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Targeting the cellular sphingolipid system as novel therapeutic strategy for bone diseases

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(Vienna, 09 June 2017) Osteoporosis is by far the most frequent metabolic bone disease affecting both women and men. The International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA) estimates that in the European Union 22 million women and 5.5 million men have osteoporosis. With the aging of our societies, osteoporosis will become an ever increasing challenge to our health care systems. Thus, there is an urgent need for novel therapies for osteoporosis. In the invited review article recently published in Expert Opinion on Therapeutic Targets, researches from MedUni Vienna made an effort to look from another angle on the therapeutic options for osteoporosis and other bone-related disorders and proposed that pharmacological interference with the cellular sphingolipid system may lead to novel osteotropic therapies.

Says Peter Pietschmann, lead investigator and expert in bone biology from MedUni Vienna's Institute of Pathophysiology and Allergy Research: “Over the past decades, our therapeutic options for the disease have significantly improved; as an example, bisphosphonates and denosumab should be mentioned. Nevertheless, even in countries with very advanced health care systems, an alarmingly high fraction of osteoporosis patients does not receive adequate treatment. On the one hand, patients with osteoporosis very likely will need long term (if not lifelong) treatment. On the other hand, significant concerns regarding the long term safety of bisphosphates, the most commonly prescribed treatment for osteoporosis, were raised.”

Sphingosine 1-phosphate signaling in bone remodeling: multifaceted roles and therapeutic potential - this first comprehensive review highlights the theme of physiological and pathological bone remodeling in the context of multifaceted interrelations with the sphingolipid-driven mechanisms. What is “the sphingolipid machinery”? The sphingolipid machinery consists of natural bioactive sphingolipid mediators, sphingolipid- producing/modifying/degrading enzymes, lipid-specific G-protein-coupled receptors and a set of lipid transporters. Strong evidence indicates that sphingolipid-related targets as well as sphingolipid analogs have great potential for treatment of various diseases including autoimmune disorders and cancer. “Newly emerging, there are furthermore strong lines of evidence – although puzzling – suggesting a multistep involvement of bioactive sphingolipids in a variety of aspects of bone metabolism. Summing-up the current knowledge on the (patho)biology of the sphingolipid machinery encouraged us to introduce for the first time the term/concept “sphingolipid-related checkpoint” – similarly to "cell cycle checkpoint" and "immune checkpoint" – as critical sphingolipid machinery-related decision-making point to be considered for therapeutic intervention”, say lead investigator Diana Mechtcheriakova, an expert in the field of sphingolipid-related drug discovery and systems biology, and lead author Anastasia Mechtcheriakova from MedUni Vienna's Institute of Pathophysiology and Allergy Research.

Is the modulation of the cellular sphingolipid system the new frontier of osteoporosis medicine?  The authors propose the relevant checkpoints of the sphingolipid machinery as promising therapeutic targets for bone diseases. As a future perspective, the authors believe that implementation of systems biology approaches through integrative analysis of available data in the “omics” format will allow to identify novel druggable pathways and targets.

The work was supported by the Austrian Science Fund FWF (http://www.fwf.ac.at/; Projekt P23228-B19).

Expert Opinion on Therapeutic Targets
Meshcheryakova, A., D. Mechtcheriakova, and P. Pietschmann, Sphingosine 1-phosphate signaling in bone remodeling: multifaceted roles and therapeutic potential. Expert Opin Ther Targets, 2017. DOI: 10.1080/14728222.2017.1332180.