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Osteoarthritis

Disease ID:719
Name:Osteoarthritis
Associated with:6 targets
5 immuno-relevant targets
25 immuno-relevant ligands
Database Links
Disease Ontology: DOID:8398

Targets

chemerin receptor 1
References:  10
GPR22
Role:  Genome wide association studies (GWAS) has linked a locus on chromosome 7q22, including GPR22, with osteoarthritis. GPR22-positive chodrocyte-like cells have been found in osteophytes in instability-induced osteoarthritis.
References:  11,16,25
MMP3
Comments:  The collagenolytic MMPs 3 and 13 are strongly implicated in cartilage destruction in OA.
MMP13
Comments:  The collagenolytic MMPs 3 and 13 are strongly implicated in cartilage destruction in OA.
Ligand interactions: 
Ligand Comments
AZD6605
Showed efficacy in preclinical studies, but development was discontinued.
ADAMTS4
Comments:  ADAMTS4 and -5 are major players in development of OA. In human OA ADAMTS4 is induced by IL-1α and TNF-α, two cytokines involved in OA.
ADAMTS5
Comments:  ADAMTS4 and -5 are major players in development of OA.

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
piclidenoson
Immuno Disease Comments: Clinical candidate for OA of the knee (Phase 2 NCT00837291).
Clinical Use: Piclidenoson (CF101) is being evaluated in a number of clinical trials, as a potential therapy for several autoimmune-inflammatory disorders (rheumatoid arthritis, Phase III, NCT02647762 [26]; plaque psoriasis, Phase II [6]; uveitis Phase II) and glaucoma (Phase II, NCT01033422 [12]). | View clinical data
fenoprofen
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including OA.
Clinical Use: Fenoprofen is used to treat inflammatory conditions such as rheumatoid- and osteo-arthritis in addition to being used for pain relief. | View clinical data
lutikizumab
Immuno Disease Comments: Phase 2 clinical candidate for OA.
Clinical Use: ABT-981 has reached Phase 2a clinical trial in patients with OA of the knee (NCT02087904) and hand (NCT02384538). Phase 1 satety and tolerability findings from NCT01668511 are published in [29]. | View clinical data
GW406381 4
Immuno Disease Comments: Phase 3 clinical candidate for OA- see NCT00120900. However GW406381 failed to demonstrate clinically meaningful efficacy in pain related to OA of the knee.
Clinical Use: GW406381 has completed Phase 3 clinical evaluation in knee osteoarthritis [4], rheumatoid arthritis, and post-dental surgery pain (clinically meaningful analgesia was demnostrated in this acute pain setting, but time to onset was >1 hour) [27]. | View clinical data
Bioactivity Comments: GW406381 is almost 30000 times more potent at COX2 compared to COX1 [2]. | View biological activity
PF-04905428
Immuno Disease Comments: Phase 2 clinical trial NCT00418782 was terminated due to interim assessment suggesting a lack of efficacy.
Clinical Use: A Phase III clinical trial in patients with rheumatoid arthritis (RA: NCT00628095) has been completed. Results showed PF-04905428 (CE-224,535) was not effective in treating RA [22]. | View clinical data
Bioactivity Comments: PF-04905428 was tested for its ability to inhibit lL-1β release from ATP-stimulated monocytes. This assay provides an IC50 of 1.3nM [23]. We have tagged P2X7 receptor as the primary molecular target based on details in [9] and [8], despite neither of these publications containing a bona fide affinity value for PF-04905428 binding.
The selectivity of PF-04905428 for the human P2X7 receptor precludes its evaluation in rodent disease models. | View biological activity
mefenamic acid
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including OA.
Clinical Use: Used in the treatment of rheumatoid arthritis, osteoarthritis, dysmenorrhea, inflammation, fever and pain. | View clinical data
ibuprofen
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including OA.
Clinical Use: Ibuprofen is used widely for its analgesic and antipyretic actions. | View clinical data
triamcinolone
Immuno Disease Comments: Glucocorticoid drug used to treat many inflammatory condtions including OA.
Clinical Use: Triamcinolone is used for its antiinflammatory or immunosuppressive actions in many conditions. For example, oral triamcinolone is used to treat conditions such as allergic disorders, skin conditions, ulcerative colitis, arthritis, lupus, psoriasis, and breathing disorders. This drug is also used topically as an anti-inflammatory and anti-pruritic agent. Injectable forms of the drug may be used to reduce intra-articular joint pain, stiffness and swelling associated with rheumatoid and osteoarthritic arthritis, bursitis, epicondylitis, and tenosynovitis. | View clinical data
rofecoxib
Immuno Disease Comments: Withdrawn from US market due to safety concerns.
Clinical Use: A non-steroidal anti-inflammatory drug previously used in the treatment of rheumatoid arthritis, osteoarthritis, primary dysmenorrhea, acture migraine and acute pain. Withdrawn from the US market in 2004 due to concerns about safety. | View clinical data
etoricoxib
Immuno Disease Comments: Selective COX2 inhibitor approved for the treatment of many inflammatory conditions including OA.
Clinical Use: Used in the treatment of rheumatoid arthritis, osteoarthritis, chronic lower back pain, ankylosing spondylitis, acute pain and gout. There is no information regarding approval for medicinal use of etoricoxib on the US FDA website. Individual national agencies may have granted marketing approval. | View clinical data
lumiracoxib
Immuno Disease Comments: Selective COX2 inhibitor withdrawn from use in the EU, Canada, Australia, and New Zealand but available elsewhere, for the treatment of OA.
Clinical Use: A non-steroidal anti-inflammatory drug that has been used in the treatment of osteoarthritis. Withdrawn from use in the EU, Canada, Australia, and New Zealand, lumiracoxib is still used clinically in several countries in Central and South America. | View clinical data
