A human osteoarthritis mimicking goat cartilage explant-based disease model for drug screening

Main Article Content

Arijit Bhattacharjee
Dhirendra Katti

Abstract

Osteoarthritis (OA) is the most prevalent human joint disease with a massive global disease burden. Despite having a large socioeconomic burden, OA remains a neglected disease with no clinically approved disease modifying therapies. One of the key reasons for this is that the available disease models poorly recapitulate human OA-like traits possibly because of the challenge of mimicking the disease in an ECM rich cartilage tissue. Therefore, in this study, we report the establishment and validation of a clinically relevant ex vivo OA model using IL1β treated goat articular cartilage explants. Treatment with IL1β induced OA-like traits in goat cartilage explants and caused a shift in cartilage homeostasis towards enhanced catabolism, resulting in higher matrix degradation, overexpression of degradative and inflammatory mediators and chondrocyte hypertrophy. We then validated the developed disease model for drug response using three different drugs viz. BMP7, rapamycin and celecoxib, all of which demonstrated concentration-dependent disease amelioration in the explant model. Finally, we evaluated the translational relevance of the developed ex vivo OA model by comparing it with late-stage OA patient samples and observed a striking resemblance in terms of matrix degradation, expression of degradative enzymes, chondrocyte hypertrophy and inflammation. Overall, the goat ex vivo OA model elicited a biological response to cytokine treatment which mirrors human OA-like traits that may reduce discordance between preclinical and clinical studies in OA drug development.

Article Details

How to Cite
Bhattacharjee, A. and Katti, D. (2022) “A human osteoarthritis mimicking goat cartilage explant-based disease model for drug screening”, ALTEX - Alternatives to animal experimentation. doi: 10.14573/altex.2107071.
Section
Articles
References

Aigner, T., Fundel, K., Saas, J. et al. (2006). Large‐scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology 54, 3533-3544 doi:10.1002/art.22174.

Barbosa, I., Garcia, S., Barbier-Chassefière, V. et al. (2003). Improved and simple micro assay for sulfated glycosaminoglycans quantification in biological extracts and its use in skin and muscle tissue studies. Glycobiology 13, 647-653 doi:10.1093/glycob/cwg082.

Bhattacharjee, A., Kumar, K., Arora, A. et al. (2016). Fabrication and characterization of pluronic modified poly (hydroxybutyrate) fibers for potential wound dressing applications. Materials Science and Engineering: C 63, 266-273 doi:10.1016/j.msec.2016.02.074.

Bhattacharjee, A. and Katti, D. S. (2018). Pore alignment in gelatin scaffolds enhances chondrogenic differentiation of infrapatellar fat pad derived mesenchymal stromal cells. ACS Biomaterials Science & Engineering 5, 114-125 doi:10.1021/acsbiomaterials.8b00246

Caramés, B., Hasegawa, A., Taniguchi, N. et al. (2012). Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Annals of the Rheumatic Diseases 71, 575-581 doi:10.1136/annrheumdis-2011-200557

Chan, B., Fuller, E., Russell, A. et al. (2011). Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis. Osteoarthritis and Cartilage 19, 874-885 doi:10.1016/j.joca.2011.04.014.

Chang, S. H., Mori, D., Kobayashi, H. et al. (2019). Excessive mechanical loading promotes osteoarthritis through the gremlin-1–NF-κB pathway. Nature Communications 10, 1-13 doi:10.1038/s41467-019-09491-5.

Chubinskaya, S., Hurtig, M. and Rueger, D. C. (2007). OP-1/BMP-7 in cartilage repair. International Orthopaedics 31, 773-781 doi:10.1007/s00264-007-0423-9

Cope, P., Ourradi, K., Li, Y. et al. (2019). Models of osteoarthritis: The good, the bad and the promising. Osteoarthritis and Cartilage 27, 230-239 doi:10.1016/j.joca.2018.09.016

Corciulo, C., Lendhey, M., Wilder, T. et al. (2017). Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression. Nature Communications 8, 1-13 doi:10.1038/ncomms15019.

Ding, L., Heying, E., Nicholson, N. et al. (2010). Mechanical impact induces cartilage degradation via mitogen activated protein kinases. Osteoarthritis and Cartilage 18, 1509-1517 doi:10.1016/j.joca.2010.08.014

Feng, Z., Li, X., Lin, J. et al. (2017). Oleuropein inhibits the il-1β-induced expression of inflammatory mediators by suppressing the activation of nf-κb and mapks in human osteoarthritis chondrocytes. Food and Function 8, 3737-3744. doi:10.1039/c7fo00823f

Gabriel, N., Innes, J. F., Caterson, B. et al. (2010). Development of an in vitro model of feline cartilage degradation. Journal of Feline Medicine and Surgery 12, 614-620 doi:10.1016/j.jfms.2010.03.007

Glyn-Jones, S., Palmer, A., Agricola, R. et al. (2015). Osteoarthritis. The Lancet 386, 376-387 doi:10.1016/S0140-6736(19)30417-9.

