Maternal Brain Hormone MBH Builds Stronger Bones in Mice

Mammalian mothers make major sacrifices while caring for their offspring. To supply newborns with milk, their bodies draw calcium from their own bones.

Scientists have long asked why this demand does not cause mothers’ skeletons to collapse under the strain. Now, US researchers led by the University of California, San Francisco (UCSF) believe they have answered that question.

The researchers identified an entirely new hormone in female mice that encourages the formation of exceptionally dense, strong bone.

Neuroscientists have called it the maternal brain hormone (MBH). Although it was discovered in mothers, it builds robust, healthy bones in mice of every age and sex.

"One of the remarkable things about these findings is that if we hadn't been studying female mice, which unfortunately is the norm in biomedical research, then we could have completely missed out on this finding," says pharmacologist Holly Ingraham, who leads her own laboratory at UCSF.

"It underscores just how important it is to look at both male and female animals across the lifespan to get a full understanding of biology."

Maternal brain hormone MBH and bone strength

Male brains have been the subject of most brain research to date, while just 2 percent of published neuroimaging studies have investigated hormonal influences such as sex steroids.

Oestrogen, a bone-building sex steroid that has broad effects on the brain, rises and falls over a lifetime. After menopause, however, it is produced in lower amounts, making older women susceptible to the bone-damaging effects of osteoporosis.

Oestrogen also declines during breastfeeding, slowing bone formation. At the same time, a mother’s body extracts, or ‘resorbs’, calcium from her skeleton to keep nourishing her newborn, seemingly placing her bones at even greater risk.

In 2019, Ingraham’s UCSF laboratory unexpectedly found that blocking oestrogen in a particular area of the female mouse brain markedly increased the animals’ bone strength.

This suggested that another bone-forming hormone was taking over from oestrogen. Researchers have now identified that hormone.

MBH is the known protein CCN3. It is released by neurons in the arcuate nucleus, a brain region involved in puberty and reproduction.

During normal lactation in mice, these neurons sharply increase their production of MBH as oestrogen levels decrease.

Laboratory testing showed that MBH activates stem-cell activity in mouse and human bone tissue. In live mice of all ages and both sexes, higher MBH levels enhanced bone remodelling and sped up fracture healing.

MBH protects lactating mice from bone loss

This effect is especially significant in female mice. A rodent mother feeding a large litter must give up nearly 30 percent of her bone density.

Although these losses return to normal after lactation ends and oestrogen rises again, both mothers and pups would do badly without the balancing effect of MBH. In experiments involving live mice, artificially suppressing MBH production caused mothers to lose substantially more bone density than usual, while their pups quickly lost weight.

Conversely, giving additional MBH to young adult and elderly mice, both female and male, produced striking increases in bone mass and strength within weeks.

In older female mice with extremely low oestrogen levels, MBH therapy more than doubled bone mass.

"There are some situations where highly mineralized bones are not better; they can be weaker and actually break more easily," says stem-cell biologist Thomas Ambrosi of the University of California, Davis.

"But when we tested these bones, they turned out to be much stronger than usual. We've never been able to achieve this kind of mineralization and healing outcome with any other strategy."

There was further encouraging evidence. Researchers placed MBH in a hydrogel patch and applied it directly to a broken bone in an older mouse, where it stimulated bone growth at the fracture site.

More work is required to establish how effectively these findings apply to people. During breastfeeding, humans temporarily lose around 10 percent of their bone density, considerably less than mice do.

"Bone loss happens not only in post-menopausal women but often occurs in breast cancer survivors that take certain hormone blockers; in younger, highly trained elite female athletes; and in older men whose relative survival rate is poorer than women after a hip fracture," explains Ingraham.

"It would be incredibly exciting if [MBH] could increase bone mass in all these scenarios."

The study was published in Nature.