scholarly journals Discovery and Characterization of a Novel Inhibitor of Matrix Metalloprotease-13 That Reduces Cartilage Damage in Vivo without Joint Fibroplasia Side Effects

2007 ◽  
Vol 282 (38) ◽  
pp. 27781-27791 ◽  
Author(s):  
Adam R. Johnson ◽  
Alexander G. Pavlovsky ◽  
Daniel F. Ortwine ◽  
Faith Prior ◽  
Chiu-Fai Man ◽  
...  
Keyword(s):  
Side Effects ◽  
Cartilage Damage ◽  
Type Ii Collagen ◽  
Selective Inhibition ◽  
Cartilage Degradation ◽  
Zinc Ion ◽  
Structural Protein ◽  
Structure Based Drug Design ◽  
Mmp Inhibitors

Matrix metalloproteinase-13 (MMP13) is a Zn2+-dependent protease that catalyzes the cleavage of type II collagen, the main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation in osteoarthritis, making this protease an attractive therapeutic target. However, clinically tested MMP inhibitors have been associated with a painful, joint-stiffening musculoskeletal side effect that may be due to their lack of selectivity. In our efforts to develop a disease-modifying osteoarthritis drug, we have discovered MMP13 inhibitors that differ greatly from previous MMP inhibitors; they do not bind to the catalytic zinc ion, they are noncompetitive with respect to substrate binding, and they show extreme selectivity for inhibiting MMP13. By structure-based drug design, we generated an orally active MMP13 inhibitor that effectively reduces cartilage damage in vivo and does not induce joint fibroplasias in a rat model of musculoskeletal syndrome side effects. Thus, highly selective inhibition of MMP13 in patients may overcome the major safety and efficacy challenges that have limited previously tested non-selective MMP inhibitors. MMP13 inhibitors such as the ones described here will help further define the role of this protease in arthritis and other diseases and may soon lead to drugs that safely halt cartilage damage in patients.

scholarly journals Selonsertib Alleviates the Progression of Rat Osteoarthritis: An in vitro and in vivo Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiyuan Yan ◽  
Yingchi Zhang ◽  
Gaohong Sheng ◽  
Bowei Ni ◽  
Yifan Xiao ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Cartilage Damage ◽  
Cartilage Degradation ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Therapeutic Effects ◽  
Exact Role

Osteoarthritis (OA) is a prevalent degenerative joint disease. Its development is highly associated with inflammatory response and apoptosis in chondrocytes. Selonsertib (Ser), the inhibitor of Apoptosis Signal-regulated kinase-1 (ASK1), has exhibited multiple therapeutic effects in several diseases. However, the exact role of Ser in OA remains unclear. Herein, we investigated the anti-arthritic effects as well as the potential mechanism of Ser on rat OA. Our results showed that Ser could markedly prevent the IL-1β-induced inflammatory reaction, cartilage degradation and cell apoptosis in rat chondrocytes. Meanwhile, the ASK1/P38/JNK and NFκB pathways were involved in the protective roles of Ser. Furthermore, intra-articular injection of Ser could significantly alleviate the surgery induced cartilage damage in rat OA model. In conclusion, our work provided insights into the therapeutic potential of Ser in OA, indicating that Ser might serve as a new avenue in OA treatment.

scholarly journals The Effects of Morus alba and Acacia catechu on Quality of Life and Overall Function in Adults with Osteoarthritis of the Knee

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Douglas S. Kalman ◽  
Susan J. Hewlings
Keyword(s):  
Cartilage Damage ◽  
Type Ii Collagen ◽  
Cartilage Degradation ◽  
Morus Alba ◽  
Osteoarthritis Of The Knee ◽  
Significant Difference ◽  
Womac Questionnaire ◽  
Acacia Catechu ◽  
Double Blinded ◽  
And Function