Han, B., Li, Q., Wang, C. et al. (2019). Decorin regulates the aggrecan network integrity and biomechanical functions of cartilage extracellular matrix. ACS Nano 13, 11320-11333 doi:10.1021/acsnano.9b04477

Hunter, D. J., Pike, M. C., Jonas, B. L. et al. (2010). Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskeletal Disorders 11, 1-8 doi:10.1186/1471-2474-11-232

Hunter, D. J., March, L. and Chew, M. (2020). Osteoarthritis in 2020 and beyond: A lancet commission. The Lancet 396, 1711-1712 doi:10.1016/S0140-6736(20)32230-3.

Johnson, C. I., Argyle, D. J. and Clements, D. N. (2016). In vitro models for the study of osteoarthritis. The Veterinary Journal 209, 40-49 doi:10.1016/j.tvjl.2015.07.011

Kamisan, N., Naveen, S. V., Ahmad, R. E. et al. (2013). Chondrocyte density, proteoglycan content and gene expressions from native cartilage are species specific and not dependent on cartilage thickness: A comparative analysis between rat, rabbit and goat. BMC Veterinary Research 9, 1-9 doi:10.1186/1746-6148-9-62

Kapoor, M., Martel-Pelletier, J., Lajeunesse, D. et al. (2011). Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nature Reviews Rheumatology 7, 33-42 doi:10.1038/nrrheum.2010.196

Karsdal, M., Michaelis, M., Ladel, C. et al. (2016). Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: Lessons learned from failures and opportunities for the future. Osteoarthritis and Cartilage 24, 2013-2021 doi:10.1016/j.joca.2016.07.017

Le Graverand-Gastineau, M.-P. H. (2009). OA clinical trials: Current targets and trials for OA. Choosing molecular targets: What have we learned and where we are headed? Osteoarthritis and Cartilage 17, 1393-1401 doi:10.1016/j.joca.2009.04.009

Li, Q., Han, B., Wang, C. et al. (2020). Decorin mediates cartilage matrix degeneration and fibrillation in post-traumatic osteoarthritis. Arthritis & Rheumatology

doi:10.1002/art.41254

Li, Y., Wang, Y., Chubinskaya, S. et al. (2015). Effects of insulin-like growth factor-1 and dexamethasone on cytokine-challenged cartilage: Relevance to post-traumatic osteoarthritis. Osteoarthritis and Cartilage 23, 266-274 doi:10.1016/j.joca.2014.11.006

Little, C., Smith, M., Cake, M. et al. (2010). The OARSI histopathology initiative–recommendations for histological assessments of osteoarthritis in sheep and goats. Osteoarthritis and Cartilage 18, S80-S92 doi:10.1016/j.joca.2010.04.016

Little, C. B. and Hunter, D. J. (2013). Post-traumatic osteoarthritis: From mouse models to clinical trials. Nature Reviews Rheumatology 9, 485-497 doi:10.1038/nrrheum.2013.72

Lohmander, L. S. and Roos, E. M. (2019). Disease modification in oa—will we ever get there? Nature Reviews Rheumatology 15, 133-135 doi:10.1038/s41584-019-0174-1

Lories, R. J. (2008). Joint homeostasis, restoration, and remodeling in osteoarthritis. Best Practice & Research Clinical Rheumatology 22, 209-220 doi:10.1016/j.berh.2007.12.001

Marotta, M. and Martino, G. (1985). Sensitive spectrophotometric method for the quantitative estimation of collagen. Analytical Biochemistry 150, 86-90 doi:10.1016/0003-2697(85)90443-9

McCoy, A. M. (2015). Animal models of osteoarthritis: Comparisons and key considerations. Veterinary Pathology 52, 803-818 doi:10.1177/0300985815588611

McNulty, A. L., Rothfusz, N. E., Leddy, H. A. et al. (2013). Synovial fluid concentrations and relative potency of interleukin‐1 alpha and beta in cartilage and meniscus degradation. Journal of Orthopaedic Research 31, 1039-1045 doi:10.1002/jor.22334

