Top

Published in:

01-07-2012 | Original Research

Downregulation of the Inflammatory Response by CORM-3 Results in Protective Effects in a Model of Postmenopausal Arthritis

Authors: Lidia Ibáñez, Maria José Alcaraz, Nuria Maicas, David Guede, José Ramón Caeiro, Roberto Motterlini, Maria Luisa Ferrándiz

Published in: Calcified Tissue International | Issue 1/2012

Abstract

CO-releasing molecules (CORMs) are a new class of drugs able to release small amounts of CO in biological systems. We have shown previously that one of these molecules, CORM-3, exerts anti-inflammatory effects in animal models. The aim of this study was to assess the effects of CORM-3 on bone metabolism in a model of postmenopausal rheumatoid arthritis osteoporosis. Ovariectomy was followed by collagen-induced arthritis in female DBA-1/J mice. Animals showing arthritis on day 22 after immunization were then randomized into control and treatment groups. CORM-3 was administered at 10 mg/kg, intraperitoneally, once a day. Alendronate was administered at 100 μg/kg, orally, once a day. On days 36 and 50 after immunization, animals were killed and tissues analyzed. The arthritic score was significantly reduced by CORM-3 but not by alendronate treatment. Histopathological analyses indicated that both compounds reduced cellular infiltration and cartilage degradation. Local bone erosion and reduction in TNFα levels were seen for CORM-3 on day 50 and for alendronate on day 36. Serum levels of COMP, IL-6, MMP-3, CTX-I, alkaline phosphatase, and osteocalcin were decreased by both treatments, whereas TNFα levels were reduced by CORM-3 and TRAP-5b by alendronate. Micro-computed tomographic analysis showed protective effects on trabecular bone, which were more prominent for CORM-3 on day 36 and for alendronate on day 50. Our results suggest that CORMs represent a novel anti-inflammatory strategy to counteract joint bone erosion with partial protective effects on systemic bone loss in postmenopausal rheumatoid arthritis.

Goldring SR, Gravallese EM (2000) Mechanisms of bone loss in inflammatory arthritis: diagnosis and therapeutic implications. Arthritis Res 2:33–37PubMedCrossRef

Forsblad DH, Larsen A, Waltbrand E, Kvist G, Mellstrom D, Saxne T, Ohlsson C, Nordborg E, Carlsten H (2003) Radiographic joint destruction in postmenopausal rheumatoid arthritis is strongly associated with generalised osteoporosis. Ann Rheum Dis 62:617–623CrossRef

Goemaere S, Ackerman C, Goethals K, De Keyser F, Van der Straeten C, Verbruggen G, Mielants H, Veys EM (1990) Onset of symptoms of rheumatoid arthritis in relation to age, sex and menopausal transition. J Rheumatol 17:1620–1622PubMed

D’Elia HF, Larsen A, Mattsson LA, Waltbrand E, Kvist G, Mellstrom D, Saxne T, Ohlsson C, Nordborg E, Carlsten H (2003) Influence of hormone replacement therapy on disease progression and bone mineral density in rheumatoid arthritis. J Rheumatol 30:1456–1463PubMed

Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH (1990) Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 322:1265–1271PubMedCrossRef

Eggelmeijer F, Papapoulos SE, van Paassen HC, Dijkmans BA, Valkema R, Westedt ML, Landman JO, Pauwels EK, Breedveld FC (1996) Increased bone mass with pamidronate treatment in rheumatoid arthritis: results of a three-year randomized, double-blind trial. Arthritis Rheum 39:396–402PubMedCrossRef

Breuil V, Euller-Ziegler L (2006) Bisphosphonate therapy in rheumatoid arthritis. Joint Bone Spine 73:349–354PubMedCrossRef

Motterlini R, Otterbein LE (2010) The therapeutic potential of carbon monoxide. Nat Rev Drug Discov 9:728–743PubMedCrossRef

Alcaraz MJ, Guillen MI, Ferrandiz ML, Megias J, Motterlini R (2008) Carbon monoxide-releasing molecules: a pharmacological expedient to counteract inflammation. Curr Pharm Des 14:465–472PubMedCrossRef

10.

Ferrándiz ML, Maicas N, Garcia-Arnandis I, Terencio MC, Motterlini R, Devesa I, Joosten LAB, van den Berg WB, Alcaraz MJ (2008) Treatment with a CO-releasing molecule (CORM-3) reduces joint inflammation and erosion in murine collagen-induced arthritis. Ann Rheum Dis 67:1211–1217PubMedCrossRef

11.

Maicas N, Ferrandiz ML, Devesa I, Motterlini R, Koenders MI, van den Berg WB, Alcaraz MJ (2010) The CO-releasing molecule CORM-3 protects against articular degradation in the K/BxN serum transfer arthritis model. Eur J Pharmacol 634:184–191PubMedCrossRef

12.

