Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Skeletal Radiology
Published in: Skeletal Radiology 1/2017

01-01-2017 | Scientific Article

In vitro chondrocyte toxicity following long-term, high-dose exposure to Gd-DTPA and a novel cartilage-targeted MR contrast agent

Authors: Sharon Midura, Erika Schneider, Gerald M. Rosen, Carl S. Winalski, Ronald J. Midura

Published in: Skeletal Radiology | Issue 1/2017

Login to get access

Abstract

Objective

To determine the concentrations exhibiting toxicity of a cartilage-targeted magnetic resonance imaging contrast agent compared with gadopentetate dimeglumine (Gd-DT-PA) in chondrocyte cultures.

Materials and methods

A long-term Swarm rat chondrosarcoma chondrocyte-like cell line was exposed for 48 h to 1.0–20 mM concentrations of diaminobutyl-linked nitroxide (DAB4-DLN) citrate, 1.0–20 mM Gd-DTPA, 1.0 μM staurosporine (positive control), or left untreated. Cell appearance, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays of metabolic activity, quantitative PicoGreen assays of DNA content, and calcein-AM viability assays were compared.

Results

At 1.0–7.5 mM, minimal decrease in cell proliferation was found for both agents. At all doses of both agents, cell culture appearances were similar after 24 h of treatment. At the higher doses, differences in cell culture appearance were found after 48 h of treatment, with dose-dependent declines in chondrocyte populations for both agents. Concentration-dependent declines in DNA content and calcein fluorescence were found after 48 h of treatment, but beginning at a lower dose of DAB4-DLN citrate than Gd-DTPA. Dose-dependent decreases in MTT staining (cell metabolism) were apparent for both agents, but larger effects were evident at a lower dose for DAB-DLN citrate. Poor MTT staining of cells exposed for 48 h to 20 mM DAB4-DLN citrate probably indicates dead or dying cells.

