The type 2 cannabinoid receptor regulates susceptibility to osteoarthritis in mice.
OBJECTIVE
Cannabinoid receptors and their ligands have been implicated in the regulation of various physiological processes but their role in osteoarthritis has not been investigated. The aim of this study was to evaluate the role of the type 2 cannabinoid receptor (Cnr2) in regulating susceptibility to osteoarthritis in mice.


METHODS
We analysed the severity of knee osteoarthritis as assessed by the Osteoarthritis Research Society International (OARSI) scoring system in mice with targeted deletion of Cnr2 (Cnr2(-/-)) and wild type (WT) littermates. Studies were conducted in mice subjected to surgical destabilisation of the medial meniscus (DMM) and in those with spontaneous age-related osteoarthritis (OA).


RESULTS
Osteoarthritis was more severe following DMM in the medial compartment of the knee in Cnr2(-/-) compared with WT mice (mean ± sem score = 4.9 ± 0.5 vs 3.6 ± 0.3; P = 0.017). Treatment of WT mice with the CB2-selective agonist HU308 following DMM reduced the severity of OA in the whole joint (HU308 = 8.4 ± 0.2 vs vehicle = 10.4 ± 0.6; P = 0.007). Spontaneous age related osteoarthritis was also more severe in the medial compartment of the knee in 12-month old Cnr2(-/-) mice compared with WT (5.6 ± 0.5 vs 3.5 ± 0.3, P = 0.008). Cultured articular chondrocytes from Cnr2(-/-) mice produced less proteoglycans in vitro than wild type chondrocytes.


CONCLUSIONS
These studies demonstrate that the Cnr2 pathway plays a role in the pathophysiology of osteoarthritis in mice and shows that pharmacological activation of CB2 has a protective effect. Further studies of the role of cannabinoid receptors in the pathogenesis of osteoarthritis in man are warranted.
Rheumatology and Bone Diseases Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK. Electronic address: antonia.sophocleous@ed.ac.uk.
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Sophocleous
Rheumatology and Bone Diseases Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK. Electronic address: anna.borjesson@igmm.ed.ac.uk.
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Börjesson
Osteoarticular Research Group, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK. Electronic address: donald.salter@ed.ac.uk.
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Salter
Rheumatology and Bone Diseases Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK. Electronic address: stuart.ralston@ed.ac.uk.
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Ralston
D000375:Aging / Q000502:physiology; D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology; D019902:Chondrocytes / Q000378:metabolism; D004198:Disease Susceptibility; D008592:Menisci, Tibial / Q000187:drug effects; D051379:Mice; D010003:Osteoarthritis / Q000209:etiology*; D020370:Osteoarthritis, Knee / Q000209:etiology; D011509:Proteoglycans / Q000096:biosynthesis; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000172:deficiency / Q000502:physiology*; D055114:X-Ray Microtomography
D002186:Cannabinoids; C571431:Cnr2 protein, mouse; D011509:Proteoglycans; D043885:Receptor, Cannabinoid, CB2; C402416:HU 308
CB2; Cannabinoids; Cartilage; Cnr2; Mouse model; Osteoarthritis