How small mutations can disturb bone growth

Important mechanisms for the development of craniosynostosis have been discovered. Recently, Prof. Dr. Christoph Garbers was appointed chair for experimental pathology for the Institute of Pathology of the OVGU.  In their new work in the journal „Cell Reports“, he and his team showed why the cytocine interleukin-11 plays such an important role in cranial development.

Cranial development in mammals is a complex and finely regulated process. The neurocranium, which provides a stable shell for the brain, consists of five bones. In newborns, gaps called fontanelles are present between these bones. After the first year of life, these gaps close and the neurocranium is completed. This ensures that the skull can grow further as the brain grows. If these seams close early, the condition is called craniosynostosis. This occurs in approximately 1 in 2,500 newborns. 

Prof. Garbers research group uncovered the mechanism that is responsible for this malformation. The basis of this work was the fact that in the last few years, multiple patients had small mutations in the gene for the receptor interleukin-11 (IL-11R). In normal cases, the neurotransmitter interleukin-11 (IL-11) binds to the IL-11R on the cell surface of osteoblasts, the cells that are responsible for the growth of new bone tissue. After binding to the IL-11, the signals are transmitted to the inside of the cell, which causes the osteoblasts to begin generating new bone tissue. The researchers were able to show that the mutations prevented the IL-11R inside the cell from being produced correctly because it could not be transported to the cell surface. Instead it got stuck in the endoplasmatic reticulum inside the cell. Because of this, the classical signal path, IL-11 binding to IL-11R and IL-11R sends further signals inside the cell, does not function any more and, according to the researchers´ data, this is responsible for normal cranial bone development.

There is a second pathway through which IL-11 signals can be passed on, by binding to the soluble receptor, which is present in the tissue instead of being bound to the surface of the cell. This system of IL-11 and its receptor can bind to a molecule on the surface of the cell and activate signals inside the cell. The fact that the classic signalling pathway described above is responsible for bone alteration is critical for a very specific reason, which Prof. Garbers explained, „Currently, in phase-II studies, an inhibitor for the second pathway, olamkicept, is being tested. We hope that it can be used to treat the chronic inflammatory bowel disease colitis ulcerosa. Our results show that this therapy does not impair normal bone development because that occurs through classic signalling pathways.“

As mentioned before, Prof. Garbers recently began in Magdeburg. His research fits perfectly with the Health Campus Immunology, Infectiology and Inflammation, and he found a variety of contacts and collaborators for his work through the Collaborative Research Center 854, which focuses on the molecular organisation of cellular communication in the immune system. 

Link to original publication: Agthe M, Brügge J, Garbers Y, Wandel M, Kespohl B, Arnold P, Flynn CM, Lokau J, Aparicio-Siegmund S, Bretscher C, Rose-John S, Waetzig GH, Putoczki T, Grötzinger J, Garbers C. Mutations in Craniosynostosis Patients Cause Defective Interleukin-11 Receptor Maturation and Drive Craniosynostosis-like Disease in Mice. Cell Rep. 2018 Oct 2;25(1):10-18.e5.

Text: Dr. Martina Beyrau