Osteoporosis: new pieces to a big puzzle
The protein menin identified as key player in the formation of bones and the development of jaw cancer

Ulm University

Scientists at Ulm University utilised menin and CXCL10 to decode important factors in the development of osteoporosis. These findings offer a starting point for the development of new therapies for this prevalent disease. At the same time, the researchers discovered a trigger of a rare tumour of the lower jaw.

Around ten percent of the population in Germany suffer from osteoporosis. The diseases manifests in seven percent of women over 55 years and almost 20 percent in women older than 80 years. It is increasingly found in men also. The bones of those affected progressively lose their density, which makes them prone to fractures. This leaves particularly many old people in need of care. 

The scientists at the Institute of Comparative Molecular Endocrinology (CME) at Ulm University have made significant progress in their investigations of the widespread disease osteoporosis. 'We discovered a new factor in the regulation of bone density,' says the Director of the Institute, Professor Jan Tuckermann. Centrepiece of this research was the so-called tumour suppressor menin. The absence of this gene in osteocytes - the cells that are responsible for bone remodelling - caused a high reproduction of bone dissolving cells (osteoclasts) in the bones of mice.

At the same time, the researcher from Ulm identified the molecule CXCL10, which is sent out by the osteocytes. 'When this molecule is released, there are more osteoclasts,' explains Tuckermann. 'While there are a number of other factors, we added two new known factors to this puzzle game,' says the molecular biologist, who became Director of the CME in 2012.

New approaches to treating osteoporosis could be a long-term goal. 'Common therapies inhibit bone resorption,' Tuckermann elaborates. This is a good thing initially, because it prevents further loss of bone mass. It does, however, compromise the quality of the bone. This is because osteoclasts are involved in bone remodelling as well, a process that occurs constantly to adapt the skeleton to changing demands. Now that one of the communication pathways between osteocytes and osteoclasts has been identified, the researchers can attempt to inhibit the interaction of these cells. 'One approach could be to reduce the molecule CXCL10 with antibodies,' says Tuckermann. At least now there is a starting point for such considerations.

Another side-effect of the seven-year-long research: In some cases, the loss of menin in the osteoclasts of mice led to the formation of a tumour in the lower jaw. Experts of the Bone Tumour Reference Centre in Basel, a cooperation partner of the CME, pointed out the similarity with the ossification syndrome found in humans. This little researched tumour disease leads to heavy cell growth in the lower jaw. At present, this very rare, benign tumour can only be treated with invasive and disfiguring surgeries. Until now, little was known about the triggering factors of this tumour disease. In a mouse model, the researchers in Ulm have now discovered that menin controls the cell growth inhibitor p21 - and thus suppresses the growth of tumours. When menin is absent, p21 reduces its activity and certain cells start to grow increasingly.

In a next step, the CME and the colleagues from the German-Austrian-Swiss Task Force for Tumours of the Jaw and Face (DÖSAK) will analyse human specimen of the ossification syndrome in order to test the findings from the research on mice. 'We are hoping to find therapeutic approaches that can prevent the development of these tumours,' says Tuckermann. Animal experiments cannot always be avoided in this type of work. The researchers do make sure to keep the numbers of animals at a minimum while still being able to draw valid conclusions for the explanation of human disease patterns. The project received funding from the German Research Foundation through the focus programme Immunobone 1468, the Trauma SFB 1149 and the Trilaterale Consortium Tu 220/12-1.

Text: Jens Eber
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Literature reference:
Liu P, Lee S, Knoll J, Rauch A, Ostermay S, Luther J, Malkusch N, Lerner UH, Zaiss MM, Neven M, Wittig R, Rauner M, David JP, Bertolino P, Zhang CX, Tuckermann JP: Loss of menin in osteoblast lineage affects osteocyte-osteoclast crosstalk causing osteoporosis; Cell Death & Differentiation. 2017 Apr; 24(4):672-682. https://doi.org/10.1038/cdd.2016.165

Lee S, Liu P, Teinturier R, Jakob J, Tschaffon M, Tasdogan A, Wittig R, Hoeller S, Baumhoer D, Frappart L, Vettorazzi S, Bertolino P, Zhang C, Tuckermann J: Deletion of Menin in craniofacial osteogenic cells in mice elicits development of mandibular ossifying fibroma; Oncogene. 2017 Oct 9., doi:10.1038/onc.2017.364

Bone tissue is the result of a complex remodelling process (osteogenesis). This requires the perfect coordination of bone formation and resorption. In consequence, cells that break down bone (osteoclasts) are equally important as bone-forming cells (osteoblasts).

Osteocytes, on the other hand, are the bone cells found in the mineralised matrix of bone tissue. They arise from the differentiation of osteoblasts during bone formation.

This micro computer tomography image compares cross sections of bones. Normal wild-type mice have a sufficient number of bone trabeculae (left). In mice where Men 1 is deficient in the osteocytes, the number of bone trabeculae is significantly reduced, leading to osteoporosis (image: Institute of Molecular Endocrinology)
These micro computer tomography images show the bottom side of mouse skulls. The lower jaw of the wild-type mouse is developed normally (left). The mice without Men 1 in the osteoclasts, on the other hand, developed tumours on both sides of their lower jaws (right). (Image: Institute of Molecular Endocrinology)
Prof. Jan Tuckermann, Director of the Institute of Comparative Molecular Endocrinology (photo: Elvira Eberhardt / Ulm University)
The first authors of both studies Dr. Peng Liu und Dr. Soo Lee (photo: Elvira Eberhardt)