Background & Aims

Osteoarthritis (OA) is a chronic degenerative joint disease which is associated with gradual progressive loss of articular cartilage, resulting in functional disability (OARSI, 2017). OA affected about 528 million people in 2019, a 113% rise since 1990 [1] and expected to increase 7-fold by 2030 [2]. Joint pain due to OA is the most common type of pain worldwide, accounting for maximum disability (IASP, 2020). Intra-articular monoiodoacetate (MIA) administration inhibits glyceraldehyde-3-phosphate dehydrogenase in the glycolysis pathway, resulting in the apoptosis of chondrocytes [3]. Transforming Growth Factor-? (TGF-?) is a pleiotropic cytokine with a dual role that acts either as a hormone or, more commonly, as a local mediator to regulate a wide range of biological functions [4]. Their effect on articular cartilage is not fully known. The aim is to determine the role of TGF-? inhibitor in attenuating the progression of cartilage damage in a chemically-induced rat model of OA.

Methods

Male Sprague-Dawley rats (250 g, approximately; n = 60) were divided into three equal groups. The control group received intra-articular saline in the right knee joint, whereas the arthritic group received 50?g of 1.5% MIA and the third group was co-administered MIA and TGF- ? inhibitor [Disitertide (Tocris; UK. Catalog number: 7717)] using a Hamilton syringe under anesthesia. These rats were then tested periodically from day 0 to day 21. Referred secondary nociception was assessed using Hargreaves instrument and static weight bearing by Incapacitance meter. Finally, rats were euthanized and knee joints collected after perfusion-fixation. The joints were decalcified and processed for histological staining with Hematoxylin & Eosin, Safranin O, Toluidine blue and Masson’s Trichrome. Histomorphometric analysis such as articular cartilage thickness and number of chondrocytes were performed. Histological scoring was made using OARSI guidelines [5,6] and Modified Mankin Scoring [7]

Results

The saline group had no significant change, while the arthritic group showed nociception, which was at its maximum on day 14. The third group showed significant improvement on day 14. Weight bearing was significantly reduced on day 4, followed by reduced weight bearing from day 7 to day 21 in the arthritic group, whereas the third group showed improvement from day 4 till day 14, though this beneficial effect dissipated by day 21. Histomorphometric analysis of cartilage in all three groups showed increased cartilage thickness in the MIA group, and this was attenuated after TGF-?i administration. The scoring of parameters of damage to articular cartilage by three different methods showed that MIA had the maximum damage, whereas saline-treated rats had none. Articular cartilage damage was partially reversed by TGF-? inhibitor.

Conclusions

Transforming Growth Factor-? (TGF-?) inhibitor improves joint function with partial restoration of cartilage morphology in the MIA rat model of osteoarthritis. This promising finding needs further study in different rodent models of OA.

References

1. GBD 2019: Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. https://vizhub.healthdata.org/gbd-results/.
2. Martel-Pelletier, J., Barr, A. J., Cicuttini, F. M., Conaghan, P. G., Cooper, C., Goldring, M. B., Goldring, S. R., Jones, G., Teichtahl, A. J., & Pelletier, J. P. (2016). Osteoarthritis. Nature Reviews. Disease Primers, 2(1). https://doi.org/10.1038/nrdp.2016.72
3. Pitcher, T., Sousa-Valente, J., & Malcangio, M. (2016). The monoiodoacetate model of osteoarthritis pain in the mouse. Journal of Visualized Experiments: JoVE, 111. https://doi.org/10.3791/53746-v
4. Alberts, B., Heald, R., Johnson, A., Morgan, D., Raff, M., & Walter, K. R. A. (2022). Molecular biology of THE CELL (B. Twitchell, Ed.; 7th ed.). W.W. Norton & Company.
5. Pritzker, K. P. H., Gay, S., Jimenez, S. A., Ostergaard, K., Pelletier, J.-P., Revell, P. A., Salter, D., & van den Berg, W. B. (2006). Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis and Cartilage, 14(1), 13–29.
6. Gerwin, N., Bendele, A. M., Glasson, S., & Carlson, C. S. (2010). The OARSI histopathology initiative – recommendations for histological assessments of osteoarthritis in the rat. Osteoarthritis and Cartilage, 18, S24–S34. https://doi.org/10.1016/j.joca.2010.05.030
7. Mankin, H. J., Dorfman, H., Lippiello, L., & Zarins, A. (1971). Biochemical and metabolic abnormalities in articular cartilage from osteo-arthritic human hips. II. Correlation of morphology with biochemical and metabolic data. The Journal of Bone and Joint Surgery. American Volume, 53(3), 523–537.

Presenting Author

Hari Hara Hanusun

Poster Authors

HARI HARA HANUSUN N

MD

All India Institute of Medical Sciences, New Delhi

Lead Author

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Topics

  • Models: Acute Pain