flurbiprofen
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including OA.
Clinical Use: Flurbiprofen is approved to treat the pain and inflammation associated with rheumatic diseases and other musculoskeletal disorders, as well as dysmenorrhoea, migraine and as postoperative analgesia. | View clinical data
naproxen
Immuno Disease Comments: Approved NSAID used for many inflammatory conditions including OA.
Clinical Use: Used in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendinitis, bursitis, and acute gout. Also used in pain relief in the treatment of primary dysmenorrhea. | View clinical data
meclofenamic acid
Immuno Disease Comments: NSAID used to treat the pain and inflammation of OA.
Clinical Use: Used to treat muscular pain, arthritis and dysmenorrhea. There is no information regarding approval for clinical use of this drug on the US FDA website. Other national approval agencies may have granted marketing authorisation. | View clinical data
piroxicam
Immuno Disease Comments: NSAID used to treat the pain and inflammation of OA.
Clinical Use: Used to treat rheumatoid and osteoarthritis, primary dysmenorrhoea and postoperative pain. | View clinical data
suprofen
Immuno Disease Comments: NSAID used to treat the pain and inflammation of OA.
Clinical Use: Used as an antiarthritic and to treat inflammations of the eye. Marketing authorisation has been discontinued in the US, but other national approval agencies may continue to grant marketing authorisation. | View clinical data
nimesulide
Immuno Disease Comments: NSAID used to treat the pain and inflammation of OA.
Clinical Use: Approved to treat acute pain, in patients suffering from osteoarthritis or primary dysmenorrhoea for example. There is no information regarding approval for clinical use of this drug on the US FDA or European Medicines Agency websites. Individual national agencies may have granted marketing authorisation. | View clinical data
AZD6703
Immuno Disease Comments: Failed clinical candidate for OA and other inflammatory conditions.
Clinical Use: AZD6703 was investigated as a potential treatment for inflammatory diseases such as osteoarthritis. | View clinical data
AZ11657312 (salt free)
Immuno Disease Comments: Experimental compound with antiinflammatory activity predicted across a range of inflammatory indications.
Bioactivity Comments: Note that bioactivity will be associated with the hydrochloride salt. Pending publication, the data presented here is derived from the compound's record in AstaZeneca's Open Innovation Pharmacology Toolbox | View biological activity
AZD6605
Immuno Disease Comments: Showed efficacy in preclinical studies, but development was discontinued.
Clinical Use: AZD6605 was developed as a treatment for osteoarthritis based on preclinical studies, including the observation that it inhibited cartilage loss in a guinea pig model of osteoarthritis [7]. | View clinical data
polmacoxib
Immuno Disease Comments: Approved drug for OA.
Clinical Use: Polmacoxib was approved in South Korea in early 2015, for the treatment of osteoarthritis, following positive outcomes from a Phase III clinical trial (NCT01765296). | View clinical data
Bioactivity Comments: We have not tagged a primary molecular target for this compound as we have been unable to identify peer reviewed data confirming its MMOA. | View biological activity
esflurbiprofen
Immuno Disease Comments: NSAID approved for the pain and inflammation of OA.
Clinical Use: Approved in Japan; indicated for the relief of inflammation and pain associated with osteoarthritis. Clinicaltrials.gov list Phase 2 trial NCT02729207 which is evaluating esflurbiprofen in hydrogel patch form for local analgesia in ankle sprains. | View clinical data
Bioactivity Comments: Esflurbiprofen ((S)-flurbiprofen) inhibits prostaglandin biosynthesis in vitro at therapeutic concentrations [14]. COX-1 is inhibited with an IC50 of ~30nM and COX-2 with an IC50 of ~900nM [14]. | View biological activity
ATB-346
Immuno Disease Comments: ATB-346 is a clinical trial candidate for OA.
Clinical Use: A Canadian Phase 2 study in osteoarthritis of the knee has been completed with encouraging results (Canadian Clinical Trials database Control Number 191898), although results have not yet been published. | View clinical data
Bioactivity Comments: H2S is liberated upon esterase-mediated cleavage and lactonization [31]. The GI-sparing nature of this drug is evidenced by exposure not causing significant GI injury in rodents and dogs, at high doses, or in animals with impaired mucosal defense [3,13,28]. | View biological activity
naproxcinod 20
Immuno Disease Comments: Naproxcinod has completed Phase 3 clinical trial for OA.
Clinical Use: Proof-of-concept in humans is reported in [15]. The EMA granted naproxcinod orphan designation for the treatment of Duchenne muscular dystrophy [19] in 2013, followed by the US FDA in 2015. Phase 3 studies comparing naproxcinod with naproxen or placebo in patients with osteoarthritis of the hip and knee have been completed [1,20]. | View clinical data
Bioactivity Comments: The biological activity of this drug will be determined by its cyclooxygenase inhibition () and -induced effects. See the separate ligand pages for each of these active components for further information. | View biological activity
dapansutrile 18
Immuno Disease Comments: Phase 2 clinical candidate for knee OA- see NCT02104050 and NCT01768975
Clinical Use: Topically administered OLT1177 is being evaluated for clinical efficacy as a treatment for osteoarthritis pain (see Phase 2 NCT02104050 and NCT01768975). A Phase 2 trial in patients with Schnitzler syndrome (an autoinflammatory condition that is generally treated with the IL-1 receptor antagonist drug ) will evaluate any clinical benefit associated with orally delivered OLT1177 (NCT03595371). A Phase 1 study in heart failure is also underway (NCT03534297) [32]. | View clinical data