The purpose of this study was to determine the effects of UP1306 on discomfort and function in adults with osteoarthritis of the knee. In a randomized, double-blinded, placebo-controlled, parallel design, 135 subjects received UP1306, a standardized, proprietary extract of Morus alba and Acacia catechu, glucosamine chondroitin, or placebo for 12 weeks. Discomfort, stiffness, and activities of daily living measured by the WOMAC questionnaire and VAS (pain/discomfort) were improved within all groups. Range of motion and distance walked were improved. There were no changes in TNFα levels for any of the products. There was a significant difference in urinary C-telopeptides of type II collagen (CTX-II), a marker of cartilage degradation between UP1306, and placebo after 12 weeks (p=0.029). All efficacy measurements were improved from baseline to most time-points for UP1306, the comparator, and placebo without a significant association between the products. There was a significant difference between the changes of uCTX-II for UP1306 and placebo after 12 weeks. Early intervention with UP1306 aimed at reducing bone and cartilage degradation through reported inhibition of catabolic proinflammatory pathways may help to prevent joint cartilage damage. This study is registered with Clinical Trial ID ISRCTN15418623.

scholarly journals Anti-Osteoarthritic Effects of Terminalia Chebula Fruit Extract (AyuFlex®) in Interleukin-1β-Induced Human Chondrocytes and in Rat Models of Monosodium Iodoacetate (MIA)-Induced Osteoarthritis

2020 ◽  
Vol 10 (23) ◽  
pp. 8698
Author(s):  
Hae Lim Kim ◽  
Hae Jin Lee ◽  
Dong-Ryung Lee ◽  
Bong-Keun Choi ◽  
Seung Hwan Yang
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Cartilage Damage ◽  
Cartilage Degradation ◽  
Mitogen Activated Protein Kinase ◽  
Terminalia Chebula ◽  
Inflammatory Reactions ◽  
Erk Phosphorylation

Osteoarthritis (OA) is a general joint illness caused by the destruction of joint cartilage, and is common in the population of old people. Its occurrence is related to inflammatory reactions and cartilage degradation. AyuFlex® is an aqueous extract of Terminalia chebula fruit, and T. chebula has been utilized extensively in several traditional oriental medications for the management of diverse diseases. Pre-clinical and clinical research has shown its antioxidant and anti-inflammatory effectiveness. Nevertheless, the mechanism underlying the anti-arthritic effects of AyuFlex® remains unclear. In the current research, we proposed the ameliorating effects of AyuFlex® with respect to the incidence of OA and described the latent signalization in interleukin (IL)-1β-treated chondrocytes and MIA-incurred OA in a rat model. In vitro, AyuFlex® decreased oxidative stress and induction of pro-inflammatory cytokines and mediators as well as matrix metalloproteinases (MMPs), while also increasing the levels of collagen synthesis-related proteins. Mechanistically, we identified that AyuFlex® disrupted nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation via the inhibition of NF-κB p65 and extracellular regulated protein kinase (ERK) phosphorylation. The ameliorating effects of AyuFlex® were also observed in vivo. AyuFlex® significantly inhibited the MIA-incurred increase in OA symptoms such as oxidative stress, cartilage damage, and changes in cytokines and MMPs revelation in arthrodial cartilage. Therefore, our results suggest that AyuFlex® attenuates OA progression in vivo, indicating that AyuFlex® can be suggested as an excellent therapeutic remedy for the care of OA.

scholarly journals Chondroprotective Actions of Selective COX-2 Inhibitors In Vivo: A Systematic Review

2020 ◽  
Vol 21 (18) ◽  
pp. 6962 ◽  
Author(s):  
Ufuk Tan Timur ◽  
Marjolein M. J. Caron ◽  
Ralph M. Jeuken ◽  
Yvonne M. Bastiaansen-Jenniskens ◽  
Tim J. M. Welting ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Studies ◽  
Slow Release ◽  
Cartilage Damage ◽  
Cartilage Degradation ◽  
Preclinical Studies ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Slow Release System

