Antiosteoarthritic Effect of Morroniside in Chondrocyte Inflammation and Destabilization of Medial Meniscus-Induced Mouse Model

Osteoarthritis (OA) is a common degenerative disease that results in joint inflammation as well as pain and stiffness. A previous study has reported that Cornus officinalis (CO) extract inhibits oxidant activities and oxidative stress in RAW 264.7 cells. In the present study, we isolated bioactive compound(s) by fractionating the CO extract to elucidate its antiosteoarthritic effects. A single bioactive component, morroniside, was identified as a potential candidate. The CO extract and morroniside exhibited antiosteoarthritic effects by downregulating factors associated with cartilage degradation, including cyclooxygenase-2 (Cox-2), matrix metalloproteinase 3 (Mmp-3), and matrix metalloproteinase 13 (Mmp-13), in interleukin-1 beta (IL-1β)-induced chondrocytes. Furthermore, morroniside prevented prostaglandin E2 (PGE2) and collagenase secretion in IL-1β-induced chondrocytes. In the destabilization of the medial meniscus (DMM)-induced mouse osteoarthritic model, morroniside administration attenuated cartilage destruction by decreasing expression of inflammatory mediators, such as Cox-2, Mmp3, and Mmp13, in the articular cartilage. Transverse microcomputed tomography analysis revealed that morroniside reduced DMM-induced sclerosis in the subchondral bone plate. These findings suggest that morroniside may be a potential protective bioactive compound against OA pathogenesis.

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Ameliorative Effects of Loganin on Arthritis in Chondrocytes and Destabilization of the Medial Meniscus-Induced Animal Model

Pharmaceuticals ◽

10.3390/ph14020135 ◽

2021 ◽

Vol 14 (2) ◽

pp. 135

Author(s):

Eunkuk Park ◽

Chang Gun Lee ◽

Seung Hee Yun ◽

Seokjin Hwang ◽

Hyoju Jeon ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Medial Meniscus ◽

Bioactive Compound ◽

Cartilage Degeneration ◽

Cartilage Degradation ◽

Protective Effects ◽

Matrix Metalloproteinase 3 ◽

Cox 2

Arthritis is a common inflammatory disease that causes pain, stiffness, and joint swelling. Here, we investigated the ameliorative effects of loganin on arthritis in vitro and in vivo. A single bioactive compound was fractionated and isolated from Cornus officinalis (CO) extract to screen for anti-arthritic effects. A single component, loganin, was identified as a candidate. The CO extract and loganin inhibited the expression of factors associated with cartilage degradation, such as cyclooxygenase-2 (COX-2), matrix metalloproteinase 3 (MMP-3), and matrix metalloproteinase 13 (MMP-13), in interukin-1 beta (IL-1β)-induced chondrocyte inflammation. In addition, prostaglandin and collagenase levels were reduced following treatment of IL-1β-induced chondrocytes with loganin. In the destabilization of the medial meniscus (DMM)-induced mouse model, loganin administration attenuated cartilage degeneration by inhibiting COX-2, MMP-3, and MMP-13. Transverse micro-CT images revealed that loganin reduced DMM-induced osteophyte formation. These results indicate that loganin has protective effects in DMM-induced mice.

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A matrix metalloproteinase-generated neoepitope of CRP can identify knee and multi-joint inflammation in osteoarthritis

Arthritis Research & Therapy ◽

10.1186/s13075-021-02610-y ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Louie C. Alexander ◽

Grant McHorse ◽

Janet L. Huebner ◽

Anne-Christine Bay-Jensen ◽

Morten A. Karsdal ◽

...