References

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1. Baerwald C, Verdecchia P, Duquesroix B, Frayssinet H, Ferreira T. (2010) Efficacy, safety, and effects on blood pressure of naproxcinod 750 mg twice daily compared with placebo and naproxen 500 mg twice daily in patients with osteoarthritis of the hip: a randomized, double-blind, parallel-group, multicenter study. Arthritis Rheum., 62 (12): 3635-44. [PMID:20722026]

2. Beswick P, Bingham S, Bountra C, Brown T, Browning K, Campbell I, Chessell I, Clayton N, Collins S, Corfield J et al.. (2004) Identification of 2,3-diaryl-pyrazolo[1,5-b]pyridazines as potent and selective cyclooxygenase-2 inhibitors. Bioorg. Med. Chem. Lett., 14 (21): 5445-8. [PMID:15454242]

3. Blackler R, Syer S, Bolla M, Ongini E, Wallace JL. (2012) Gastrointestinal-sparing effects of novel NSAIDs in rats with compromised mucosal defence. PLoS ONE, 7 (4): e35196. [PMID:22496907]

4. Boswell DJ, Ostergaard K, Philipson RS, Hodge RA, Blum D, Brown JC, Quessy SN. (2008) Evaluation of GW406381 for treatment of osteoarthritis of the knee: two randomized, controlled studies. Medscape J Med, 10 (11): 259. [PMID:19099009]

5. Chiusaroli R, Visentini M, Galimberti C, Casseler C, Mennuni L, Covaceuszach S, Lanza M, Ugolini G, Caselli G, Rovati LC et al.. (2013) Targeting of ADAMTS5's ancillary domain with the recombinant mAb CRB0017 ameliorates disease progression in a spontaneous murine model of osteoarthritis. Osteoarthr. Cartil., 21 (11): 1807-10. [PMID:23954517]

