Abstract
Multiple myeloma (MM) patients develop osteolysis characterised by excessive osteoclastic bone destruction and lack of osteoblast bone formation. 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.
Highlights
Bone disease is a serious complication in haematological malignancies such as multiple myeloma (MM)
Previous studies by Nomura et al and our laboratories have shown that knockdown and pharmacological inhibition of monoacylglycerol lipase (MAGL)—the enzyme that is responsible for the degradation of 2-arachidonoyl glycerol (2-AG) [15, 32, 40]—inhibited the in vitro and in vivo growth of primary bone sarcoma and reduced the metastatic spread and bone damage associated with prostate and breast cancer [27, 32, 34]
We report the effects of pharmacological manipulation of MAGL on the initiation and progression of tumour burden and bone disease associated with MM
Summary
Bone disease is a serious complication in haematological malignancies such as multiple myeloma (MM). Years, there has been increasing interest in the therapeutic targeting of the endogenous cannabinoid (endocannabinoid) system for the management of skeletal-related events and a number of pre-clinical studies have implicated cannabinoid ligands and their receptors in regulation of bone cell activity, bone remodelling and bone pain [2, 19, 22, 25, 27, 28]. Barbado and colleagues have observed that administration of WIN-55,212–2 reduced the growth of human U226 MM cells in immunodeficient mice [4]. Whilst these findings suggest pharmacological manipulation of cannabinoid receptors reduces MM cell growth, little is known about whether targeting the endocannabinoid system could be of therapeutic value in the reduction of skeletal complications associated with MM
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