INTRODUCTION:

The term “Osteoarthritis” originates from Greek words Osteon" which implies the bone,"Arthon" stands for joint and “itis" indicates inflammation. This is the most common form of arthritis that effects older peoples and is considered as degenerative arthritis. It is the type of arthritis which causes disability among the old peoples. Osteoarthritis (OA) is the most common chronic irreversible disorder that effects joints.¹ Obesity, aging, trauma, genetic predisposition plays an important role in the development of OA. In accordance with latest medical knowledge, immune system plays an important role in the pathogenesis and progression of OA. During the advancement of OA, various pro-inflammatory and anti-inflammatory cytokines are expressed which having important role in the pathogenesis of OA.²

Around 9.6 percent of men and 18 percent of women, aged >60, are affected by OA. Compared to male of the same age category, postmenopausal women are more susceptible to OA.

There are numerus pharmacological approaches are available which are mainly symptomatic. Analgesics like paracetamol is widely used as a first line analgesic whereas nonsteroidal anti-inflammatory drugs like selective COX-2 inhibitors are also having importance in the treatment of OA.³ These drugs are considered as rapidly acting drug of OA and are approved by rheumatology societies. However, long term use of these drugs leads to serious cardiovascular complications like stroke and myocardial infarction. Therefore, these drugs should be avoided in the patient of OA along with cardiovascular complications. NSAIDS also responsible for formation of peptic ulcer. Due to inhibition of prostaglandin biosynthesis, NSAIDS also responsible for renal impairment. Therefore, anti-osteoarthritic drugs with better safety profile, symptom modifying effects and positive effects on cartilage are required.

Glucosamine, diacerein (DCN) and chondroitin considered as symptomatic slow acting drugs for OA (SYSADOAs) and are used in the treatment of non-acute OA. According to European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), same efficacy observed in case of DCN and non-steroidal anti-inflammatory drugs (NSAISD) after 1 month of drug therapy and DCN shows superior efficacy than that of paracetamol. DCN was recommended by ESCEO in the patients of osteoarthritis (OA) to whom paracetamol or other NSAIDS cannot be administered due to possible adverse drug reactions. On the basis of these evidence, ESCEO concluded that positive benefit-risk balance can be seen in case of DCN in knee and hip OA. Several studies have been performed on DCN since 1982 to determine its effectiveness in OA, and DCN has been marketed worldwide since 1984, except in the USA.⁴ In the year 2003, European League Against Rheumatism (EULAR) recommended DCN in its guidelines as it has been noted that DCN showed more effectivity in reducing the symptoms and structural changes of OA compared to placebo and NSAIDS.⁵ In the year 2015, a research was conducted in OA models in albino rat in which DCN showed maximum efficacy in comparison to diclofenac sodium.⁶

DCN is an anthraquinone class of slow acting drug and shows pro-anabolic, anticatabolic and anti-inflammatory effects on synovial membrane and cartilage of osteoarthritis patients. Apart from its effect in OA, DCN shows anti-inflammatory effect in the patients of post myocardial infarction therefore it improves left ventricular remodeling and cardiac functions.⁷ This cardioprotective action of DCN makes it one of the suitable drugs in the patient of OA along with cardiovascular complications where NSAIDs and selective COX-II inhibitors are contraindicated. DCN don’t have any effect on prostaglandin biosynthesis as it lacks of cyclooxygenase inhibitory effect.⁷ Therefore, it can be easily administered to the patients whose renal function is totally prostaglandin dependent.

Though DCN shows a lower onset of action compared to paracetamol, within the first month of treatment, both of these drugs show nearly identical efficacy. According to osteoarthritis research society international (OARSI), DCN having greater efficacy than paracetamol in reducing pain in OA and having significant similarities in efficacy compared to NSAIDS.⁸ The response of DCN attends gradually within 4-6 weeks because of its slow activity, but its symptomatic effect persists for 4-8 months after withdrawal.⁹ Apart from the effect in OA, DCN also useful in psoriasis, periodontitis, epidermolysis bullosa.

