The skeletal system does more than support the body and protect vital organs, according to the latest NIEHS distinguished lecturer, Gerard Karsenty, M.D., Ph.D. His research has shown that a bone protein called osteocalcin regulates insulin and glucose balance, fertility, brain development and cognition, and muscle function during exercise.
Karsenty’s talk on "The Impact of Bone on Whole Organism Physiology” April 12 was hosted by John Cidlowski, Ph.D., head of the NIEHS Molecular Endocrinology Group in the Signal Transduction Laboratory. Cidlowski noted that Karsenty is a leader in bone biology, because his research shatters our thinking of what bone does.
"One of his recent grants is titled The Dialogue Between Bone and the Brain: Endocrine and Molecular Basis,” said Cidlowski. “No one would think of studying interactions between bone and the brain, because on the surface they appear to be completely distinct."
Bone, an endocrine organ?
As a physiologist, Karsenty has based his work on the notion that no function in the body is fulfilled by a single organ, and no organ is an island. He said his research career began with curiosity about why mineralization occurs only in bone, and not in the skin or any other organ.
Karsenty’s preliminary findings suggested that osteocalcin, the most abundant noncollagenous protein in bone, may be responsible. However, his research with osteocalcin knockout mice hinted that the protein’s influence in the body goes far beyond bone.
"These mice had normal bone development, but they were fatter than wild type mice and bred poorly," Karsenty said. "The results implied that osteocalcin was a hormone that regulated insulin levels and was somehow involved in fertility."
When additional studies found that male mice with no osteocalcin had low testosterone, Karsenty studied the osteocalcin receptor in their testes, which were enriched with fat cells. People with a mutation in the human version of this receptor have testicular failure and are glucose intolerant.
Osteocalcin knockout mice also exhibited defects in memory and cognition, and they were more anxious than their wild type counterparts. Karsenty found that a skeletal condition called cleidocranial dysplasia (CCD) mimics what he saw in the osteocalcin-deficient animals. Mice and humans with CCD have a 30 percent decrease in osteocalcin and display cognitive deficiencies.
The running wheel
Exercise calls on muscle function to increase, but before this can occur, the body has to increase the uptake and breakdown of glucose and fatty acids in muscle. Karsenty wanted to see the effects of osteocalcin on this process.
He found that levels of circulating osteocalcin increased, whether it was in mice on a running wheel or humans engaged in a leisurely jog. Simultaneously, bone absorption increased, and levels of circulating insulin decreased. "None of it occurs," Karsenty added, "if you don’t have osteocalcin signaling in muscle."