Conclusion

The minimal effect of the long-term exposure of model chondrocyte cell cultures to DAB4-DLN citrate and Gd-DTPA concentrations up to 7.5 mM (3x typical arthrographic administration) is supporting evidence that these doses are acceptable for MR arthrography. The findings are reassuring given that the experimental exposure to the contrast agents at sustained concentrations was much longer than when used clinically.
Literature
1.
Winalski CS, Aliabadi P, Wright RJ, Shortkroff S, Sledge CB, Weissman BN. Enhancement of joint fluid with intravenously administered gadopentetate dimeglumine: technique, rationale, and implications. Radiology. 1993;187(1):179–85.CrossRefPubMed
2.
Agten CA, Sutter R, Buck FM, Pfirrmann CW. Hip imaging in athletes: sports imaging series. Radiology. 2016;280(2):351–69.CrossRefPubMed
3.
Bashir A, Gray ML, Boutin RD, Burstein D. Glycosaminoglycan in articular cartilage: in vivo assessment with delayed Gd(DTPA)(2-)-enhanced MR imaging. Radiology. 1997;205(2):551–8.CrossRefPubMed
4.
Gold GE, Burstein D, Dardzinski B, Lang P, Boada F, Mosher T, et al. MRI of articular cartilage in OA: novel pulse sequences and compositional/functional markers. Osteoarthritis Cartilage. 2006;14(Suppl A):A76–86.CrossRefPubMed
5.
LiMarzi GM, O’Dell MC, Scherer K, Pettis C, Wasyliw CW, Bancroft LW. Magnetic resonance arthrography of the wrist and elbow. Magn Reson Imaging Clin N Am. 2015;23(3):441–55.CrossRefPubMed
6.
Naraghi A, White LM. MRI of labral and chondral lesions of the hip. AJR Am J Roentgenol. 2015;205(3):479–90.CrossRefPubMed
7.
Sebro R, Oliveira A, Palmer WE. MR arthrography of the shoulder: technical update and clinical applications. Semin Musculoskelet Radiol. 2014;18(4):352–64.CrossRefPubMed
8.
Chundru U, Riley GM, Steinbach LS. Magnetic resonance arthrography. Radiol Clin N Am. 2009;47(3):471–94.CrossRefPubMed
9.
Kalke RJ, Di Primio GA, Schweitzer ME. MR and CT arthrography of the knee. Semin Musculoskelet Radiol. 2012;16(1):57–68.CrossRefPubMed
10.
Bashir A, Gray ML, Burstein D. Gd-DTPA2- as a measure of cartilage degradation. Magn Reson Med. 1996;36(5):665–73.CrossRefPubMed
11.
Maroudas A, Evans H. A study of ionic equilibria in cartilage. Connect Tissue Res. 1972;1(1):69–77.CrossRef
12.
Broderick JM, Baker JF, Walsh P, Mulhall KJ. In vitro assessment of primary human chondrocyte viability following treatment with intra-articular contrast media and local anaesthetic. 4th Annual Scientific Meeting of the International Society of Hip Arthroscopy. Boston, MA. 2012.
13.
Cravino M, Marmotti A, Castoldi F, Rossi R, Giacalone F. Monolayer culture’s behaviour of articular chondrocytes and sinoviocytes to the gadolinium exposure. Minerva Ortop Traumatol. 2008;59(2):99–107.
14.
Greisberg JK, Wolf JM, Wyman J, Zou L, Terek RM. Gadolinium inhibits thymidine incorporation and induces apoptosis in chondrocytes. J Orthop Res. 2001;19(5):797–801.CrossRefPubMed
15.
Midura S, Schneider E, Sakamoto FA, Rosen GM, Winalski CS, Midura RJ. In vitro toxicity in long-term cell culture of MR contrast agents targeted to cartilage evaluation. Osteoarthritis Cartilage. 2014;22(9):1337–45.CrossRefPubMed
16.
Baker JF, Mulhall KJ. Local anaesthetics and chondrotoxicity: what is the evidence? Knee Surg Sports Traumatol Arthrosc. 2012;20(11):2294–301.CrossRefPubMed
17.
Gomoll AH, Yanke AB, Kang RW, Chubinskaya S, Williams JM, Bach BR, et al. Long-term effects of bupivacaine on cartilage in a rabbit shoulder model. Am J Sports Med. 2009;37(1):72–7.CrossRefPubMed
18.
Seshadri V, Coyle CH, Chu CR. Lidocaine potentiates the chondrotoxicity of methylprednisolone. Arthroscopy. 2009;25(4):337–47.CrossRefPubMed
19.
Grobner T. Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4):1104–8.CrossRefPubMed
20.
Lin SP, Brown JJ. MR contrast agents: physical and pharmacologic basics. J Magn Reson Imaging. 2007;25(5):884–99.CrossRefPubMed
21.
Wertman R, Altun E, Martin DR, Mitchell DG, Leyendecker JR, O’Malley RB, et al. Risk of nephrogenic systemic fibrosis: evaluation of gadolinium chelate contrast agents at four American universities. Radiology. 2008;248(3):799–806.CrossRefPubMed
22.
Marckmann P. An epidemic outbreak of nephrogenic systemic fibrosis in a Danish hospital. Eur J Radiol. 2008;66(2):187–90.CrossRefPubMed
23.
McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Murray DL, Thielen KR, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology. 2015;275(3):772–82.CrossRefPubMed
24.
Winalski CS, Shortkroff S, Mulkern RV, Schneider E, Rosen GM. Magnetic resonance relaxivity of dendrimer-linked nitroxides. Magn Reson Med. 2002;48(6):965–72.CrossRefPubMed
25.
Winalski CS, Shortkroff S, Schneider E, Yoshioka H, Mulkern RV, Rosen GM. Targeted dendrimer-based contrast agents for articular cartilage assessment by MR imaging. Osteoarthritis Cartilage. 2008;16(7):815–22.CrossRefPubMed