Role of Il-1β in the Pathogenesis of Osteoarthritis:

OA is the most common chronic condition affecting the joints and is currently recognized as potentially irreversible disease. One of the main factors in the pathogenesis of OA is the involvement of immune system. The immune cell secreted cytokines are the key players of inflammatory disorders like OA.¹⁰ A review of the ever-growing number of studies focuses on the specific role of cytokine network in OA pathogenesis. The synthesis and function of different cytokine vary depending on the length and severity of the disease. The group of various proinflammatory cytokines like IL-1β, IL-6, IL-15, IL-17, IL-18 and TNF-α having important role in the pathogenesis of OA. These cytokines involved in stimulation of various catabolic process which ultimately responsible for articular cartilage destruction. These cytokines trigger various intracellular cell signalling pathways which results in formation of other proinflammatory cytokines, enzymes.¹¹ In the pathogenesis of OA, multiple members of IL-1 superfamily are involved among which IL-1α, IL-1β, IL-18, IL-33, IL-36 (α, β, γ) are proinflammatory cytokines involved in various inflammatory reactions whereas IL-1 receptor antagonist (IL-1Ra), IL-36 receptor antagonist (IL-36Ra), IL-37, IL-38 shows anti-inflammatory effects.¹² IL-1β is one of the dominant proinflammatory cytokine that plays a crucial role in the early stages of OA.¹³ It stimulates the inflammatory reactions in OA directly as well as in collaboration with other proinflammatory cytokines. Apart from the activated macrophages, activated chondrocytes, mononuclear cells and synoviocytes also releases IL-1β.¹⁴ Cartilage and subchondral bone of OA patient also express increased level of IL-1β.¹⁵ Initially, IL-1β is produced as precursor protein known as pro-IL-1β consisting of 269 amino acids. Caspase 1 (IL-1 β converting enzyme or ICE) causes proteolysis of pro-IL-1β to produce active IL-1β with 153 amino acid sequence that is released into extracellular space.¹⁶ Expression of interleukin-1 receptor 1 (IL-1R1) in chondrocytes is increased in OA patients that serves as a target of IL-1β. Chondrocytes in cartilage that’s are located in close proximity to macroscopic OA shows overexpression of IL-1R1 compared to chondrocytes of normal cartilage of the same joints. Thus, overexpression of IL-1R1 in chondrocytes of OA cartilage makes these cells highly sensitive to IL-1 β which ultimately responsible for alteration of gene expression in chondrocytes. Exposure of human chondrocyte to IL-1 β leads to modification in the expression of 79 genes including overexpression of IL-1 β gene. Binding of IL-1β to IL-1R1 receptor results in additional IL-1R3 chain recruitment. It is having intracellular portion Toll-IL-1R which forms complex by further recruiting the adapter protein known as MyD88. This entire complex binds to enzymatic domain of IRAK (IL-1 receptor associated kinase) which leads to activation of TRAF6, that causes further binding of TAB1, TAK1 & TAB2. TAK1 causes phosphorylation of IκB kinase complex which leads to the activation of transcription factor NF-_ΚB. It also activates p38MAPK and c-Jun N-terminal kinase (JNK). Activation of Transcriptional factor activation causes increased expression of numerous genes encoding for adhesion molecules, chemokines, cytokines, enzymes, & various inflammatory mediators. IL-1β shows deleterious effects in OA both by its capacity to increase catabolic effect and decrease anabolic effect of cartilage.¹⁷ It increases the expression of various proteolytic enzymes like A Disintegrin-like and Metalloproteinases with Thrombospondin Motifs (ADAMTS) and matrix metalloproteinases (MMPs) that responsible for cartilage destruction in OA.¹⁷ IL-1β treatment increases the expression of MMP-1, MMP-3 and MMP-13 in normal chondrocytes and OA chondrocytes.¹⁸ Incubation of human chondrocercoma cell lines and primary chondrocytes with 10ng/ml recombinant IL-1β showed increased expression of MMP-1 and MMP-13.¹⁹ MMP-1 is also referred as interstitial collagenase and responsible for degradation of type I, type II & type III collagen.²⁰ However, MMP-1 shows most destructive activity against type III collagen. The MMP-1 expression level is 10 times greater than the MMP-13. MMP-3 is also referred as stromyelin-1 & are normally absent in the joint tissues. MMP-3 levels increased in the joint tissue during osteoarthritis & RA which results in degradation of collagen type II, IV, III, IX and X, laminin, elastin etc.²¹ MMP-3 also acts as a transcription factor and upregulate the expression of other MMPs. Apart from these effects, MMP-3 also activates proMMP-1 which ultimately responsible for increased MMP-1 formation.²² MMP-13 mainly expressed by articular chondrocytes and responsible for degradation of type II collagen and shows five to ten times more destructive effects to type II collagen than MMP-1.²³ MMP-13 also destroys other matrix components like proteoglycan, osteonectin, perlecan, type IV and type IX collagen. ADAMTS also denoted as agrecanases, responsible for breakdown of aggrecans. IL-1β increases the expression of ADAMTS-4 and ADAMT-5 in normal human chondrocytes and OA chondrocyte. Apart from ADAMTS and MMP, IL-1β administration also increases the expression of cathepsin B in chondrocytes of OA patients.²⁴ Cathepsin act as an important mediator of cartilage degradation in OA.²⁵ IL-1β stimulates the production of fibroblast activation protein-α (FAPα) in chondrocytes.²⁶ It is a type II membrane localized serine proteinase enzyme that shows both exo- and endopeptidase activity and is responsible for breakdown of gelatin (denatured collagen) after initial breakdown by collagenases. IL-1β also stimulates chondrocytes to release lysosomal glycosidases that responsible for degradation of cartilage matrix.²⁷ It stimulates various inflammatory reactions in synoviocytes and chondrocytes which upon stimulation releases various proinflammatory cytokines like IL-6, IL-8, IL-10, TNF-α and IL-1β. IL-1β responsible for induction of proinflammatory mediators like chemokines, cytokines, proteolytic enzymes and angiogenic factors and cellular infiltration of T cells and macrophages in synovium of OA. MMPs induced by IL-1β responsible for cellular infiltration.²⁸ TNF-α, PGE2, IL-8, complement factors produced by chondrocytes upon stimulation of IL-1β causes cellular infiltration of T cells and macrophages, inflammation of the local area and tissue injury. Angiogenic factors like vascular endothelial growth factor (VEGF), chemokines like RANTES (Regulated upon activation, Normal T Cell Expressed and Presumably Secreted) and its receptors like CCR4 also induced by IL-1β and responsible for infiltration of inflammatory cells into the synovium. IL-1β mediated activation of macrophages causes fibroblast proliferation and leads to formation of pannus that ultimately responsible for degradation of cartilage. IL-1β also stimulates osteoclast cells that responsible for bone resorption. (Figure 1).

