JZL184, A Monoacylglycerol Lipase Inhibitor, Induces Bone Loss in a Multiple Myeloma Model of Immunocompetent Mice

• DOI: 10.1007/s00223-020-00689-0
• Publication Date: 2020-04-13T18:02:17Z
• Authors: Silvia Marino; Giovana Carrasco; Boya Li; Karan M. Shah; Darren L. Lath; Antonia Sophocleous; Michelle A. Lawson; Aymen I. Idris
• Keywords: Osteolysis; 2-Arachidonoylglycerol

Abstract Multiple myeloma (MM) patients develop osteolysis characterised by excessive osteoclastic bone destruction and lack of osteoblast formation. Pharmacological manipulation monoacylglycerol lipase (MAGL), an enzyme responsible for the degradation endocannabinoid 2-arachidonoyl glycerol (2-AG), reduced skeletal tumour burden associated with osteosarcoma advanced breast prostate cancers. MM hematopoietic, immune marrow cells express high levels type 2 cannabinoid receptor osteoblasts secrete 2-AG. However, effects MAGL on have not been investigated. Here, we report that treatment pre-osteoclasts non-cytotoxic concentrations JZL184, a verified inhibitor, enhanced MM- RANKL-induced osteoclast formation size in vitro. Exposure to JZL184 presence cell-derived factors growth but had no effect ability these mature or form nodules. In vivo, administration induced modest, yet significant, loss at both trabecular cortical compartments long bones immunocompetent mice inoculated syngeneic 5TGM1-GFP cells. Notably, failed inhibit vitro panel mouse human cell lines, reduce mice. Thus, inhibitors such as can exacerbate MM-induced loss.