title: The calcitonin and glucocorticoids combination: mechanistic insights into their class-effect synergy in experimental arthritis.
abstract: BACKGROUND
  Previous work reported the anti-arthritic synergy afforded by combining calcitonin (CT) and glucocorticoids (GC). Here we focus on the pairing of elcatonin (eCT) and dexamethasone (Dex), querying whether: i) this was a class-effect action; ii) mechanistic insights could be unveiled; iii) the synergy affected canonical GC adverse effects.
  
  
  METHODS
  Using the rat collagen-induced arthritis model, different combinations of eCT and Dex, were administered from disease onset to peak (day 11 to 18). Macroscopic disease score was monitored throughout, with biochemical and histological analyses conducted on plasma and tissues at day 18. The effect on acute hyperglycaemia and liver enzyme message were also assessed.
  
  
  RESULTS
  Whilst eCT alone was inactive, it synergised at 1 µg/kg with low doses of Dex (7.5 or 15 µg/kg) to yield an anti-arthritic efficacy equivalent to a 4- to 7-fold higher Dex dose. Mechanistically, the anti-arthritic synergy corresponded to a marked attenuation in RA-relevant analytes. CXCL5 expression, in both plasma and joint, was markedly inhibited by the co-therapy. Finally, co-administration of eCT did not exacerbate metrics of GC adverse effects, and rescued some of them.
  
  
  CONCLUSIONS
  We present evidence of a class-effect action for the anti-arthritic synergy of CT/GC combination, underpinned by the powerful inhibition of joint destruction markers. Furthermore, we identify CXCL5 as a marker for the combination therapy with potential diagnostic and prognostic utility. Substantial GC dose reduction, together with the absence of exacerbated adverse effects, indicated a significant clinical potential for this co-therapy in RA and beyond.
authors: The William Harvey Research Institute, Barts and The London School of Medicine, London, United Kingdom.
authors: Adam
authors: A
authors: Al-Kashi
authors: Trinidad
authors: T
authors: Montero-Melendez
authors: Niloufar
authors: N
authors: Moradi-Bidhendi
authors: James P
authors: JP
authors: Gilligan
authors: Nozer
authors: N
authors: Mehta
authors: Mauro
authors: M
authors: Perretti
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D002116:Calcitonin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use*; D003907:Dexamethasone / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects / Q000627:therapeutic use*; D007150:Immunohistochemistry; D051381:Rats
chemical_list: D005938:Glucocorticoids; D003907:Dexamethasone; D002116:Calcitonin; C012755:elcatonin
references: Ann Allergy Asthma Immunol. 2001 Feb;86(2):203-10
references: 11258691
references: Arthritis Res Ther. 2009;11(1):R12
references: 19171052
references: Br J Pharmacol. 2011 May;163(1):29-43
references: 21198556
references: Arthritis Rheum. 1980 Oct;23(10):1139-47
references: 7191707
references: Science. 1961 Dec 22;134(3495):2038
references: 13881212
references: Ann Rheum Dis. 2006 Mar;65(3):285-93
references: 16107513
references: Rheumatol Int. 2011 Apr;31(4):543-7
references: 20665024
references: J Clin Endocrinol Metab. 1990 Sep;71(3):675-81
references: 2168433
references: BioDrugs. 2008;22(3):137-44
references: 18481897
references: N Engl J Med. 2005 Oct 20;353(16):1711-23
references: 16236742
references: Ernst Schering Res Found Workshop. 2002;(40):357-71
references: 12355726
references: Agents Actions. 1982 Dec;12(5-6):671-3
references: 7164938
references: J Gerontol. 1990 Sep;45(5):M153-8
references: 2203846
references: J Pharmacol Exp Ther. 2004 Sep;310(3):1133-41
references: 15113846
references: Clin Exp Pharmacol Physiol. 2001 Dec;28(12):993-6
references: 11903301
references: Endocrinol Jpn. 1981 Dec;28(6):709-14
references: 6213404
references: Methods Enzymol. 1997;287:250-65
references: 9330327
references: J Clin Invest. 1999 Nov;104(10):1363-74
references: 10562298
references: Mol Med Today. 1999 Aug;5(8):367-9
references: 10475714
references: Calcif Tissue Int. 2009 Dec;85(6):465-83
references: 19915788
references: Agents Actions. 1977 Dec;7(5-6):533-8
references: 146410
references: Retina. 2009 Jun;29(6 Suppl):S21-3
references: 19553792
references: Ann N Y Acad Sci. 2007 Nov;1117:181-95
references: 18056043
references: Palliat Med. 2010 Oct;24(7):737-9
references: 20685772
references: Q J Exp Physiol. 1988 Jul;73(4):471-85
references: 2845462
references: Biol Chem. 2001 Oct;382(10):1491-9
references: 11727833
references: Inflamm Res. 2002 Jan;51(1):8-15
references: 11852911
references: Clin Exp Rheumatol. 1993 Sep-Oct;11(5):503-7
references: 8275585
references: Osteoporos Int. 2007 May;18(5):681-5
references: 17124552
references: Br Med J. 1970 Jan 17;1(5689):135-7
references: 5460839
references: Am J Respir Cell Mol Biol. 2006 May;34(5):616-24
references: 16424382
references: Agents Actions. 1990 Mar;29(3-4):308-14
references: 2140234
references: Nat Protoc. 2007;2(5):1269-75
references: 17546023
references: Acta Endocrinol (Copenh). 1983 Apr;102(4):572-6
references: 6303033
references: Arthritis Rheum. 2008 Jul;58(7):1968-73
references: 18576313
references: J Steroid Biochem Mol Biol. 2010 May 31;120(2-3):96-104
references: 20206690
references: Mol Cell Endocrinol. 2007 Sep 15;275(1-2):109-17
references: 17630119
references: Clin Biochem. 2008 Aug;41(12):955-9
references: 18471998
references: J Biol Chem. 1994 May 6;269(18):13289-95
references: 8175759
references: J Clin Invest. 1994 Sep;94(3):1012-8
references: 8083342
references: Endocrinol Jpn. 1981 Feb;28(1):51-7
references: 7250069
references: Br J Pharmacol. 2000 Dec;131(7):1345-54
references: 11090106
references: Am J Respir Crit Care Med. 1998 Mar;157(3 Pt 2):S1-53
references: 9520807
references: Lancet. 2008 Jan 19;371(9608):205-14
references: 18207016
references: Pharmacol Res. 2005 Nov;52(5):422-8
references: 16118056
references: Osteoporos Int. 2009 Sep;20(9):1595-601
references: 19145396
references: Ann Rheum Dis. 2010 Feb;69(2):325-31
references: 19773290
references: BMC Musculoskelet Disord. 2010 Apr 05;11:62
references: 20367884
references: Am J Pathol. 2007 Mar;170(3):1018-27
references: 17322385
references: Mol Cell Biol. 1995 Feb;15(2):943-53
references: 7823959