Apart from increased catabolic effects on cartilage, IL-1β also shows decreased anabolic effects on chondrocytes and cartilage. More than 40% downregulation of aggrecan mRNA expression seen after the treatment of human OA chondrocytes with IL-1β. Venkatesan, et al reported that IL-1β treatment causes time dependent reduction in proteoglycan (PG) synthesis and accumulation in rat femoral explants. Attur, et al revealed that significant suppression of PG synthesis in bovine and human chondrocytes occurs after administration of 5ng/ml of IL-1β.²⁹The inhibitory effect of IL-1β on PG biosynthesis is mainly due to inhibition of galactose- β1,3-glucuronosyltransferase I (GlcAT-1), the main enzyme required for the biosynthesis of core protein of PG known as glycosaminoglycan. Apart from its decreased anabolic effect on aggrecan and PG, IL-1β shows its decreased anabolic effects on collagen, the major protein of articular joints. Human chondrocyte cells treated with IL-1β results in decreased expression of type II collagen.³⁰Apoptosis of chondrocytes also stimulated by IL-1β. Human chondrocytes treated with IL-1β results in depolarization of mitochondria and overexpression of Bcl-2 family proteins. Exact mechanism of chondrocyte apoptosis is not fully understood but it is believed that nitric oxide (NO) act as important mediator of apoptosis. NO generation is unnoticeable in normal human cartilage but OA cartilage express detectable amount of NO and its expression is increased by IL-1β. TGF-β is highly essential for the growth and maintenance of cartilage structure. Lack of TGF- β may leads to OA like conditions. In chondrocytes, IL-1β upregulates the expression of inhibitory protein of transforming growth factor β (TGF- β) signaling known as SMAD7 and inhibits the synthesis of type II TGF- β receptors. Thus, IL-1β blocks the signal transduction pathway of receptor- regulated SMADs which is essential for upregulation of transcription factors of TGF-β signaling pathway. (Figure 2).