6. David M, Akerman L, Ziv M, Kadurina M, Gospodinov D, Pavlotsky F, Yankova R, Kouzeva V, Ramon M, Silverman MH et al.. (2012) Treatment of plaque-type psoriasis with oral CF101: data from an exploratory randomized phase 2 clinical trial. J Eur Acad Dermatol Venereol, 26 (3): 361-7. [PMID:21504485]

7. De Savi C, Waterson D, Pape A, Lamont S, Hadley E, Mills M, Page KM, Bowyer J, Maciewicz RA. (2013) Hydantoin based inhibitors of MMP13--discovery of AZD6605. Bioorg. Med. Chem. Lett., 23 (16): 4705-12. [PMID:23810497]

8. Dombroski MA, Duplantier AJ. (2005) Benzamide inhibitors of the P2X7 receptor. Patent number: US6974812 B2. Assignee: Pfizer Inc.. Priority date: 31/12/2002. Publication date: 13/12/2005.

9. Duplantier AJ, Dombroski MA, Subramanyam C, Beaulieu AM, Chang SP, Gabel CA, Jordan C, Kalgutkar AS, Kraus KG, Labasi JM et al.. (2011) Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X7 receptor antagonists leading to the discovery of the clinical candidate CE-224,535. Bioorg. Med. Chem. Lett., 21 (12): 3708-11. [PMID:21565499]

10. Eisinger K, Bauer S, Schäffler A, Walter R, Neumann E, Buechler C, Müller-Ladner U, Frommer KW. (2012) Chemerin induces CCL2 and TLR4 in synovial fibroblasts of patients with rheumatoid arthritis and osteoarthritis. Exp. Mol. Pathol., 92 (1): 90-6. [PMID:22037282]

11. Evangelou E, Valdes AM, Kerkhof HJ, Styrkarsdottir U, Zhu Y, Meulenbelt I, Lories RJ, Karassa FB, Tylzanowski P, Bos SD et al.. (2011) Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22. Ann. Rheum. Dis., 70 (2): 349-55. [PMID:21068099]

12. Fishman P, Cohen S, Bar-Yehuda S. (2013) Targeting the A3 adenosine receptor for glaucoma treatment (review). Mol Med Rep, 7 (6): 1723-5. [PMID:23563604]

13. Fomenko I, Sklyarov A, Bondarchuk T, Biletska L, Panasyuk N, Wallace JL. (2014) Effects of conventional and hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs in rats with stress-induced and epinephrine-induced gastric damage. Stress, 17 (6): 528-37. [PMID:25238023]

14. Geisslinger G, Schaible HG. (1996) New insights into the site and mode of antinociceptive action of flurbiprofen enantiomers. J Clin Pharmacol, 36 (6): 513-20. [PMID:8809636]

15. Hawkey CJ, Jones JI, Atherton CT, Skelly MM, Bebb JR, Fagerholm U, Jonzon B, Karlsson P, Bjarnason IT. (2003) Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: proof of concept study in humans. Gut, 52 (11): 1537-42. [PMID:14570719]

16. Kerkhof HJ, Lories RJ, Meulenbelt I, Jonsdottir I, Valdes AM, Arp P, Ingvarsson T, Jhamai M, Jonsson H, Stolk L, Thorleifsson G, Zhai G, Zhang F, Zhu Y, van der Breggen R, Carr A, Doherty M, Doherty S, Felson DT, Gonzalez A, Halldorsson BV, Hart DJ, Hauksson VB, Hofman A, Ioannidis JP, Kloppenburg M, Lane NE, Loughlin J, Luyten FP, Nevitt MC, Parimi N, Pols HA, Rivadeneira F, Slagboom EP, Styrkársdóttir U, Tsezou A, van de Putte T, Zmuda J, Spector TD, Stefansson K, Uitterlinden AG, van Meurs JB. (2010) A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22. Arthritis Rheum., 62 (2): 499-510. [PMID:20112360]

17. Larkin J, Lohr TA, Elefante L, Shearin J, Matico R, Su JL, Xue Y, Liu F, Genell C, Miller RE et al.. (2015) Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification. Osteoarthr. Cartil., 23 (8): 1254-66. [PMID:25800415]

