title: Cannabinoid WIN‑55,212‑2 mesylate inhibits ADAMTS‑4 activity in human osteoarthritic articular chondrocytes by inhibiting expression of syndecan‑1.
abstract: A central feature of osteoarthritis (OA) is the loss of articular cartilage, which is primarily attributed to cartilage breakdown. A group of metalloproteinases termed the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family are reported to be important in cartilage breakdown. Recent studies have suggested that ADAMTS‑4 is a major contributor to the pathogenesis of OA and that syndecan‑1 is closely associated with activation of ADAMTS‑4 in human chondrocytes. Accumulating evidence also suggests that cannabinoids have chondroprotective effects. The current study explored the effects of synthetic cannabinoid WIN‑55,212‑2 mesylate (WIN‑55) on the expression of syndecan‑1 and ADAMTS‑4, as well as ADAMTS‑4 activity, in unstimulated and interleukin (IL)‑1β‑stimulated OA chondrocytes. Primary human OA articular chondrocytes were treated with WIN‑55 in the presence or absence of IL‑1β and cannabinoid receptor antagonists. The results of the present study demonstrated that WIN‑55 inhibited ADAMTS‑4 activity in unstimulated and IL‑1β‑stimulated primary human OA articular chondrocytes in a concentration‑dependent manner. Cannabinoid receptor type 1 (CB1) and 2 (CB2) were constitutively expressed in human OA articular chondrocytes. Furthermore, selective CB2 antagonist, JTE907, but not selective CB1 antagonist, MJ15, abolished the inhibitory effect of WIN‑55 on ADAMTS‑4 activity. WIN55 inhibited the expression of syndecan‑1 but not ADAMTS‑4, and overexpression of syndecan‑1 reversed the inhibitory effect of WIN‑55 on the ADAMTS‑4 activity in unstimulated and IL‑1β‑stimulated human OA articular chondrocytes. Despite having no significant effect on syndecan‑1 gene promoter activity, WIN‑55 markedly decreased the stability of syndecan‑1 mRNA via CB2. In conclusion, to the best of our knowledge, the present study provides the first in vitro evidence supporting that the synthetic cannabinoid WIN‑55 inhibits ADAMTS‑4 activity in unstimulated and IL‑1β‑stimulated human OA articular chondrocytes by decreasing the mRNA stability/expression of syndecan‑1 via CB2. This suggests a novel mechanism by which cannabinoids may prevent cartilage breakdown in OA. In addition, it also provides novel insights into the pharmacological effects of synthetic cannabinoids on OA.
authors.affiliation: Department of Rehabilitation, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Wanchun
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Rehabilitation, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Changjie
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Rehabilitation, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000071121:ADAMTS4 Protein / Q000037:antagonists & inhibitors*; D048588:Benzoxazines / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053668:Syndecan-1 / Q000235:genetics*
chemical_list: D048588:Benzoxazines; D053583:Interleukin-1beta; D009025:Morpholines; D009281:Naphthalenes; D043885:Receptor, Cannabinoid, CB2; D053668:Syndecan-1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000071121:ADAMTS4 Protein