Fig1: Increased catabolic effects of IL - 1β in OA.

Fig 2: Decreased anabolic effects of IL - 1β in OA

ROLE OF DIACEREIN (DCN) IN OSTEOARTHRITIS:

DCN having onset of action within 4-6 weeks and shows effect after 4-8 weeks of discontinuation of drug therapy.³¹ It acts by inhibition of IL-1β converting enzyme (ICE) that leads to decreased biosynthesis of IL-1β.³² Inhibition of biosynthesis of IL-1β by DCN leads to improvement of all pathological responses that involved in the articular cartilage destruction in OA. As DCN blocks formation of active IL-1β, the formation of IL-1β mediated expression of various proteolytic enzymes like MMP-1, MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 also reduced which leads to decreased cartilage destruction.³³ Apart from these, DCN induced inhibition of active IL-1β biosynthesis also increases TGF- β1 and TGF- β2 expression that is highly essential for cartilage growth and maintenance of cartilage structure. DCN reduces the ratio of chondroitin-6-sulphate to chondroitin-4-sulphate because it decreases chondroitin-4-sulphate depletion. Aggrecan protective effect can be seen as it mainly consists of chondroitin sulphate and keratin sulphate. This is highly required for cartilage to counter the pressure. It also responsible for inhibition of IL-1β mediated activation of NF-_ΚB and activator protein-1 (AP-1) transcription factors that leads to inhibition of expression of proinflammatory cytokines, adhesion molecules, enzymes etc. DCN inhibits the binding of these transcription factors.³⁴ It decreases the expression of IL-1 receptors on the surface of chondrocytes and also indirectly increases the expression of IL-1 receptor antagonist. DCN also inhibits IL-1β mediated inducible nitric oxide synthase (iNOS) and NO production which leads to decreased chondrocyte apoptosis as it is believed that NO plays important role in chondrocyte apoptosis. During neurodegenerative and inflammatory disorders, palmitoylethanolamide (PEA) produced by mammalian cells that shows anti-inflammatory and analgesic properties.³⁵ PEA also downregulates degradation of mast cells and release of inflammatory mediators.³⁶PEA is metabolized to palmitic acid and ethanolamine by the enzyme N-acylethanolamine-hydrolyzing acid amidase (NAAA). DCN shows potent inhibitory effect on NAAA that leads to inhibition of inflammatory effects due to increased level of PEA. Apart from its inhibitory effect on phagocytic effect and migration on macrophages, DCN also inhibit superoxide production, phagocytic activity and chemotaxis of neutrophils. During degradation of cartilage, Plasminogen activator (PA) system is proposed to play the key role in the remodeling of extracellular matrix. This system consisting of urokinase type plasminogen activator (uPA), tissue type plasminogen activator (tPA), urokinase type plasminogen activator receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1). uPA is a serine protease enzyme having molecular weight of 55-kDa. It is released as inactive form known as pro-uPA. Binding of pro-uPA to its receptor uPAR leads to activation of pro-uPA to uPA which responsible for conversion of plasminogen to plasmin.³⁷ Increased expression of uPA can be detected in OA and rheumatoid arthritis (RA) synovial fibroblast.³⁸ DCN reduces the expression of urokinase type plasminogen activator receptor (uPAR) nearly normal level and decreases the fibrinolytic activity in synovial fluid. (Figure 3).

