Morin is a flavonoid isolated from members of the Moraceae family. Morin has been reported to possess antioxidative and anticarcinogenic activities. However, the antiosteoarthritic properties of morin have not been investigated. In this study, we evaluate the antiarthritic properties of morin through in vitro and in vivo studies. We examined the effects of morin on the expression levels of matrix metalloproteinase (MMP)-3, MMP-13 and tissue inhibitors of metalloproteinase (TIMP)-1 in interleukin-1β (IL-1β)-induced rat chondrocytes by realtime polymerase chain reaction and Western blotting. The effects of morin on the phosphorylation of mitogen-activated protein kinases were also investigated. The in vivo antiosteoarthritic effects of morin were evaluated in the rat model of anterior cruciate ligament transection (ACLT)-induced osteoarthritis (OA). We found that morin inhibited the expression of MMP-3 and MMP-13 and increased the expression of TIMP-1 in IL-1β-induced rat chondrocytes. In addition, morin inhibited IL-1β-induced phosphorylation of extracellular signal-regulated kinase and p38. For the in vivo study in a rat model of OA induced by ACLT, in which morin was orally administered to rat, the results show that morin suppressed cartilage degradation. Our results suggest that morin may be considered as a possible therapeutic agent for the treatment of OA.
MitchellPG, MagnaHA, ReevesLM, Lopresti-MorrowLL, YocumSA, RosnerPJ, GeogheganKF, HamborJE. Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J Clin Invest1996;97:761–8
3.
BurragePS, MixKS, BrinckerhoffCE. Matrix metalloproteinases: role in arthritis. Front Biosci2006;11:529–43
LazzaroniM, Bianchi PorroG. Gastrointestinal side-effects of traditional non-steroidal anti-inflammatory drugs and new formulations. Aliment Pharmacol Ther2004;20(Suppl. 2):48–58
6.
Varas-LorenzoC, CastellsagueJ, StangMR, Perez-GutthannS, AguadoJ, RodriguezLA. The use of selective cyclooxygenase-2 inhibitors and the risk of acute myocardial infarction in Saskatchewan, Canada. Pharmacoepidemiol Drug Saf2009;18:1016–25
7.
ZhangR, KangKA, PiaoMJ, MaengYH, LeeKH, ChangWY, YouHJ, KimJS, KangSS, HyunJW. Cellular protection of morin against the oxidative stress induced by hydrogen peroxide. Chem Biol Interact2009;177:21–7
SreedharanV, VenkatachalamKK, NamasivayamN. Effect of morin on tissue lipid peroxidation and antioxidant status in 1, 2-dimethylhydrazine induced experimental colon carcinogenesis. Invest New Drugs2009;27:21–30
10.
GalvezJ, CoelhoG, CrespoME, CruzT, Rodriguez-CabezasME, ConchaA, GonzalezM, ZarzueloA. Intestinal anti-inflammatory activity of morin on chronic experimental colitis in the rat. Aliment Pharmacol Ther2001;15:2027–39
11.
KimJW, LeeJH, HwangBY, MunSH, KoNY, Kim doK, KimB, KimHS, KimYM, ChoiWS. Morin inhibits Fyn kinase in mast cells and IgE-mediated type I hypersensitivity response in vivo. Biochem Pharmacol2009;77:1506–12
12.
SivaramakrishnanV, Niranjali DevarajS. Morin regulates the expression of NF-kappaB-p65, COX-2 and matrix metalloproteinases in diethylnitrosamine induced rat hepatocellular carcinoma. Chem Biol Interact2009;180:353–9
13.
LeeSW, SongYS, ShinSH, KimKT, ParkYC, ParkBS, YunI, KimK, LeeSY, ChungWT, LeeHJ, YooYH. Cilostazol protects rat chondrocytes against nitric oxide-induced apoptosis in vitro and prevents cartilage destruction in a rat model of osteoarthritis. Arthritis Rheum2008;58:790–800
14.
LiangCZ, ZhangJK, ShiZ, LiuB, ShenCQ, TaoHM. Matrine induces caspase-dependent apoptosis in human osteosarcoma cells in vitro and in vivo through the upregulation of Bax and Fas/FasL and downregulation of Bcl-2. Cancer Chemother Pharmacol2012;69:317–31
15.