Jochems C, Islander U, Erlandsson M, Verdrengh M, Ohlsson C, Carlsten H (2005) Osteoporosis in experimental postmenopausal polyarthritis: the relative contributions of estrogen deficiency and inflammation. Arthritis Res Ther 7:R837–R843PubMedCrossRef

13.

Clark JE, Naughton P, Shurey S, Green CJ, Johnson TR, Mann BE, Foresti R, Motterlini R (2003) Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ Res 93:e2–e8PubMedCrossRef

14.

Kind PR, King EJ (1954) Estimation of plasma phosphatase by determination of hydrolysed phenol with amino-antipyrine. J Clin Pathol 7:322–326PubMedCrossRef

15.

Feldkamp LA, Davis LC, Krettek C (1984) Practical cone-beam algorithm. J Opt Soc Am A 1:612–619CrossRef

16.

Remy E, Thiel E (2002) Medial axis for chamfer distances: computing look-up tables and neighbourhoods in 2D or 3D. Pattern Recognit Lett 23:649–661CrossRef

17.

Ulrich D, van Rietbergen B, Laib A, Ruegsegger P (1999) The ability of three-dimensional structural indices to reflect mechanical aspects of trabecular bone. Bone 25:55–60PubMedCrossRef

18.

Urquhart P, Rosignoli G, Cooper D, Motterlini R, Perretti M (2007) Carbon monoxide-releasing molecules modulate leukocyte–endothelial interactions under flow. J Pharmacol Exp Ther 321:656–662PubMedCrossRef

19.

Adami S, Bhalla AK, Dorizzi R, Montesanti F, Rosini S, Salvagno G, Lo Cascio V (1987) The acute-phase response after bisphosphonate administration. Calcif Tissue Int 41:326–331PubMedCrossRef

20.

Makkonen N, Salminen A, Rogers MJ, Frith JC, Urtti A, Azhayeva E, Monkkonen J (1999) Contrasting effects of alendronate and clodronate on RAW 264 macrophages: the role of a bisphosphonate metabolite. Eur J Pharm Sci 8:109–118PubMedCrossRef

21.

Nakamura M, Ando T, Abe M, Kumagai K, Endo Y (1996) Contrast between effects of aminobisphosphonates and non-aminobisphosphonates on collagen-induced arthritis in mice. Br J Pharmacol 119:205–212PubMed

22.

Deng X, Yu Z, Funayama H, Yamaguchi K, Sasano T, Sugawara S, Endo Y (2007) Histidine decarboxylase–stimulating and inflammatory effects of alendronate in mice: involvement of mevalonate pathway, TNFalpha, macrophages, and T-cells. Int Immunopharmacol 7:152–161PubMedCrossRef

23.

D’Amelio P, Grimaldi A, Cristofaro MA, Ravazzoli M, Molinatti PA, Pescarmona GP, Isaia GC (2010) Alendronate reduces osteoclast precursors in osteoporosis. Osteoporos Int 21:1741–1750PubMedCrossRef

24.

Ribbens C, Porras M, Franchimont N, Kaiser MJ, Jaspar JM, Damas P, Houssiau FA, Malaise MG (2002) Increased matrix metalloproteinase-3 serum levels in rheumatic diseases: relationship with synovitis and steroid treatment. Ann Rheum Dis 61:161–166PubMedCrossRef

25.

Okada Y, Nagase H, Harris ED Jr (1987) Matrix metalloproteinases 1, 2, and 3 from rheumatoid synovial cells are sufficient to destroy joints. J Rheumatol 14(spec no):41–42PubMed

26.

Mamehara A, Sugimoto T, Sugiyama D, Morinobu S, Tsuji G, Kawano S, Morinobu A, Kumagai S (2010) Serum matrix metalloproteinase-3 as predictor of joint destruction in rheumatoid arthritis, treated with non-biological disease modifying anti-rheumatic drugs. Kobe J Med Sci 56:E98–E107PubMed

27.

Fujikawa K, Kawakami A, Tamai M, Uetani M, Takao S, Arima K, Iwamoto N, Aramaki T, Kawashiri S, Ichinose K, Kamachi M, Nakamura H, Origuchi T, Ida H, Aoyagi K, Eguchi K (2009) High serum cartilage oligomeric matrix protein determines the subset of patients with early-stage rheumatoid arthritis with high serum C-reactive protein, matrix metalloproteinase-3, and MRI-proven bone erosion. J Rheumatol 36:1126–1129PubMedCrossRef

28.

Lehmann HJ, Mouritzen U, Christgau S, Cloos PA, Christiansen C (2002) Effect of bisphosphonates on cartilage turnover assessed with a newly developed assay for collagen type II degradation products. Ann Rheum Dis 61:530–533PubMedCrossRef

29.

Shirai T, Kobayashi M, Nishitani K, Satake T, Kuroki H, Nakagawa Y, Nakamura T (2011) Chondroprotective effect of alendronate in a rabbit model of osteoarthritis. J Orthop Res 29:1572–1577PubMedCrossRef

30.