Keyword(s):

Synovial Fluid ◽

Matrix Metalloproteinase ◽

Type I Collagen ◽

Joint Inflammation ◽

Cartilage Degradation ◽

Womac Pain ◽

Type Iii Collagen ◽

Type I ◽

Radiographic Imaging ◽

Type Iii

Abstract Objective To compare C-reactive protein (CRP) and matrix metalloproteinase-generated neoepitope of CRP (CRPM) as biomarkers of inflammation and radiographic severity in patients with knee osteoarthritis. Methods Participants with symptomatic osteoarthritis (n=25) of at least one knee underwent knee radiographic imaging and radionuclide etarfolatide imaging to quantify inflammation of the knees and other appendicular joints. For purposes of statistical analysis, semi-quantitative etarfolatide and radiographic imaging scores were summed across the knees; etarfolatide scores were also summed across all joints to provide a multi-joint synovitis measure. Multiple inflammation and collagen-related biomarkers were measured by ELISA including CRP, CRPM, MMP-generated neoepitopes of type I collagen and type III collagen in serum (n=25), and CD163 in serum (n=25) and synovial fluid (n=18). Results BMI was associated with CRP (p=0.001), but not CRPM (p=0.753). Adjusting for BMI, CRP was associated with radiographic knee osteophyte score (p=0.002), while CRPM was associated with synovitis of the knee (p=0.017), synovitis of multiple joints (p=0.008), and macrophage marker CD163 in serum (p=0.009) and synovial fluid (p=0.03). CRP correlated with MMP-generated neoepitope of type I collagen in serum (p=0.045), and CRPM correlated with MMP-generated neoepitope of type III collagen in serum (p<0.0001). No biomarkers correlated with age, knee pain, or WOMAC pain. Conclusions To our knowledge, this is the first time that CRPM has been shown to be associated with knee and multi-joint inflammation based on objective imaging (etarfolatide) and biomarker (CD163) measures. These results demonstrate the capability of biomarker measurements to reflect complex biological processes and for neoepitope markers to more distinctly reflect acute processes than their precursor proteins. CRPM is a promising biomarker of local and systemic inflammation in knee OA that is associated with cartilage degradation and is independent of BMI. CRPM is a potential molecular biomarker alternative to etarfolatide imaging for quantitative assessment of joint inflammation.

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Inhibition of bovine nasal cartilage degradation by selective matrix metalloproteinase inhibitors

Biochemical Journal ◽

10.1042/bj3230483 ◽

1997 ◽

Vol 323 (2) ◽

pp. 483-488 ◽

Cited By ~ 35

Author(s):

Kevin M. BOTTOMLEY ◽

Neera BORKAKOTI ◽

David BRADSHAW ◽

Paul A. BROWN ◽

Michael J. BROADHURST ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Cartilage Degradation ◽

Cartilage Destruction ◽

Collagen Degradation ◽

Cartilage Explants ◽

Nasal Cartilage ◽

Sequence Production ◽

C Terminus ◽

Interleukin 1Α ◽

Minor Sequence

N-terminal analysis of aggrecan fragments lost from bovine nasal cartilage cultured in the presence of recombinant human interleukin 1α revealed a predominant ARGSVIL sequence with an additional ADLEX sequence. Production of the ARGSVIL-containing fragments has been attributed to the action of a putative proteinase, aggrecanase. The minor sequence (ADLEX) corresponds to a new reported cleavage product; comparison of this sequence with the available partial sequence of bovine aggrecan indicates that this is the product of a cleavage occurring towards the C-terminus of the protein. Matrix metalloproteinase (MMP) inhibitors inhibited aggrecan loss from bovine nasal explants incubated in the presence of recombinant human interleukin 1α. A strong correlation between inhibition of aggrecan metabolism and inhibition of stromelysin 1 (MMP 3) (r = 0.93) suggests a role for stromelysin or a stromelysin-like enzyme in cartilage aggrecan metabolism. However, the compounds were approx. 1/1000 as potent in inhibiting aggrecan loss from the cartilage explants as they were in inhibiting stromelysin. There was little or no correlation between inhibition of aggrecan metabolism and inhibition of gelatinase B (MMP 9) or inhibition of collagenase 1 (MMP 1). Studies with collagenase inhibitors with a range of potencies showed a correlation between inhibition of collagenase activity and inhibition of collagen degradation in the cartilage explant assay. This indicates that in interleukin 1α-driven bovine nasal cartilage destruction, stromelysin (or a closely related enzyme) is involved in aggrecan metabolism, whereas collagenase is principally responsible for collagen degradation.

