Bone Protein May Influence Age-Related Cognitive Decline

Megan Brooks

September 26, 2013

Osteocalcin, a bone-specific protein, may influence brain development and cognitive function, a finding that could lead to new approaches to the prevention and treatment of age-related cognitive decline, including Alzheimer's disease, a new animal study suggests.

In what one expert described as "potentially groundbreaking research," a series of studies by researchers at Columbia University Medical Center in New York City showed that osteocalcin crosses the blood-brain barrier and influences neurotransmitter synthesis and neurogenesis, as well as spatial learning and memory.

"As we age, bone mass decreases, and the production of osteocalcin probably does too. It is not inconceivable that treatments that boost osteocalcin levels or stimulate osteocalcin receptors could help counter the cognitive effects of aging and aging-related diseases such as Alzheimer's," team leader Gerard Karsenty, MD, PhD, chair of the Department of Genetics and Development, Columbia University Medical Center, said in a statement.

The research was published online September 26 in the journal Cell.

Therapeutic Potential?

The "powerful regulation" of bone mass exerted by the brain points to the existence of bone-derived signals modulating this regulation or other functions of the brain, the investigators note.

They conducted a series of studies in mice to flush out the role of osteocalcin in the brain. They showed that osteocalcin crosses the blood-brain barrier, binds to neurons in the brainstem, midbrain, and hippocampus, which is responsible for learning and memory, promotes neurogenesis, and increases the synthesis of several neurotransmitters, including serotonin, dopamine, and catecholamine.

They also observed that mice that were genetically engineered to lack osteocalcin have abnormally small hippocampi and exhibit increased anxiety and depressionlike behavior, as well as impaired learning and memory, relative to wild-type mice.

When osteocalcin-null mice are infused with osetocalcin, their anxiety and depression decreases, but there is no effect on learning and memory or hippocampal size, the researchers note.

The investigators also found evidence that osteocalcin acts during development. It crosses the placenta from mother to fetus, and this maternal pool of osteocalcin is necessary for formation of the hippocampus and the establishment of memory. They observed that injections of osteocalcin in osteocalcin-null mothers during pregnancy prevent the development of behavioral abnormalities in their offspring.

Dr. Gerard Karsenty

The "therapeutic potential" of this research is 2-fold, said Dr. Karsenty "One could envision that osteocalcin should prevent the decrease in cognitive functions during aging; the second one is that in countries where women are undernourished (a third of the world), osteocalcin injections prevent appearance of metabolic and psychiatric disorders in their offspring," he explained.

The next research step, Dr. Karsenty said, is to "extend the work to other animal models, to better define the molecular signaling of osteocalcin in the brain."

"Novel, Potentially Groundbreaking"

Commenting on the findings for Medscape Medical News, Clifford J. Rosen, MD, director of the Center for Clinical and Translational Research, Maine Medical Center Research Institute in Scarborough, who was not involved in the study, said the research is "novel and potentially groundbreaking, as it opens up an entirely new aspect of skeletal control over whole-body homeostasis."

He added that there are "several major questions and implications" that arise from this research.

"Since there is age-related bone loss in virtually all individuals, it is conceivable that this process directly influences cognitive function through release of undercarboxylated osteocalcin," he noted.

"It is well established that falls and fractures are commonly associated in cognitively impaired elders, but this would be the first to suggest that the 2 processes are tightly linked in a causal manner."

These studies also point to osteocalcin as a "potentially important modulator of mammalian aging, since it has been shown to regulate glucose homeostasis, male fertility, and cognitive function," Dr. Rosen said.

He added that it is logical that osteocalcin, a bone-specific protein, could have endocrine activities, because its circulating levels are relatively high.

"Moreover, nerves and their dendritic and axonic processes resemble the structure of the osteocyte, the most common cell type in the skeleton. Many investigators have started to find common developmental switches in both neurons and osteoblasts/osteocytes, suggesting there is a potentially shared series of regulatory loops," said Dr. Rosen.

"Notwithstanding the enormous opportunities this work may provide in terms of testable hypotheses, studies in humans will have to be foremost to validate that the regulatory actions of osteocalcin in mice have relevance in the development and aging of humans," he added.

Another POV

Peter R. Schofield, PhD, executive director and chief executive officer of Neuroscience Research Australia, who was not involved in the study, described the research as a "nice fundamental study showing the complexity of signaling molecules and brain development."

"I don't think you have to conclude that the skeleton is important for brain development, as there are many molecules that have multiple effects in the body; it's just that while the brain effect was not known, the skeletal one was," Dr. Schofield said.

The study was supported by grants from the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Sanofi Aventis, the Human Frontier Scientific Program, and by a National Institute of Health Director’s Pioneer Award and an Ellison Medical Foundation Senior Scholar Award. Columbia University has filed for patents relating to osteocalcin and its use to treat a variety of conditions. The authors, Dr. Rosen, and Dr. Schofield report no relevant financial relationships.

Cell. 2013;155:228-241. Abstract


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