral factor accounts for the female-specific, high bone mass previously observed by our group after deleting estrogen receptor alpha (ER α ) from ARC KISS1 neurons 1 . This exceptional bone phenotype in mutant females can be traced back to skeletal stem cells (SSCs), as reflected by their increased frequency and osteochondrogenic potential. Based on multiple assays, CCN3 emerged as the most promising secreted pro-osteogenic factor from ARC KISS1 neurons, acting on mouse and human SSCs at low subnanomolar concentrations independent of age or sex. That brain-derived CCN3 promotes bone formation was further confirmed by in vivo gain- and loss-of-function studies. Notably, a transient rise in CCN3 appears in ARC KISS1 neurons in estrogen-depleted lactating females coincident with increased bone remodeling and high calcium demand. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone that defines a novel female-specific brain-bone axis for ensuring mammalian species survival.

No Evidence of Association Between Undercarboxylated Osteocalcin and Incident Type 2 Diabetes.

Mouse models suggest that undercarboxylated osteocalcin (ucOC), produced by the skeleton, protects against type 2 diabetes development, whereas human studies have been inconclusive. We aimed to determine if ucOC or total OC is associated with incident type 2 diabetes or changes in fasting glucose, insulin resistance (HOMA-IR), or beta-cell function (HOMA-Beta). A subcohort (n = 338; 50% women; 36% black) was identified from participants without diabetes at baseline in the Health, Aging, and Body Composition Study. Cases of incident type 2 diabetes (n = 137) were defined as self-report at an annual follow-up visit, use of diabetes medication, or elevated fasting glucose during 8 years of follow-up. ucOC and total OC were measured in baseline serum. Using a case-cohort design, the association between biomarkers and incident type 2 diabetes was assessed using robust weighted Cox regression. In the subcohort, linear regression models analyzed the associations between biomarkers and changes in fasting glucose, HOMA-IR, and HOMA-Beta over 9 years. Higher levels of ucOC were not statistically associated with increased risk of incident type 2 diabetes (adjusted hazard ratio = 1.06 [95% confidence interval, 0.84-1.34] per 1 standard deviation [SD] increase in ucOC). Results for %ucOC and total OC were similar. Adjusted associations of ucOC, %ucOC, and total OC with changes in fasting glucose, HOMA-IR, and HOMA-Beta were modest and not statistically significant. We did not find evidence of an association of baseline undercarboxylated or total osteocalcin with risk of incident type 2 diabetes or with changes in glucose metabolism in older adults. © 2022 American Society for Bone and Mineral Research (ASBMR).