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Pharmacological manipulation of monoacylglycerol lipase (MAGL), an enzyme responsible for the degradation of the endocannabinoid 2-arachidonoyl glycerol (2-AG), reduced skeletal tumour burden and osteolysis associated with osteosarcoma and advanced breast and prostate cancers. MM and hematopoietic, immune and bone marrow cells express high levels of type 2 cannabinoid receptor and osteoblasts secrete 2-AG. However, the effects of MAGL manipulation on MM have not been investigated. Here, we report that treatment of pre-osteoclasts with non-cytotoxic concentrations of JZL184, a verified MAGL inhibitor, enhanced MM- and RANKL-induced osteoclast formation and size in vitro. Exposure of osteoblasts to JZL184 in the presence of MM cell-derived factors reduced osteoblast growth but had no effect on the ability of these cells to mature or form bone nodules. In vivo, administration of JZL184 induced a modest, yet significant, bone loss at both trabecular and cortical compartments of long bones of immunocompetent mice inoculated with the syngeneic 5TGM1-GFP MM cells. Notably, JZL184 failed to inhibit the in vitro growth of a panel of mouse and human MM cell lines, or reduce tumour burden in mice. Thus, MAGL inhibitors such as JZL184 can exacerbate MM-induced bone loss.<\/jats:p>","DOI":"10.1007\/s00223-020-00689-0","type":"journal-article","created":{"date-parts":[[2020,4,13]],"date-time":"2020-04-13T18:02:17Z","timestamp":1586800937000},"page":"72-85","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["JZL184, A Monoacylglycerol Lipase Inhibitor, Induces Bone Loss in a Multiple Myeloma Model of Immunocompetent Mice"],"prefix":"10.1007","volume":"107","author":[{"given":"Silvia","family":"Marino","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovana","family":"Carrasco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boya","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karan M.","family":"Shah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darren L.","family":"Lath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonia","family":"Sophocleous","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle A.","family":"Lawson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aymen I.","family":"Idris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,4,13]]},"reference":[{"key":"689_CR1","doi-asserted-by":"crossref","unstructured":"Accardi F, Toscani D, Costa F, Aversa F, Giuliani N (2017) The proteasome and myeloma-associated bone disease, Calcif Tissue Int.","DOI":"10.1007\/s00223-017-0349-1"},{"issue":"Suppl 1","key":"689_CR2","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1111\/j.1365-2826.2008.01675.x","volume":"20","author":"I Bab","year":"2008","unstructured":"Bab I, Ofek O, Tam J, Rehnelt J, Zimmer A (2008) Endocannabinoids and the regulation of bone metabolism. 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Idris is an inventor on a patent concerning the use of cannabinoid receptor ligands for the treatments of bone diseases. Other authors declare no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}