26.
King KB, Kimura JH. The establishment and characterization of an immortal cell line with a stable chondrocytic phenotype. J Cell Biochem. 2003;89(5):992–1004.CrossRefPubMed
27.
ISS 2015 Annual meeting Maui, HI: Scientific paper presentations. Skeletal Radiol. 2016;45(6):857–864.
28.
Mukhopadhyay K, Lefebvre V, Zhou G, Garofalo S, Kimura JH, de Crombrugghe B. Use of a new rat chondrosarcoma cell line to delineate a 119-base pair chondrocyte-specific enhancer element and to define active promoter segments in the mouse pro-alpha 1(II) collagen gene. J Biol Chem. 1995;270(46):27711–9.CrossRefPubMed
29.
Bosman AW, Janssen RAJ, Miejer EW. Five generations of nitroxyl-functionalized dendrimers. Macromolecules. 1997;30(12):3606–11.CrossRef
30.
Sgouras D, Duncan R. Methods for the evaluation of biocompatibility of soluble synthetic polymers which have potential for biomedical use: 1? Use of the tetrazolium-based colorimetric assay (MTT) as a preliminary screen for evaluation of in vitro cytotoxicity. J Mater Sci Mater Med. 1990;1(2):61–8.CrossRef
31.
Braun HJ, Wilcox-Fogel N, Kim HJ, Pouliot MA, Harris AH, Dragoo JL. The effect of local anesthetic and corticosteroid combinations on chondrocyte viability. Knee Surg Sports Traumatol Arthrosc. 2012;20(9):1689–95.CrossRefPubMed
32.
MacMahon PJ, Eustace SJ, Kavanagh EC. Injectable corticosteroid and local anesthetic preparations: a review for radiologists. Radiology. 2009;252(3):647–61.CrossRefPubMed
33.
Piper SL, Kramer JD, Kim HT, Feeley BT. Effects of local anesthetics on articular cartilage. Am J Sports Med. 2011;39(10):2245–53.CrossRefPubMed
34.
Rao AJ, Johnston TR, Harris AH, Smith RL, Costouros JG. Inhibition of chondrocyte and synovial cell death after exposure to commonly used anesthetics: chondrocyte apoptosis after anesthetics. Am J Sports Med. 2014;42(1):50–8.CrossRefPubMed
35.
Chu CR, Coyle CH, Chu CT, Szczodry M, Seshadri V, Karpie JC, et al. In vivo effects of single intra-articular injection of 0.5% bupivacaine on articular cartilage. J Bone Joint Surg Am. 2010;92(3):599–608.CrossRefPubMed
36.
Chu CR, Izzo NJ, Papas NE, Fu FH. In vitro exposure to 0.5% bupivacaine is cytotoxic to bovine articular chondrocytes. Arthroscopy. 2006;22(7):693–9.CrossRefPubMed
37.
Caron MM, Emans PJ, Coolsen MM, Voss L, Surtel DA, Cremers A, et al. Redifferentiation of dedifferentiated human articular chondrocytes: comparison of 2D and 3D cultures. Osteoarthritis Cartilage. 2012;20(10):1170–8.CrossRefPubMed
38.
Kopka L, Funke M, Fischer U, Keating D, Oestmann J, Grabbe E. MR arthrography of the shoulder with gadopentetate dimeglumine: influence of concentration, iodinated contrast material, and time on signal intensity. AJR Am J Roentgenol. 1994;163(3):621–3.CrossRefPubMed
39.
Masi JN, Newitt D, Sell CA, Daldrup-Link H, Steinbach L, Majumdar S, et al. Optimization of gadodiamide concentration for MR arthrography at 3 T. AJR Am J Roentgenol. 2005;184(6):1754–61.CrossRefPubMed
40.
Bozyczko-Coyne D, McKenna BW, Connors TJ, Neff NT. A rapid fluorometric assay to measure neuronal survival in vitro. J Neurosci Methods. 1993;50(2):205–16.CrossRefPubMed
41.
Rahmouni A, Mathieu D, Chambon C, Dao TH, Hernigou P, Vasile N. Intraarticular tolerability and kinetics of gadolinium tetra-azacyclododecane tetraacetic acid. Acad Radiol. 1995;2(5):413–7.CrossRefPubMed
42.
43.
Engel A. Magnetic resonance knee arthrography. Enhanced contrast by gadolinium complex in the rabbit and in humans. Acta Orthop Scand Suppl. 1990;240:1–57.PubMed
Metadata
Title
In vitro chondrocyte toxicity following long-term, high-dose exposure to Gd-DTPA and a novel cartilage-targeted MR contrast agent
Authors
Sharon Midura
Erika Schneider
Gerald M. Rosen
Carl S. Winalski
Ronald J. Midura
Publication date
01-01-2017
Publisher
Springer Berlin Heidelberg
Published in
Skeletal Radiology / Issue 1/2017
Print ISSN: 0364-2348
Electronic ISSN: 1432-2161
DOI
https://doi.org/10.1007/s00256-016-2502-8

Other articles of this Issue 1/2017

Skeletal Radiology 1/2017 Go to the issue

Browser's Notes

Browser‘s Notes

Scientific Article

Delaminating infraspinatus tendon tears with differential retraction: imaging features and surgical relevance

Case Report

Detection of incorrect manufacturer labelling of hip components

Scientific Article

Comparing an accelerated 3D fast spin-echo sequence (CS-SPACE) for knee 3-T magnetic resonance imaging with traditional 3D fast spin-echo (SPACE) and routine 2D sequences

Case Report

Calcified synovial metastasis in the knee from renal cell carcinoma: a case report

Scientific Article

Freehand direct arthrography of the shoulder using near real-time guidance in an open 1.0-T MRI scanner