Ralston SH, Hacking L, Willocks L, Bruce F, Pitkeathly DA (1989) Clinical, biochemical, and radiographic effects of aminohydroxypropylidene bisphosphonate treatment in rheumatoid arthritis. Ann Rheum Dis 48:396–399PubMedCrossRef

31.

Zhang Q, Badell IR, Schwarz EM, Boulukos KE, Yao Z, Boyce BF, Xing L (2005) Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2. Arthritis Rheum 52:2708–2718PubMedCrossRef

32.

Kitazawa R, Kimble RB, Vannice JL, Kung VT, Pacifici R (1994) Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice. J Clin Invest 94:2397–2406PubMedCrossRef

33.

Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J, Pacifici R (2000) Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 106:1229–1237PubMedCrossRef

34.

Nanes MS (2003) Tumor necrosis factor-alpha: molecular and cellular mechanisms in skeletal pathology. Gene 321:1–15PubMedCrossRef

35.

Ochi S, Shinohara M, Sato K, Gober HJ, Koga T, Kodama T, Takai T, Miyasaka N, Takayanagi H (2007) Pathological role of osteoclast costimulation in arthritis-induced bone loss. Proc Natl Acad Sci USA 104:11394–11399PubMedCrossRef

36.

Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC, Abrams JS, Boyce B, Broxmeyer H, Manolagas SC (1992) Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 257:88–91PubMedCrossRef

37.

Axmann R, Bohm C, Kronke G, Zwerina J, Smolen J, Schett G (2009) Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum 60:2747–2756PubMedCrossRef

38.

Song H, Bergstrasser C, Rafat N, Hoger S, Schmidt M, Endres N, Goebeler M, Hillebrands JL, Brigelius-Flohe R, Banning A, Beck G, Loesel R, Yard BA (2009) The carbon monoxide releasing molecule (CORM-3) inhibits expression of vascular cell adhesion molecule-1 and E-selectin independently of haem oxygenase-1 expression. Br J Pharmacol 157:769–780PubMedCrossRef

39.

Wei Y, Chen P, De Bruyn M, Zhang W, Bremer E, Helfrich W (2010) Carbon monoxide–releasing molecule-2 (CORM-2) attenuates acute hepatic ischemia reperfusion injury in rats. BMC Gastroenterol 10:42PubMedCrossRef

40.

Martin T, Gooi JH, Sims NA (2009) Molecular mechanisms in coupling of bone formation to resorption. Crit Rev Eukaryot Gene Expr 19:73–88PubMed

41.

Cantatore FP, Acquista CA, Pipitone V (1999) Evaluation of bone turnover and osteoclastic cytokines in early rheumatoid arthritis treated with alendronate. J Rheumatol 26:2318–2323PubMed

42.

Alcaraz MJ, Fernandez P, Guillen MI (2003) Anti-inflammatory actions of the heme oxygenase-1 pathway. Curr Pharm Des 9:2541–2551PubMedCrossRef

43.

Zwerina J, Tzima S, Hayer S, Redlich K, Hoffmann O, Hanslik-Schnabel B, Smolen JS, Kollias G, Schett G (2005) Heme oxygenase 1 (HO-1) regulates osteoclastogenesis and bone resorption. FASEB J 19:2011–2013PubMed

44.

Lin TH, Tang CH, Hung SY, Liu SH, Lin YM, Fu WM, Yang RS (2010) Upregulation of heme oxygenase-1 inhibits the maturation and mineralization of osteoblasts. J Cell Physiol 222:757–768PubMed

Title: Downregulation of the Inflammatory Response by CORM-3 Results in Protective Effects in a Model of Postmenopausal Arthritis
Authors: Lidia Ibáñez
Maria José Alcaraz
Nuria Maicas
David Guede
José Ramón Caeiro
Roberto Motterlini
Maria Luisa Ferrándiz
Publication date: 01-07-2012
Publisher: Springer-Verlag
Published in: Calcified Tissue International / Issue 1/2012
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI: https://doi.org/10.1007/s00223-012-9612-7

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Downregulation of the Inflammatory Response by CORM-3 Results in Protective Effects in a Model of Postmenopausal Arthritis

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2012

Targeted Disruption of TGFBI in Mice Reveals Its Role in Regulating Bone Mass and Bone Size through Periosteal Bone Formation

The Effect of Care Pathways for Hip Fractures: A Systematic Review

Endogenous Estradiol and The Risk of Incident Fracture in Postmenopausal Women: The OPUS Study

Novel Sequence Variations in the CER1 Gene Are Strongly Associated with Low Bone Mineral Density and Risk of Osteoporotic Fracture in Postmenopausal Women

Potential Impact of Benzodiazepine Use on the Rate of Hip Fractures in Five Large European Countries and the United States

Cathepsin K Preferentially Solubilizes Matured Bone Matrix

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page