Mengshol, J. A., Vincenti, M. P. and Brinckerhoff, C. E. (2001). IL-1 induces collagenase-3 (MMP-13) promoter activity in stably transfected chondrocytic cells: Requirement for runx-2 and activation by p38 mapk and JNK pathways. Nucleic Acids Research 29, 4361-4372 doi:10.1093/nar/29.21.4361

Mobasheri, A., Rayman, M. P., Gualillo, O. et al. (2017). The role of metabolism in the pathogenesis of osteoarthritis. Nature Reviews Rheumatology 13, 302-311 doi:10.1038/nrrheum.2017.50

Murab, S., Chameettachal, S., Bhattacharjee, M. et al. (2013). Matrix-embedded cytokines to simulate osteoarthritis-like cartilage microenvironments. Tissue Engineering Part A 19, 1733-1753. doi:10.1089/ten.tea.2012.0385

Netzel-Arnett, S., Mallya, S. K., Nagase, H. et al. (1991). Continuously recording fluorescent assays optimized for five human matrix metalloproteinases. Analytical Biochemistry 195, 86-92 doi:10.1016/0003-2697(91)90299-9

Occhetta, P., Mainardi, A., Votta, E. et al. (2019). Hyperphysiological compression of articular cartilage induces an osteoarthritic phenotype in a cartilage-on-a-chip model. Nature Biomedical Engineering 3, 545-557 doi:10.1038/s41551-019-0406-3

Robinson, W. H., Lepus, C. M., Wang, Q. et al. (2016). Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nature Reviews Rheumatology 12, 580-592 doi:10.1038/nrrheum.2016.136

Roos, E. M. and Arden, N. K. (2016). Strategies for the prevention of knee osteoarthritis. Nature Reviews Rheumatology 12, 92-101 doi:10.1038/nrrheum.2015.135

Saito, T. and Tanaka, S. (2017). Molecular mechanisms underlying osteoarthritis development: Notch and nf-κb. Arthritis Research & Therapy 19, 1-7 doi:10.1186/s13075-017-1296-y

Schneider, C. A., Rasband, W. S. and Eliceiri, K. W. (2012). NIH image to Imagej: 25 years of image analysis. Nature Methods 9, 671-675 doi:10.1038/nmeth.2089

Shi, Y., Hu, X., Cheng, J. et al. (2019). A small molecule promotes cartilage extracellular matrix generation and inhibits osteoarthritis development. Nature Communications 10, 1-14 doi:10.1038/s41467-019-09839-x

Siengdee, P., Radeerom, T., Kuanoon, S. et al. (2015). Effects of corticosteroids and their combinations with hyaluronanon on the biochemical properties of porcine cartilage explants. BMC Veterinary Research 11, 1-11 doi: 10.1186/s12917-015-0611-6

Thudium, C. S., Engstrom, A., Groen, S. S. et al. (2019). An ex vivo tissue culture model of cartilage remodeling in bovine knee explants. Journal of Visualized Experiments: JoVE doi:10.3791/59467

Ulivi, V., Giannoni, P., Gentili, C. et al. (2008). P38/nf‐kb‐dependent expression of cox‐2 during differentiation and inflammatory response of chondrocytes. Journal of Cellular Biochemistry 104, 1393-1406. doi:10.1002/jcb.21717

Van der Kraan, P. and Van den Berg, W. (2012). Chondrocyte hypertrophy and osteoarthritis: Role in initiation and progression of cartilage degeneration? Osteoarthritis and Cartilage 20, 223-232 doi:10.1016/j.joca.2011.12.003

Wang, B., Chen, P., Jensen, A.-C. B. et al. (2009). Suppression of MMP activity in bovine cartilage explants cultures has little if any effect on the release of aggrecanase-derived aggrecan fragments. BMC Research Notes 2, 1-8 doi:10.1186/1756-0500-2-259

Wieland, H. A., Michaelis, M., Kirschbaum, B. J. et al. (2005). Osteoarthritis—an untreatable disease? Nature Reviews Drug Discovery 4, 331-344 doi:10.1038/nrd1693.

Zhang, W., Ouyang, H., Dass, C. R. et al. (2016). Current research on pharmacologic and regenerative therapies for osteoarthritis. Bone Research 4, 1-14 doi:10.1038/boneres.2015.40

Zweers, M. C., de Boer, T. N., van Roon, J. et al. (2011). Celecoxib: Considerations regarding its potential disease-modifying properties in osteoarthritis. Arthritis Research & Therapy 13, 1-11 doi:10.1186/ar3437