HayamiT, PickarskiM, ZhuoY, WesolowskiGA, RodanGA, Duong leT. Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. Bone2006;38:234–43
16.
ShikhmanAR, AmielD, D'LimaD, HwangSB, HuC, XuA, HashimotoS, KobayashiK, SashoT, LotzMK. Chondroprotective activity of N-acetylglucosamine in rabbits with experimental osteoarthritis. Ann Rheum Dis2005;64:89–94
17.
OegemaTRJr, DeloriaLB, SandyJD, HartDA. Effect of oral glucosamine on cartilage and meniscus in normal and chymopapain-injected knees of young rabbits. Arthritis Rheum2002;46:2495–503
18.
TangT, MunetaT, JuYJ, NimuraA, MiyazakiK, MasudaH, MochizukiT, SekiyaI. Serum keratan sulfate transiently increases in the early stage of osteoarthritis during strenuous running of rats: protective effect of intraarticular hyaluronan injection. Arthritis Res Ther2008;10:R13
19.
NaitoK, WatariT, FuruhataA, YomogidaS, SakamotoK, KurosawaH, KanekoK, NagaokaI. Evaluation of the effect of glucosamine on an experimental rat osteoarthritis model. Life Sci2010;86:538–43
20.
BauB, GebhardPM, HaagJ, KnorrT, BartnikE, AignerT. Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro. Arthritis Rheum2002;46:2648–57
21.
NaitoK, TakahashiM, KushidaK, SuzukiM, OhishiT, MiuraM, InoueT, NaganoA. Measurement of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in patients with knee osteoarthritis: comparison with generalized osteoarthritis. Rheumatology (Oxford)1999;38:510–5
22.
ClutterbuckAL, MobasheriA, ShakibaeiM, AllawayD, HarrisP. Interleukin-1beta-induced extracellular matrix degradation and glycosaminoglycan release is inhibited by curcumin in an explant model of cartilage inflammation. Ann N Y Acad Sci2009;1171:428–35
23.
ZayedN, AfifH, ChabaneN, Mfuna-EndamL, BenderdourM, Martel-PelletierJ, PelletierJP, MotianiRK, TrebakM, DuvalN, FahmiH. Inhibition of interleukin-1beta-induced matrix metalloproteinases 1 and 13 production in human osteoarthritic chondrocytes by prostaglandin D2. Arthritis Rheum2008;58:3530–40
24.
LiaciniA, SylvesterJ, LiWQ, ZafarullahM. Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix Biol2002;21:251–62
25.
FanZ, YangH, BauB, SoderS, AignerT. Role of mitogen-activated protein kinases and NFkappaB on IL-1beta-induced effects on collagen type II, MMP-1 and 13 mRNA expression in normal articular human chondrocytes. Rheumatol Int2006;26:900–3
26.
AhmedS, WangN, HafeezBB, CheruvuVK, HaqqiTM. Punica granatum L. Extract inhibits IL-1beta-induced expression of matrix metalloproteinases by inhibiting the activation of MAP kinases and NF-kappaB in human chondrocytes in vitro. J Nutr2005;135:2096–102
27.
KimuraH, YukitakeH, SuzukiH, TajimaY, GomaibashiK, MorimotoS, FunabashiY, YamadaK, TakizawaM. The chondroprotective agent ITZ-1 inhibits interleukin-1beta-induced matrix metalloproteinase-13 production and suppresses nitric oxide-induced chondrocyte death. J Pharmacol Sci2009;110:201–11
28.
HsiangCY, WuSL, HoTY. Morin inhibits 12-O-tetradecanoylphorbol-13-acetate-induced hepatocellular transformation via activator protein 1 signaling pathway and cell cycle progression. Biochem Pharmacol2005;69:1603–11
29.
NakagawaS, AraiY, MazdaO, KishidaT, TakahashiKA, SakaoK, SaitoM, HonjoK, ImanishiJ, KuboT. N-acetylcysteine prevents nitric oxide-induced chondrocyte apoptosis and cartilage degeneration in an experimental model of osteoarthritis. J Orthop Res2010;28:156–63