Figure 3: Role of diacerein in osteoarthritis

Possible Role of Diacerein (DCN) in Rheumatoid Arthritis:

Numerus literature states that IL-1β plays a crucial role in the pathogenesis of RA. It directly involved in the secretion of various proteolytic enzymes like MMP-1, MMP-3 & MMP-13 and ADAMTS which are mainly involved cartilage destruction.^39,40,41 IL-1β responsible for reactive oxygen species (ROS) which increases the production of superoxides like hydroxylated radicals and peroxides by neutrophils that plays an important role in cartilage destruction. It also responsible for hyperplasticity of fibroblast like synoviocytes (FLS) of intimal layer of synovial membrane that leads to the formation of pannus and responsible for cartilage destruction.⁴² TGF-β signaling pathway that plays significant role in cartilage growth. IL-1β shows inhibitory effect on TGF-β pathway and prevent TGF-β mediated cartilage growth and maintenance. IL-1β also stimulates iNOS and NO production which involved in chondrocyte apoptosis. Urokinase type plasminogen activator (uPA) and its receptor uPAR are overexpressed in the RA synovium. uPA act as a proinflammatory mediator that having important role in the cartilage destruction.

As DCN blocks the biosynthetic pathway of active IL-1β, it can show beneficial effect in RA by decreasing the formation of various types of MMPs and ADAMTS as well as by decreasing the formation of superoxide by neutrophils which ultimately shows protective effect on RA cartilage. IL-1β inhibitory effect of DCN also improves TGF-β mediated cartilage growth. DCN shows chondroprotective effect by reducing NO mediated chondrocyte apoptosis as it inhibits IL-1β mediated iNOS and NO production. Apart from these effects, DCN also reduces the expression of IL-1 receptors on the surface of chondrocytes and also increases the expression of IL-1 receptor antagonist. It also downregulates the expression of urokinase type plasminogen activator receptor (uPAR) which decreases the fibrinolytic activity in synovial fluid [29-33]. These IL-1β inhibitory effects of DCN can show beneficial role in RA.

CONCLUSION:

DCN is emerging as a potential alternative to NSAIDs like nonselective and selective COX-II inhibitors. As it lacks of prostaglandin biosynthesis effects, it can be easily used in OA patients having cardiovascular, renal complications and gastric ulceration. By inhibiting generation of active IL-1β, DCN inhibits IL-1β mediated various mechanisms involved in cartilage destruction. Apart from these, DCN also shows chondroprotective effect by reducing NO mediated chondrocyte apoptosis. These beneficial effects of DCN makes it a potential drug in the treatment of OA. Various literature review suggests that IL- β also plays important role in the pathogenesis of RA like over expression of MMP-1, MMP-3 & MMP-13, ADAMTS, iNOS, NO & ROS which responsible for articular cartilage destruction in RA. Thus, DCN mediated inhibition of active IL-1β generation can be useful in the treatment of RA.

REFERENCES:

1. Ouhaddi Y, Najar M, Paré F, Lussier B, Urade Y, Benderdour M, Pelletier JP, Martel-Pelletier J, Fahmi H. L-PGDS deficiency accelerated the development of naturally occurring age-related osteoarthritis. Aging (Albany NY). 2020;12(24):24778-24797. doi: 10.18632/aging.202367

2. Nees TA, Rosshirt N, Zhang JA, Reiner T, Sorbi R, Tripel E, Walker T, Schiltenwolf M, Hagmann S, Moradi B. Synovial cytokines significantly correlate with osteoarthritis-related knee pain and disability: inflammatory mediators of potential clinical relevance. Journal of clinical medicine. 2019;8(9):1343. https://doi.org/10.3390/jcm8091343

3. Fokunang CN, Fokunang ET, Frederick K, Ngameni B, Ngadjui B. Overview of non-steroidal anti-inflammatory drugs (NSAIDS) in resource limited countries. MOJ Toxicol. 2018;4(1):5-13. DOI: 10.15406/mojt.2018.04.00081

4. Amar S, Smith L, Fields GB. Matrix metalloproteinase collagenolysis in health and disease. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2017 Nov 1;1864(11):1940-51. DOI: 10.1016/j.bbamcr.2017.04.015