Knee osteoarthritis (OA) is a condition mainly characterized by cartilage degradation. Currently, no effective treatment exists to slow down the progression of OA-related cartilage damage. Selective COX-2 inhibitors may, next to their pain killing properties, act chondroprotective in vivo. To determine whether the route of administration is important for the efficacy of the chondroprotective properties of selective COX-2 inhibitors, a systematic review was performed according to the PRISMA guidelines. Studies investigating OA-related cartilage damage of selective COX-2 inhibitors in vivo were included. Nine of the fourteen preclinical studies demonstrated chondroprotective effects of selective COX-2 inhibitors using systemic administration. Five clinical studies were included and, although in general non-randomized, failed to demonstrate chondroprotective actions of oral selective COX-2 inhibitors. All of the four preclinical studies using bolus intra-articular injections demonstrated chondroprotective actions, while one of the three preclinical studies using a slow release system demonstrated chondroprotective actions. Despite the limited evidence in clinical studies that have used the oral administration route, there seems to be a preclinical basis for considering selective COX-2 inhibitors as disease modifying osteoarthritis drugs when used intra-articularly. Intra-articularly injected selective COX-2 inhibitors may hold the potential to provide chondroprotective effects in vivo in clinical studies.

scholarly journals Study of Osteoarthritis Treatment with Anti-Inflammatory Drugs: Cyclooxygenase-2 Inhibitor and Steroids

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Hongsik Cho ◽  
Andrew Walker ◽  
Jeb Williams ◽  
Karen A. Hasty
Keyword(s):  
Gene Expression ◽  
Type Ii Collagen ◽  
Cartilage Degradation ◽  
Cyclooxygenase 2 ◽  
Cox Inhibitor ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Anti Inflammatory

Patients with osteoarthritis (OA), a condition characterized by cartilage degradation, are often treated with steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) selective NSAIDs. Due to their inhibition of the inflammatory cascade, the drugs affect the balance of matrix metalloproteinases (MMPs) and inflammatory cytokines, resulting in preservation of extracellular matrix (ECM). To compare the effects of these treatments on chondrocyte metabolism, TNF-αwas incubated with cultured chondrocytes to mimic a proinflammatory environment with increasing production of MMP-1 and prostaglandin E2 (PGE2). The chondrocytes were then treated with either a steroid (prednisone), a nonspecific COX inhibitor NSAID (piroxicam), or a COX-2 selective NSAID (celecoxib). Both prednisone and celecoxib decreased MMP-1 and PGE-2 production while the nonspecific piroxicam decreased only the latter. Both prednisone and celecoxib decreased gene expression of MMP-1 and increased expression of aggrecan. Increased gene expression of type II collagen was also noted with celecoxib. The nonspecific piroxicam did not show these effects. The efficacy of celecoxibin vivowas investigated using a posttraumatic OA (PTOA) mouse model.In vivo, celecoxib increases aggrecan synthesis and suppresses MMP-1. In conclusion, this study demonstrates that celecoxib and steroids exert similar effects on MMP-1 and PGE2 productionin vitroand that celecoxib may demonstrate beneficial effects on anabolic metabolismin vivo.

scholarly journals Melatonin Prevents Osteoarthritis-Induced Cartilage Degradation via Targeting MicroRNA-140

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Yijian Zhang ◽  
Jun Lin ◽  
Xinfeng Zhou ◽  
Xi Chen ◽  
Angela Carley Chen ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Interleukin 1 ◽  
Type Ii Collagen ◽  
Cartilage Degradation ◽  
A Disintegrin And Metalloproteinase ◽  
Surgically Induced ◽  
Metalloproteinase 9 ◽  
Synthesis And Degradation

Osteoarthritis (OA) is characterized by the progressive destruction of articular cartilage, which is involved in the imbalance between extracellular matrix (ECM) synthesis and degradation. MicroRNA-140-5p (miR-140) is specifically expressed in cartilage and plays an important role in OA-induced matrix degradation. The aim of this study was to investigate (1) whether intra-articular injection of melatonin could ameliorate surgically induced OA in mice and (2) whether melatonin could regulate matrix-degrading enzymes at the posttranscriptional level by targeting miR-140. In an in vitro OA environment induced by interleukin-1 beta (IL-1β), melatonin treatment improved cell proliferation of human chondrocytes, promoted the expression of cartilage ECM proteins (e.g., type II collagen and aggrecan), and inhibited the levels of IL-1β-induced proteinases, such as matrix metalloproteinase 9 (MMP9), MMP13, ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4), and ADAMTS5. Both the microarray and polymerase chain reaction (PCR) experiments revealed that miR-140 was a melatonin-responsive microRNA and melatonin upregulated miR-140 expression, which was suppressed by IL-1β stimulation. In vivo experiments demonstrated that intra-articular injection of melatonin prevented disruptions of cartilage matrix homeostasis and successfully alleviated the progression of surgery-induced OA in mice. Transfection of miR-140 antagomir completely counteracted the antiarthritic effects of melatonin by promoting matrix destruction. Our findings demonstrate that melatonin protects the articular cartilage from OA-induced degradation by targeting miR-140, and intra-articular administration of melatonin may benefit patients suffering from OA.