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Interleukin-18 Promotes Joint Inflammation and Induces Interleukin-1-Driven Cartilage Destruction

American Journal Of Pathology ◽

10.1016/s0002-9440(10)63357-3 ◽

2004 ◽

Vol 165 (3) ◽

pp. 959-967 ◽

Cited By ~ 52

Author(s):

Leo A.B. Joosten ◽

Ruben L. Smeets ◽

Marije I. Koenders ◽

Liduine A.M. van den Bersselaar ◽

Monique M.A. Helsen ◽

...

Keyword(s):

Interleukin 1 ◽

Joint Inflammation ◽

Cartilage Destruction ◽

Interleukin 18

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The Protective Effect of Kirenol in Osteoarthritis: an in Vitro and in Vivo Study

10.21203/rs.3.rs-1162087/v1 ◽

2022 ◽

Author(s):

Wei Hu ◽

Chao Mao ◽

Weibin Sheng

Keyword(s):

Cartilage Degradation ◽

Cartilage Destruction ◽

In Vivo Study ◽

Griess Reaction ◽

Tnf Α ◽

Collagen Ii ◽

Cox 2 ◽

Product Compound

Abstract Background: Osteoarthritis (OA) is a chronic degenerative disease, its main characteristic involves articular cartilage destruction and inflammation response, absent of effective medical treatment. Our current research aimed to explore anti-inflammatory effect of kirenol, a diterpenoid natural product compound, in the development of OA and its potential molecular mechanism through in vitro and in vivo study.Methods: In vitro, chondrocytes were pretreated with kirenol for 2 h before IL-1β stimulation. Production of NO, PGE2, TNF-α, IL-6, aggrecan, collagen-II, MMP13and ADAMTS5 were evaluated by the Griess reaction and ELISAs. The mRNA (aggrecan and collagen-II) and protein expression (COX-2, iNOS, P65, IκB, PI3K, AKT) were measured by qRT-PCR and Western blot respectively. Immunofluorescence was used to assess the expression of collagen-II and P65. The in vivo effect of kirenol was evaluated in mice OA models induced by destabilization of the medial meniscus (DMM).Results: We found that kirenol inhibited IL-1β-induced expression of NO, PGE2, TNF-α, IL-6, COX-2, iNOS, ADAMTS-5. Besides, kirenol remarkably decreased IL-1β-induced degradation of aggrecan and collagen-II. Furthermore, kirenol significantly inhibited IL-1β-induced phosphorylation of PI3K/Akt and NF-κB signaling. In vivo, the cartilage in kirenol-treated mice exhibited less cartilage degradation and lower OARSI scores.Conclusions: Taken together, the results of this study provide potent evidence that kirenol could be utilized as a potentially therapeutic agent in prevention and treatment of OA.

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FRI0035 Joint Inflammation and Cartilage Destruction in Experimental Osteoarthritis Is Not Mediated by Interleukin-1

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-eular.3500 ◽

2016 ◽

Vol 75 (Suppl 2) ◽

pp. 438.2-438

Author(s):

S. Van Dalen ◽

A. Blom ◽

L. Joosten ◽

A. Sloetjes ◽

M. Helsen ◽

...

Keyword(s):

Interleukin 1 ◽

Joint Inflammation ◽

Cartilage Destruction ◽

Experimental Osteoarthritis ◽

And Cartilage

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Flavocoxid (Limbrel ®) manages osteoarthritis through modification of multiple inflammatory pathways: a review

Functional Foods in Health and Disease ◽

10.31989/ffhd.v2i11.74 ◽

2012 ◽

Vol 2 (11) ◽

pp. 379 ◽

Cited By ~ 2

Author(s):

Bruce P. Burnett ◽

Robert M. Levy

Keyword(s):