5. Napoli D. Diacerein for use in treating psoriasis. Patent No. EP 1248 608 B1. 2003.

6. Upadhyay R, swain TR, Mohapatra S, Upadhyay MR. Evaluation of Prophylactic Diacerein Treatment on Anti-Arthritic Activity in Freund’s Complete Adjuvant-Induced Arthritis in Rat Model. Journal of Clinical & Diagnostic Research. 2021;15(1): 14-19. DOI: 10.7860/JCDR/2021/47663.14461

7. Almezgagi M, Zhang Y, Hezam K, Shamsan E, Gamah M, Al-Shaebi F, Abbas AB, Shoaib M, Saif B, Han Y, Jia R. Diacerein: Recent insight into pharmacological activities and molecular pathways. Biomedicine & Pharmacotherapy. 2020;131:110594. https://doi.org/10.1016/j.biopha.2020.110594

8. Pavelka K, Bruyere O, Cooper C, Kanis JA, Leeb BF, Maheu E, Martel-Pelletier J, Monfort J, Pelletier JP, Rizzoli R, Reginster JY. Diacerein: benefits, risks and place in the management of osteoarthritis. An opinion-based report from the ESCEO. Drugs & aging. 2016 Feb 1;33(2):75-85. DOI:10.1007/s40266-016-0347-4

9. Akhter N, Khan AA, Ayaz SB, Akhter SM, L Afza A. Diacerein: A treatment option in painful primary knee. Pakistan Armed Forces Medical Journal. 2015 Feb 28;65(1):77-80.

10. Min S, Wang C, Lu W, Xu Z, Shi D, Chen D, Teng H, Jiang Q. Serum levels of the bone turnover markers dickkopf-1, osteoprotegerin, and TNF-α in knee osteoarthritis patients. Clinical Rheumatology. 2017 Oct 1;36(10):2351-8. DOI: 10.1007/s10067-017-3690-x.

11. Dinarello CA. Introduction to the interleukin-1 family of cytokines and receptors: Drivers of innate inflammation and acquired immunity. Immunological reviews. 2018 Jan;281(1):5-7. DOI: 10.1111/imr.12624

12. Sokolove J, Lepus CM. Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Therapeutic advances in musculoskeletal disease. 2013 Apr;5(2):77-94. https://doi.org/10.1177/1759720X12467868

13. Vincent TL. IL-1 in osteoarthritis: time for a critical review of the literature. F1000Research. 2019;1-8. https://doi.org/10.12688/f1000research.18831.1

14. Wang F, Liu J, Chen X, Zheng X, Qu N, Zhang B, Xia C. IL-1β receptor antagonist (IL-1Ra) combined with autophagy inducer (TAT-Beclin1) is an effective alternative for attenuating extracellular matrix degradation in rat and human osteoarthritis chondrocytes. Arthritis Research & Therapy. 2019 Dec;21(1):1-4. https://doi.org/10.1186/s13075-019-1952-5

15. Castañeda S, Vicente EF. Osteoarthritis: More than Cartilage Degeneration. Clinical Reviews in Bone and Mineral Metabolism. 2017 Jun 1;15(2):69-81. DOI :https://doi.org/10.1007/s12018-017-9228-6

16. Bolívar BE, Vogel TP, Bouchier‐Hayes L. Inflammatory caspase regulation: maintaining balance between inflammation and cell death in health and disease. The FEBS Journal. 2019 Jul;286(14):2628-44. DOI: 10.1111/febs.14926.

17. Fan Z, Bau B, Yang H, Soeder S, Aigner T. Freshly isolated osteoarthritic chondrocytes are catabolically more active than normal chondrocytes, but less responsive to catabolic stimulation with interleukin‐1β. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2005 Jan;52(1):136-43. DOI: 10.1002/art.20725

18. Sirikaew N, Chomdej S, Tangyuenyong S, Tangjitjaroen W, Somgird C, Thitaram C, Ongchai S. Proinflammatory cytokines and lipopolysaccharides up regulate MMP-3 and MMP-13 production in Asian elephant (Elephas maximus) chondrocytes: attenuation by anti-arthritic agents. BMC veterinary research. 2019 Dec;15(1):1-3.DOI: 10.1186/s12917-019-2170-8.

