Lead


Lay summary
Cannabinoid receptors are G-protein coupled receptors that are expressed in the central nervous system (predominantly CB1 receptors) and in peripheral tissues like spleen and immune cells (CB1 and CB2 receptors). In vivo, CB receptors are activated by arachidonic acid-derived endocannabinoids, such as 2-arachidonoyl ethanolamine (anandamide or AEA) and 2-arachidonoylglycerol (2-AG). While cannabinoid research in the last 20 years has mainly focused on the function and regulation of centrally expressed CB1 receptors, the role of peripherally expressed CB receptors and the endocannabinoid system is still poorly understood. In the last 5 years, peripherally expressed CB receptors (in particular CB2) have been shown to be a potential therapeutic target for the treatment of diseases as diverse as inflammation (gut, liver, brain), chronic peripheral pain, atherosclerosis, and osteoporosis. In these studies, the potential therapeutic use of both CB1 and CB2 agonists and/or antagonists was mainly deduced from animal experiments and a mechanistic understanding at the level of receptor pharmacology is still widely lacking. In osteoclasts, CB receptors are assumed to play a prominent role for osteoclast formation and the regulation of bone resorption. However, data obtained in animal models with different CB1 and CB2 ligands are contradictory. A major problem is that different research groups frequently employ distinct CB receptor agonists, inverse agonists and/or antagonists, which may trigger distinctly different signals in different tissues upon receptor activation. Moreover, data on human osteoclasts are still widely lacking. Since osteoclasts can be generated from monocytes and CB receptor surface expression is high in primary CD14+ monocytes, as well as different CD14+ cancer cell lines, we focus our research on primary monocytes/macrophages and osteoclasts in order to study the role of the endocannabinoid system in immune and bone destructing cells. In particular, it is till unclear how CB receptor ligand interactions can modulate cellular function. The project also aims at studying the regulation of surface expression of CB receptors in monocytes and osteoclasts as receptor density critically controls GPCR signalling. A better understanding of how CB receptor surface expression is regulated in monocytes/macrophages and osteoclasts and how CB ligands influence the function of these cells with regard to therapeutic intervention is of key important for drug discovery and the development of new therapies as e.g. related to inflammatory bone desctruction.