New findings explain why we stop growing at one point

Published 2014-05-09 13:43. Updated 2014-05-13 09:37

Many children suffer from growth abnormalities, such as growing to a very short or extremely tall height. In a recent study, an international research team led from Karolinska Institutet demonstrates genes responsible for the function of the growth plates, which in turn controls short or tall stature. The findings, published in Nature Communications, could be important for developing new drugs for children with growth abnormalities.

Longitudinal growth rate and final height in adult humans depend on the proper function of the growth plates, which are thin cartilage discs located at the end of long bones. These growth plates consist of special cells called chondrocytes, which make a cartilage template for the bone to be formed on. Immature (stem-like) chondrocytes first start proliferating; then maturing (differentiate and enlarge); and finally die, allowing new bone tissue to be formed on the remaining cartilage matrix.

Thus, bones grow longitudinally only while the growth plates are present. They usually disappear or fuse after sexual maturation, making further longitudinal growth impossible. If growth plates fuse early, for example due to precocious puberty, this leads to short stature, and if late to tall stature. The mechanisms of growth plate fusion are unknown.

Investigated the role of G-proteins

In the current work, Assistant Professor Andrei Chagin and colleagues investigated the role of so-called G-proteins in the process of growth plate fusion. G-proteins belong to a class of proteins which mediate intracellular signaling from multiple seven-transmembrane receptors.  The research team found that particularly the signaling of the G-protein stimulatory subunit alpha (Gsα) keeps the growth plate open. When the gene coding for Gsα is removed from chondrocytes, growth plates fuse, which ultimately leads to short bones.

The researchers also found that the receptor for parathyroid hormone and parathyroid hormone related peptide (PTHR1) is the main activator of Gsα in chondrocytes, and that this receptor is particularly important for the growth plate to stay open. Ablation of PTHR1 from chondrocytes led to fusion of the growth plates, which occurred even faster than caused by the absence of Gsα.

Further, the study shed light on the underlying mechanism of growth plate fusion, which the researchers found to be related to two processes: chondrocyte maturation, and behavior of stem-like immature chondrocytes. Ablation of either PTHR1 or Gsα accelerates chondrocyte maturation and death so dramatically that new cells are not ready to be produced. At the same time PTHR1 and Gsα have different function in stem-like immature chondrocytes.

Determine our growth potential

It is believed that these cells determine our growth potential by dividing and providing precursors for all other chondrocytes in the growth plate. These stem-like chondrocytes generally divide very seldom.

“We observed that the absence of PTHR1 these cells die, whereas in the absence of Gsα they lose their stem-like quiescence, dividing and mature”, says Andrei Chagin. “This striking difference in behavior of turned out to be related to another G-protein, also activated by PTHR1, namely Gq/11. Indeed, our results demonstrate that both Gq/11 and Gsα work together to protect stem-like chondrocytes and keep them from dividing.”

The study was funded by National Institute of Health, The Swedish Research Council, The Swedish Society for Medical Research and Sällskapet Barnavård. Andrei Chagin is a principal investigator at the Department of Physiology and Pharmacology at Karolinska Institutet. Researchers from Germany and the U.S. also took part in the investigation. 


G-protein stimulatory subunit alpha and Gq/11α G-proteins are both required to maintain quiescent stem-like chondrocytes
Chagin AS, Vuppalapati KK, Kobayashi T, Guo J, Hirai T, Chen M, Offermanns S, Weinstein LS, Kronenberg HM.
Nature Communications, 2014 Apr 30;5:3673. doi: 10.1038/ncomms4673