19. Kang DG, Lee HJ, Lee CJ, Park JS. Inhibition of the expression of matrix metalloproteinases in articular chondrocytes by resveratrol through affecting nuclear factor-kappa B signaling pathway. Biomolecules & therapeutics. 2018 Nov;26(6):560. DOI: 10.4062/biomolther.2018.132.

20. Amar S, Smith L, Fields GB. Matrix metalloproteinase collagenolysis in health and disease. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2017 Nov 1;1864(11):1940-51. DOI: 10.1016/j.bbamcr.2017.04.015.

21. Pérez-García S, Carrión M, Gutiérrez-Cañas I, Villanueva-Romero R, Castro D, Martínez C, González-Álvaro I, Blanco FJ, Juarranz Y, Gomariz RP. Profile of matrix-remodeling proteinases in osteoarthritis: impact of fibronectin. Cells. 2020 Jan;9(1):40. DOI: 10.3390/cells9010040.

22. Pittayapruek P, Meephansan J, Prapapan O, Komine M, Ohtsuki M. Role of matrix metalloproteinases in photoaging and photocarcinogenesis. International journal of molecular sciences. 2016 Jun;17(6): 868.DOI: 10.3390/ijms17060868

23. Hu Q, Ecker M. Overview of MMP-13 as a Promising Target for the Treatment of Osteoarthritis. International Journal of Molecular Sciences. 2021 Jan;22(4):1742. https://doi.org/10.3390/ijms22041742

24. Ali SY. The degradation of cartilage matrix by an intracellular protease. Biochemical Journal. 1964 Dec;93(3):611-8. DOI: 10.1042/bj0930611.

25. Kozawa E, Cheng XW, Urakawa H, Arai E, Yamada Y, Kitamura S, Sato K, Kuzuya M, Ishiguro N, Nishida Y. Increased expression and activation of cathepsin K in human osteoarthritic cartilage and synovial tissues. Journal of Orthopaedic Research. 2016 Jan;34(1):127-34. https://doi.org/10.1002/jor.23005

26. Levy MT, McCaughan GW, Abbott CA, Park JE, Cunningham AM, Müller E, Rettig WJ, Gorrell MD. Fibroblast activation protein: a cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis. Hepatology. 1999 Jun;29(6):1768-78. https:// doi.org/10.1002/hep.510290631

27. Pfander D, Heinz N, Rothe P, Carl HD, Swoboda B. Tenascin and aggrecan expression by articular chondrocytes is influenced by interleukin 1β: a possible explanation for the changes in matrix synthesis during osteoarthritis. Annals of the rheumatic diseases. 2004 Mar 1;63(3):240-4. http://dx.doi.org/10.1136/ard.2002.003749

28. Sirikaew N, Chomdej S, Tangyuenyong S, Tangjitjaroen W, Somgird C, Thitaram C, Ongchai S. Proinflammatory cytokines and lipopolysaccharides up regulate MMP-3 and MMP-13 production in Asian elephant (Elephas maximus) chondrocytes: attenuation by anti-arthritic agents. BMC veterinary research. 2019 Dec;15(1):1-3.DOI: 10.1186/s12917-019-2170-8.

29. Shakibaei M, John T, Seifarth C, Mobasheri AL. Resveratrol inhibits IL‐1β–induced stimulation of caspase‐3 and cleavage of PARP in human articular chondrocytes in vitro. Annals of the New York Academy of Sciences. 2007 Jan;1095(1):554-63. DOI: 10.1196/annals.1397.060.

30. Lopez-Armada MJ, Carames B, Lires-Dean M, Cillero-Pastor B, Ruiz-Romero C, Galdo F, Blanco FJ. Cytokines, tumor necrosis factor-α and interleukin-1β, differentially regulate apoptosis in osteoarthritis cultured human chondrocytes. Osteoarthritis and cartilage. 2006 Jul 1;14(7):660-9. DOI: 10.1016/j.joca.2006.01.005.

