Paradoxical effects of JZL184, an inhibitor of monoacylglycerol lipase, on bone remodelling in healthy and cancer-bearing miceResearch in context
Silvia Marino,
Daniëlle de Ridder,
Ryan T. Bishop,
Nathalie Renema,
Marco Ponzetti,
Antonia Sophocleous,
Mattia Capulli,
Abdullah Aljeffery,
Giovana Carrasco,
Marianela Dalghi Gens,
Asim Khogeer,
Stuart H. Ralston,
Jürg Gertsch,
Francois Lamoureux,
Dominique Heymann,
Nadia Rucci,
Aymen I. Idris
Affiliations
Silvia Marino
Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK; Bone and Cancer Group, Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XR, UK
Daniëlle de Ridder
Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Ryan T. Bishop
Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Nathalie Renema
INSERM, U1238, University of Nantes, Faculty of Medicine, 1 rue Gaston Veil, 44035 Nantes, Cedex 1, France
Marco Ponzetti
University of L'Aquila, Department of Biotechnological and Applied Clinical Sciences, L'Aquila, Italy
Antonia Sophocleous
Rheumatic disease unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK; Department of Life Sciences, School of Sciences, European University Cyprus, 6 Diogenes Street, 1516 Nicosia, Cyprus
Mattia Capulli
University of L'Aquila, Department of Biotechnological and Applied Clinical Sciences, L'Aquila, Italy
Abdullah Aljeffery
Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Giovana Carrasco
Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Marianela Dalghi Gens
Institute of Biochemistry and Molecular Medicine, University of Bern, Switzerland
Asim Khogeer
Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK; Bone and Cancer Group, Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XR, UK
Stuart H. Ralston
Rheumatic disease unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
Jürg Gertsch
Institute of Biochemistry and Molecular Medicine, University of Bern, Switzerland
Francois Lamoureux
INSERM, U1238, University of Nantes, Faculty of Medicine, 1 rue Gaston Veil, 44035 Nantes, Cedex 1, France
Dominique Heymann
Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK; INSERM, U1232, CRCINA, Institut de Cancérologie de l'Ouest, University of Nantes, Université d'Angers, Blvd Jacques Monod, 44805 Saint-Herblain, France
Nadia Rucci
Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK; University of L'Aquila, Department of Biotechnological and Applied Clinical Sciences, L'Aquila, Italy
Aymen I. Idris
Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK; Bone and Cancer Group, Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XR, UK; Corresponding author at: Department of Oncology and Metabolism, Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
Background: Cancer-associated bone disease is a serious complication in bone sarcomas and metastatic carcinomas of breast and prostate origin. Monoacylglycerol lipase (MAGL) is an enzyme of the endocannabinoid system, and is responsible for the degradation of the most abundant endocannabinoid in bone, 2-arachidonoyl glycerol (2AG). Methods: The effects of the verified MAGL inhibitor on bone remodelling were assessed in healthy mice and in mouse models of bone disease caused by prostate and breast cancers and osteosarcoma. Findings: JZL184 reduced osteolytic bone metastasis in mouse models of breast and prostate cancers, and inhibited skeletal tumour growth, metastasis and the formation of ectopic bone in models of osteosarcoma. Additionally, JZL184 suppressed cachexia and prolonged survival in mice injected with metastatic osteosarcoma and osteotropic cancer cells. Functional and histological analysis revealed that the osteoprotective action of JZL184 in cancer models is predominately due to inhibition of tumour growth and metastasis. In the absence of cancer, however, exposure to JZL184 exerts a paradoxical reduction of bone volume via an effect that is mediated by both Cnr1 and Cnr2 cannabinoid receptors. Interpretation: MAGL inhibitors such as JZL184, or its novel analogues, may be of value in the treatment of bone disease caused by primary bone cancer and bone metastasis, however, activation of the skeletal endocannabinoid system may limit their usefulness as osteoprotective agents. Keywords: MAGL, Cannabinoid, Breast, Prostate, Bone, Cancer, Sarcoma, Osteolysis, Osteoclast, Metastasis