18. Marchetti C, Swartzwelter B, Koenders MI, Azam T, Tengesdal IW, Powers N, de Graaf DM, Dinarello CA, Joosten LAB. (2018) NLRP3 inflammasome inhibitor OLT1177 suppresses joint inflammation in murine models of acute arthritis. Arthritis Res. Ther., 20 (1): 169. [PMID:30075804]

19. Miglietta D, De Palma C, Sciorati C, Vergani B, Pisa V, Villa A, Ongini E, Clementi E. (2015) Naproxcinod shows significant advantages over naproxen in the mdx model of Duchenne Muscular Dystrophy. Orphanet J Rare Dis, 10: 101. [PMID:26296873]

20. Schnitzer TJ, Hochberg MC, Marrero CE, Duquesroix B, Frayssinet H, Beekman M. (2011) Efficacy and safety of naproxcinod in patients with osteoarthritis of the knee: a 53-week prospective randomized multicenter study. Semin. Arthritis Rheum., 40 (4): 285-97. [PMID:20828790]

21. Song RH, Tortorella MD, Malfait AM, Alston JT, Yang Z, Arner EC, Griggs DW. (2007) Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis Rheum., 56 (2): 575-85. [PMID:17265492]

22. Stock TC, Bloom BJ, Wei N, Ishaq S, Park W, Wang X, Gupta P, Mebus CA. (2012) Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate. J. Rheumatol., 39 (4): 720-7. [PMID:22382341]

23. Subramanyam C, Duplantier AJ, Dombroski MA, Chang SP, Gabel CA, Whitney-Pickett C, Perregaux DG, Labasi JM, Yoon K, Shepard RM et al.. (2011) Discovery, synthesis and SAR of azinyl- and azolylbenzamides antagonists of the P2X₇ receptor. Bioorg. Med. Chem. Lett., 21 (18): 5475-9. [PMID:21782426]

24. Troeberg L, Nagase H. (2012) Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim. Biophys. Acta, 1824 (1): 133-45. [PMID:21777704]

25. Valdes AM, Spector TD. (2010) The genetic epidemiology of osteoarthritis. Curr Opin Rheumatol, 22 (2): 139-43. [PMID:20090528]

26. Varani K, Padovan M, Govoni M, Vincenzi F, Trotta F, Borea PA. (2010) The role of adenosine receptors in rheumatoid arthritis. Autoimmun Rev, 10 (2): 61-4. [PMID:20691813]

27. Varner J, Lomax M, Blum D, Quessy S. (2009) A randomized, controlled, dose-ranging study investigating single doses of GW406381, naproxen sodium, or placebo in patients with acute pain after third molar tooth extraction. Clin J Pain, 25 (7): 577-83. [PMID:19692798]

28. Wallace JL, Caliendo G, Santagada V, Cirino G. (2010) Markedly reduced toxicity of a hydrogen sulphide-releasing derivative of naproxen (ATB-346). Br. J. Pharmacol., 159 (6): 1236-46. [PMID:20128814]

29. Wang SX, Abramson SB, Attur M, Karsdal MA, Preston RA, Lozada CJ, Kosloski MP, Hong F, Jiang P, Saltarelli MJ et al.. (2017) Safety, tolerability, and pharmacodynamics of an anti-interleukin-1α/β dual variable domain immunoglobulin in patients with osteoarthritis of the knee: a randomized phase 1 study. Osteoarthr. Cartil., 25 (12): 1952-1961. [PMID:28964890]

30. Yamanishi Y, Boyle DL, Clark M, Maki RA, Tortorella MD, Arner EC, Firestein GS. (2002) Expression and regulation of aggrecanase in arthritis: the role of TGF-beta. J. Immunol., 168 (3): 1405-12. [PMID:11801682]

31. Zheng Y, Yu B, Ji K, Pan Z, Chittavong V, Wang B. (2016) Esterase-Sensitive Prodrugs with Tunable Release Rates and Direct Generation of Hydrogen Sulfide. Angew. Chem. Int. Ed. Engl., 55 (14): 4514-8. [PMID:26822005]

32. Zhou W, Chen C, Chen Z, Liu L, Jiang J, Wu Z, Zhao M, Chen Y. (2018) NLRP3: A Novel Mediator in Cardiovascular Disease. J Immunol Res, 2018: 5702103. [PMID:29850631]