31. Pelletier JP, Yaron M, Haraoui B, Cohen P, Nahir MA, Choquette D, Wigler I, Rosner IA, Beaulieu AD. Efficacy and safety of diacerein in osteoarthritis of the knee: A double‐blind, placebo‐controlled trial. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2000 Oct;43(10):2339-48. DOI: 10.1016/j.joca.2007.02.021.

32. Felisaz N, Boumediene K, Ghayor C, Herrouin JF, Bogdanowicz P, Galerra P, Pujol JP. Stimulating effect of diacerein on TGF-β1 and β2 expression in articular chondrocytes cultured with and without interleukin-1. Osteoarthritis and Cartilage. 1999 May 1;7(3):255-64. DOI: 10.1053/joca.1998.0199

33. Louthrenoo W, Nilganuwong S, Aksaranugraha S, Asavatanabodee P, Saengnipanthkul S, Thai Study Group. The efficacy, safety and carry-over effect of diacerein in the treatment of painful knee osteoarthritis: a randomised, double-blind, NSAID-controlled study. Osteoarthritis and cartilage. 2007 Jun 1;15(6):605-14.DOI: 10.1016/j.joca.2007.02.021.

34. Martin G, Bogdanowicz P, Domagala F, Ficheux H, Pujol JP. Rhein inhibits interleukin-1β-induced activation of MEK/ERK pathway and DNA binding of NF-κB and AP-1 in chondrocytes cultured in hypoxia: a potential mechanism for its disease-modifying effect in osteoarthritis. Inflammation. 2003 Aug 1;27(4):233-46. https://doi.org/10.1023/A:1025040631514

35. Kaur D, Kaur J, Kamal SS. Diacerein, its beneficial impact on chondrocytes and notable new clinical applications. Brazilian Journal of Pharmaceutical Sciences. 2018;54(4). https://doi.org/10.1590/s2175-97902018000417534

36. Li J, Ny A, Leonardsson G, Nandakumar KS, Holmdahl R, Ny T. The plasminogen activator/plasmin system is essential for development of the joint inflammatory phase of collagen type II-induced arthritis. The American Journal of Pathology. 2005 Mar 1;166(3):783-92. DOI: 10.1016/S0002-9440(10)62299-7.

37. Nonaka TO, Kikuchi HI, Ikeda TE, Okamoto YO, Hamanishi CH, Tanaka SE. Hyaluronic acid inhibits the expression of u-PA, PAI-1, and u-PAR in human synovial fibroblasts of osteoarthritis and rheumatoid arthritis. The Journal of Rheumatology. 2000 Apr;27(4):997-1004.

38. Shakibaei M, Schulze-Tanzil G, John T, Mobasheri A. Curcumin protects human chondrocytes from IL-1β-induced inhibition of collagen type II and β1-integrin expression and activation of caspase-3: an immunomorphological study. Annals of Anatomy-Anatomischer Anzeiger. 2005 Nov 2;187(5-6):487-97. DOI: 10.1016/j.aanat.2005.06.007.

39. Mengshol JA, Vincenti MP, Coon CI, Barchowsky A, Brinckerhoff CE. Interleukin‐1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c‐Jun N‐terminal kinase, and nuclear factor κB: differential regulation of collagenase 1 and collagenase 3. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2000 Apr;43(4):801-11. DOI: 10.1002/1529-0131(200004)43:4<801

40. Vincenti MP, Brinckerhoff CE. Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Research & Therapy. 2002 Apr 1;4(3):157. https://doi.org/10.1186/ar401

41. Szopińskal et al. The pathogenesis of rheumatoid arthritis in radiological science.Part I: Formation of inflammatory infiltrates within the synovial membrane. Journal of Ultrasonography. 2012 Jun; 12(49): 202–213. DOI: 10.15557/JoU.2012.0007

42. Van't Hof RJ, Hocking L, Wright PK, Ralston SH. Nitric oxide is a mediator of apoptosis in the rheumatoid joint. Rheumatology. 2000 Sep 1;39(9):1004-8. DOI: 10.1093/rheumatology/39.9.1004

Received on 25.05.2021 Modified on 03.07.2021

Research J. Pharm. and Tech. 2022; 15(6):2715-2720.

DOI: 10.52711/0974-360X.2022.00454