Pumping calcium for bigger bones

New intracellular signaling mechanism discovered for long bone growth
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Kyoto, Japan --  Like fuel for cars, bones require calcium for growth and development. How this works in cars is well known, but the same cannot be said for bones.

Now a study at Kyoto University has identified that c-type natriuretic peptide, or CNP, facilitates intracellular Ca2+ signals in growth plate cartilage cells, or chondrocytes, for stimulating growth at both ends of developing long bones.

"The signaling pathway was as we predicted, but the results of our experiment turned out clearer than expected," says lead author Atsuhiko Ichimura. 

In addition to identifying CNP signaling pathways using pharmacological and genetic experiments, a potential target protein in the pathway has also been eyed for developing new therapeutic agents to treat growth disorders such as retardation.

While the CNP analog peptide VOXZOGO™, or vosoritide, has been approved for treating achondroplasia in Europe and the United States, the molecular mechanism in which CNP promotes bone growth has long remained unclear.

To investigate the physiological links between the pathway and bone growth, the research team developed unique methods to analyze intracellular Ca2+ concentration in living chondrocytes, using bone samples from mutant mice. 

The pharmacological data suggest that CNP is involved in elevating the chemical cyclic guanosine monophosphate, or cGMP, at the cell membrane level. The study shows that a cascade of ionic channel events boosts Ca2+ cellular concentration, inducing long bone outgrowth. 

"It was surprising to discover that CNP facilitates ion channel activity, thereby inducing artificial regulation of bone growth," adds Ichimura.

The team believes that the development of chemical agents that specifically target this pathway may lead to promising clinical treatments for bone-related developmental disorders. Also, the technology could be applied to artificially modify body size in farm and pet animals.

"It has taken us more than 30 years to find the novel signaling cascade of CNP," notes Ichimura. "Now, these results may enable us to develop new bone growth-stimulating agents."

C-type natriuretic peptide facilitates autonomic calcium entry in growth plate chondrocytes for stimulating bone growth
Ichimura, Atsuhiko
Publication information


【KURENAI ACCESS URL】http://hdl.handle.net/2433/268928

Yuu Miyazaki, Atsuhiko Ichimura, Ryo Kitayama, Naoki Okamoto, Tomoki Yasue, Feng Liu, Takaaki Kawabe, Hiroki Nagatomo, Yohei Ueda, Ichiro Yamauchi, Takuro Hakata, Kazumasa Nakao, Sho Kakizawa, Miyuki Nishi, Yasuo Mori, Haruhiko Akiyama, Kazuwa Nakao, Hiroshi Takeshima (2022). C-type natriuretic peptide facilitates autonomic Ca²⁺ entry in growth plate chondrocytes for stimulating bone growth. eLife, 11:e71931.