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EBioMedicine. 2019 Jun;44:452-466. doi: 10.1016/j.ebiom.2019.05.048. Epub 2019 May 29.

Paradoxical effects of JZL184, an inhibitor of monoacylglycerol lipase, on bone remodelling in healthy and cancer-bearing mice.

Author information

1
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.
2
Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
3
INSERM, U1238, University of Nantes, Faculty of Medicine, 1 rue Gaston Veil, 44035 Nantes, Cedex 1, France.
4
University of L'Aquila, Department of Biotechnological and Applied Clinical Sciences, L'Aquila, Italy.
5
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.
6
Institute of Biochemistry and Molecular Medicine, University of Bern, Switzerland.
7
Rheumatic disease unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
8
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.
9
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.
10
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. Electronic address: aymen.idris@sheffield.ac.uk.

Abstract

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:

Bone; Breast; Cancer; Cannabinoid; MAGL; Metastasis; Osteoclast; Osteolysis; Prostate; Sarcoma

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