Side Effects ◽

Joint Inflammation ◽

International Normalized Ratio ◽

Cartilage Degradation ◽

Necrosis Factor Alpha ◽

Inflammatory Pathways ◽

Equivalent Efficacy ◽

Cox 2 ◽

Anti Inflammatory ◽

Medical Foods

Limbrel (flavocoxid) is marketed as an FDA-regulated medical food for the clinical dietary management of osteoarthritis (OA) to be used under physician supervision. Flavocoxid is composed of a >90% mixture of baicalin and catechin and represents a non-targeted anti-inflammatory which works differently than non-steroidal anti-inflammatory drugs (NSAIDs) that bind to and only inhibit the cyclooxygenase moieties of COX-1 and COX-2. Flavocoxid binds to and weakly modulates the peroxidase activity of the COX enzymes permitting low level expression of prostaglandins (PGs), prostacyclin (PGI2) and thromboxane (TxA2). In addition, flavocoxid weakly inhibits phospholipase A2 (PLA2) and 5-lipoxygenase (5-LOX) as well as increases IϰBα and prevents nuclear factor kappa B (NFϰB) activation/induction of inflammatory genes such as tumor necrosis factor-alpha (TNFα), interleukin-1β (IL-1 β), IL-6, COX-2, inducible nitric oxide synthase (iNOS) and 5-LOX. In clinical studies, flavocoxid shows equivalent efficacy to naproxen with statistically fewer renal (edema) and upper gastrointestinal (GI) side effects, does not affect platelet function and bleeding times, does not change international normalized ratio (INR) in warfarinized patients, is well-tolerated in patients with previous NSAID-induced GI side effects, and decreases or eliminates the use of gastroprotective medications in patients who previously required them to tolerate NSAIDs. With its broad, non-targeted and multiple weak activities which result in fewer side effects compared to NSAIDs, flavocoxid represents a different way managing OA by working on the underlying and multiple causes of cartilage degradation as well as joint inflammation. Keywords: Flavocoxid, Limbrel, osteoarthritis, inflammatory pathways, and medical foods

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Interleukin-1 does not aggravate joint inflammation and cartilage destruction in experimental osteoarthritis

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2016.01.582 ◽

2016 ◽

Vol 24 ◽

pp. S326 ◽

Cited By ~ 1

Author(s):

S. van Dalen ◽

A. Blom ◽

L. Joosten ◽

A. Sloetjes ◽

M. Helsen ◽

...

Keyword(s):

Interleukin 1 ◽

Joint Inflammation ◽

Cartilage Destruction ◽

Experimental Osteoarthritis ◽

And Cartilage

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Chondroprotective Effect of Cynaroside in IL-1β-Induced Primary Rat Chondrocytes and Organ Explants via NF-κB and MAPK Signaling Inhibition

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/9358080 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Seul Ah. Lee ◽

Bo-Ram Park ◽

Sung-Min Moon ◽

Joon Ho Hong ◽

Do Kyung Kim ◽

...

Keyword(s):

Collagen Type ◽

Cartilage Degradation ◽

Mapk Signaling ◽

Joint Disease ◽

Blue Staining ◽

Alcian Blue Staining ◽

Potential Candidate ◽

Type Ii ◽

Collagen Type Ii ◽

Cox 2

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. Interleukin-1β is the key player in the pathogenesis of OA, which induces the expression of various catabolic factors that contribute to cartilage degradation. Cynaroside (luteolin-7-O-glucoside or luteoloside) is a flavonoid that has various pharmacological properties, such as antitumor, anti-inflammatory, and antioxidant activities. In this study, we investigated the chondroprotective effects of cynaroside on IL-1β-stimulated chondrocytes and organ explants. The production of nitrite, PGE2, collagen type II, and aggrecan was measured by a Griess reagent and ELISAs, and the production of ROS was measured by H2DCF-DA fluorescence. The protein levels of iNOS, Cox-2, MMP-1, MMP-3, MMP-13, ADAMTS-4, MAPKs, and the NF-κB p65 subunit were measured by western blot. Proteoglycan analysis was performed by Alcian Blue staining (in vitro) and Safranin O staining (ex vivo). Cynaroside inhibited IL-1β-induced expression of catabolic factors (nitrite, iNOS, ROS, PGE2, Cox-2, MMP-1, MMP-3, MMP-13, and ADAMTS-4) and degradation of anabolic factors (collagen type II and aggrecan). Furthermore, cynaroside suppressed IL-1β-induced phosphorylation of MAPKs and translocation of the NF-κB p65 subunit into the nucleus. Collectively, these results suggest that cynaroside may be a potential candidate for the development of new therapeutic drugs for the alleviation of OA progression.

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