scholarly journals Method for in vitro production of cartilage microtissues from scaffold-free spheroids composed of human adipose-derived stem cells

2020 ◽  
Vol 7 (4) ◽  
pp. 3697-3708
Author(s):  
Vy Thi-Kieu Tu ◽  
Ha Thi-Ngan Le ◽  
Xuan Hoang-Viet To ◽  
Phuc Dang-Ngoc Nguyen ◽  
Phat Duc Huynh ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cartilage Damage ◽  
Cartilage Regeneration ◽  
Type Ii Collagen ◽  
Adipose Derived Stem Cells ◽  
Type Ii ◽  
In Vitro Production ◽  
Engineered Cartilage

Introduction: Cartilage damage is one of the injuries that is difficult for the human body to self-repair due to the avascular and completely mature tissue with only few stem or progenitor cells present. Recently, some studies showed that engineered cartilage tissues could be used to treat or improve this injury. This study aimed to produce the cartilage microtissues from the differentiation of scaffold-free spheroids composed of human adipose-derived stem cells. Methods: Human adipose-derived stem cells (ADSCs) were isolated and expanded following the previously published study. They were then cultured in the non-adherent condition to produce spheroids. The spheroids of the ADSCs were collected and induced into cartilage microtissues in the inducible medium for 21 days. The cartilage microtissue was characterized by some cartilage phenotype markers, including the accumulation of extracellular matrix proteins (aggrecan, glycosaminoglycan, and type II collagen), and the expression of certain genes specific to chondrocytes (Sox9, Col2, Col1, and Acan). Results: The results showed that the expression of chondrocyte-specific genes gradually increased during the 21 days of culture for differentiation. On day 21, the microtissues expressed aggrecan, glycosaminoglycan, and type II collagen proteins. Conclusion: This study demonstrated that cartilage microtissues could easily be produced from scaffold-free spheroids from ADSCs. Thus, cartilage microtissues can be produced in this manner for in vivo transplantation to promote cartilage regeneration, or to produce cartilage tissues for in vitro studies.  

scholarly journals Inhibition of nuclear receptor RORα attenuates cartilage damage in osteoarthritis by modulating IL-6/STAT3 pathway

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Tongzhou Liang ◽  
Taiqiu Chen ◽  
Jincheng Qiu ◽  
Wenjie Gao ◽  
Xianjian Qiu ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Retinoic Acid Receptor ◽  
Cartilage Damage ◽  
Type Ii Collagen ◽  
Cartilage Destruction ◽  
Orphan Receptor ◽  
Expression Level ◽  
Stat3 Pathway ◽  
Pathologic Features

AbstractOsteoarthritis (OA) is characterized by cartilage destruction, chronic inflammation, and local pain. Evidence showed that retinoic acid receptor-related orphan receptor-α (RORα) is crucial in cartilage development and OA pathogenesis. Here, we investigated the role and molecular mechanism of RORα, an important member of the nuclear receptor family, in regulating the development of OA pathologic features. Investigation into clinical cartilage specimens showed that RORα expression level is positively correlated with the severity of OA and cartilage damage. In an in vivo OA model induced by anterior crucial ligament transaction, intra-articular injection of si-Rora adenovirus reversed the cartilage damage. The expression of cartilage matrix components type II collagen and aggrecan were elevated upon RORα blockade. RNA-seq data suggested that the IL-6/STAT3 pathway is significantly downregulated, manifesting the reduced expression level of both IL-6 and phosphorylated STAT3. RORα exerted its effect on IL-6/STAT3 signaling in two different ways, including interaction with STAT3 and IL-6 promoter. Taken together, our findings indicated the pivotal role of the RORα/IL-6/STAT3 axis in OA progression and confirmed that RORα blockade improved the matrix catabolism in OA chondrocytes. These results may provide a potential treatment target in OA therapy.

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