Cannabinoid WIN-55,212-2 mesylate inhibits ADAMTS-4 activity in human osteoarthritic articular chondrocytes by inhibiting expression of syndecan-1
Open accessAbstract
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.
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WIN-55,212-2 attenuates the production of the matrix-degrading enzyme disintegrin and metalloprotease with thrombospondin motifs-4 from osteoarthritis chondrocytes either unstimulated or stimulated with IL-1β.
“WIN-55,212-2 also attenuates the production of the matrix-degrading enzyme disintegrin and metalloprotease with thrombospondin motifs-4 from osteoarthritis chondrocytes either unstimulated or stimulated with IL-1β (Kong et al, 2016).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Kong et al, 2016
The attenuation of metalloprotease with thrombospondin motifs-4 production is reversed by the selective CB2 receptor antagonist JTE907, but not the selective CB1 receptor antagonist MJ15, indicating that CB2 plays a necessary role in this effect.
“The attenuation of the metalloprotease with thrombospondin motifs-4 production is reversed by the selective CB 2 receptor antagonist, JTE907, but not the selective CB 1 receptor antagonist, MJ15 indicating that CB 2 plays a necessary role in this effect.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Kong et al, 2016
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- Authors
- KONG, Y., WANG, W., ZHANG, C., WU, Y., LIU, Y., & ZHOU, X.
- Affiliations
- Central South University (CN)
- Corresponding author
- ZHOU, XIAORONG
- Venue
- Molecular Medicine Reports
- Publisher
- Spandidos Publications
- Published
- 2016-04-15
- Volume
- 13
- Issue
- 6
- Pages
- 4569-4576
- ISSN
- 1791-2997 (ISSN-L)
- 1791-3004
- PMC
- PMC4878569
- OpenAlex
- W2340401338
- Cited by
- 24
- References
- 23
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 1 · 2022: 1 · 2021: 5 · 2020: 6 · 2019: 5 · 2018: 3 · 2017: 1
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Molecular Medicine Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- ADAMTS-4, syndecan-1, osteoarthritis, articular chondrocytes, CB2 receptor, IL-1β, cartilage degeneration, metalloproteinase inhibition, mRNA stability, chondroprotection, cannabinoid receptor antagonists
- MeSH terms
- ADAMTS4 Protein, Cartilage, Articular, Cells, Cultured, Enzyme Activation, Gene Expression Regulation, Humans, Morpholines, Naphthalenes, Osteoarthritis, Signal Transduction, Chondrocytes, Receptor, Cannabinoid, CB2, Benzoxazines, Interleukin-1beta, Syndecan-1
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