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

Marino, Silvia; de Ridder, Daniëlle; Bishop, Ryan T; Renema, Nathalie; Ponzetti, Marco; Sophocleous, Antonia; Capulli, Mattia; Aljeffery, Abdullah; Carrasco, Giovana; Dalghi Gens, Marianela; Khogeer, Asim; Ralston, Stuart H; Gertsch, Jürg; Lamoureux, Francois; Heymann, Dominique; Rucci, Nadia; Idris, Aymen I (2019). Paradoxical effects of JZL184, an inhibitor of monoacylglycerol lipase, on bone remodelling in healthy and cancer-bearing mice. EBioMedicine, 44, pp. 452-466. Elsevier 10.1016/j.ebiom.2019.05.048

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Dalghi Gens, Marianela Gisela and Gertsch, Jürg

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2352-3964

Publisher:

Elsevier

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

26 Sep 2019 14:05

Last Modified:

23 Oct 2019 14:23

Publisher DOI:

10.1016/j.ebiom.2019.05.048

PubMed ID:

31151929

Uncontrolled Keywords:

Bone Breast Cancer Cannabinoid MAGL Metastasis Osteoclast Osteolysis Prostate Sarcoma

BORIS DOI:

10.7892/boris.133490

URI:

https://boris.unibe.ch/id/eprint/133490

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