Dose-dependent effect of betamethasone on the articular cartilage (experimental study)

Introduction. Glucocorticosteroid injections have been widely used in clinical practice. Betamethasone is one of the agents of this group of drugs. Its efficacy and therapeutic effect with intra-articular administration are undeniable. There are special instructions on the dosage and frequency of use of the drug but unfortunately there are cases of its wrong administration. There is also an evidence of an adverse effect on cartilage both of the drug itself and its combination with local anesthetics.

Aim. Evaluation of the results of different weekly intra-articular protocols of betamethasone administration on histological preparations of rabbit knee joints.

Methods. Histological preparations of the right knee joints of three groups of rabbits were studied: after one, three, and six administrations of betamethason per week and the control intact left knee joints.

Results. Histological preparations of the control group and the group with a single weekly administration of the drug did not have any changes in the structure of diarthrosis. Dystrophic and necrotic changes affecting all morphological components were observed in the joints of animals that received intra-articular injections of betamethason three times a week (compared to a single injection, the area of dystrophy and necrosis of the cartilage was greater by 10.05 ± 0.75 % (p less 0.05), of subchondral bone by 8.11 ± 0.5 % (p less 0.001), and of synovium by 6.25 ± 0.32 % (p less 0.05). The group with six injections of the drug per week had the most pronounced changes. The area of necrotic changes of the cartilage was greater by 6.39 ± 0.75 % than in the group with three injections per week (p less 0.001), of subchondral bone by 11.18 ± 0.5 % (p less 0.001), of synovium by 6.12 ± 0.32 % (p less 0.001).

Discussion. Inflammatory cell infiltration of joint structures was absent in all cases. It indicates an aseptic nature of tissue necrosis. Evidence has been obtained between the increase in the frequency of intra-articular injections of betamethasone and the severity of dystrophic and necrotic changes in all morphological components of the joint.

1. Farkas B., Kvell K., Czömpöly T., Illés T., Bárdos T. Increased chondrocyte death after steroid and local anesthetic combination. Clin. Orthop. Relat. Res., 2010, vol. 468, no. 11, pp. 3112-3120. DOI: 10.1007/s11999-010-1443-0

2. Dragoo J.L., Danial C.M., Braun H.J., Pouliot M.A., Kim H.J. The chondrotoxicity of single-dose corticosteroids. Knee Surg. Sports Traumatol. Arthrosc., 2012, vol. 20, no. 9, pp. 1809-1814. DOI: 10.1007/s00167-011-1820-6

3. Kabalyk M.A., Nevzorova V.A., Dubov V.S., Tsygankov M.A., Kovalenko T.S. Molekuliarnye i kletochnye effekty vnutrisustavnogo vvedeniia betametazona pri eksperimentalnom osteoartrite [Molecular and cellular effects of intraarticular injection of betamethasone in experimental osteoarthritis]. Genij Ortopedii, 2020, vol. 26, no. 1, pp. 65-71. DOI: 10.18019/1028-4427-2020-26-1-65-71 (in Russian)

4. Davis D., Cyriac M., Ge D., You Z., Savoie F.H. In vitro cytotoxic effects of benzalkonium chloride in corticosteroid injection suspension. J. Bone Joint Surg. Am., 2010, vol. 92, no. 1, pp. 129-137. DOI: 10.2106/JBJS.H.01561

5. Korzhevskii D.E. Kratkoe izlozhenie osnov gistologicheskoi tekhniki dlia vrachei i laborantov-gistologov [Summary of histological technique basics for physicians and histology technicians]. SPb., Kroft, 2005, 48 p. (in Russian)

6. Pakht A.V., Manizer N.M. Osobennosti obrabotki kostnoi tkani [Special characteristics of bone tissue processing]. Biblioteka Patologoanatoma, 2008. Issue 89: Izbrannye voprosy patologoanatomicheskoi tekhniki [Selected questions of the pathoanatomical technique], pp. 6-11. (in Russian)

7. Stefanov S.B. Morfometricheskaia setka sluchainogo shaga kak sredstvo uskorennogo izmereniia elementov morfogeneza [Morphometric grid of a random step as a means of accelerated measurement of morphogenesis elements]. Tsitologiia, 1974, vol. 16, no. 6, pp. 785-787. (in Russian)

8. Lutfi A.M., Kosel K. Effects of intra-articularly administered corticosteroids and salicylates on the surface structure of articular cartilage. J. Anat., 1978, vol. 127, pt. 2, pp. 393-402.

9. Albano M.B., Skroch G.P., Ioshii S.O., Grahels X.S., de Alencar P.G., Matias J.E. Computerized photocolorimetric analysis of the effects of intraarticular betamethasone on the proteoglycan concentration of leporine knee cartilage matrix: influence of the number of intraarticular injections. Rev. Col. Bras. Cir., 2009, vol. 36, no. 3, pp. 256-260.

10. Cecil D.L., Johnson K., Rediske J., Lotz M., Schmidt A.M., Terkeltaub R. Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products. J. Immunol., 2005, vol. 175, no. 12, pp. 8296-8302. DOI: 10.4049/jimmunol.175.12.8296

11. Pitsillides A.A., Beier F. Cartilage biology in osteoarthritis – lessons from developmental biology. Nat. Rev. Rheumatol., 2011, vol. 7, no. 11, pp. 654-663. DOI: 10.1038/nrrheum.2011.129

12. Martel-Pelletier J., Pelletier J.P. New insights into the major pathophysiological processes responsible for the development of osteoarthritis. Semin. Arthritis Rheum., 2005, vol. 34, no. 6, Suppl. 2, pp. 6-8. DOI: 10.1016/j.semarthrit.2004.03.003

13. Loeser R.F. Aging processes and the development of osteoarthritis. Curr. Opin. Rheumatol., 2013, vol. 25, no. 1, pp. 108-113. DOI: 10.1097/BOR.0b013e32835a9428

14. Samuels J., Krasnokutsky S., Abramson S.B. Osteoarthritis: a tale of three tissues. Bull. NYU Hosp. Jt. Dis., 2008, vol. 66, no. 3, pp. 244-250.

15. Scanzello C.R. Pathologic and pathogenic processes in osteoarthritis: the effects of synovitis. HSS J., 2012, vol. 8, no. 1, pp. 20-22. DOI: 10.1007/s11420-011-9228-x

16. Richardson D.W., Dodge G.R. Dose-dependent effects of corticosteroids on the expression of matrix-related genes in normal and cytokine-treated articular chondrocytes. Inflamm. Res., 2003, vol. 52, no. 1, pp. 39-49. DOI: 10.1007/s000110300012

17. Ishikawa K. Effect of intra-articular corticosteroid on the meniscus. A histological and histochemical study in rabbit knees. J. Bone Joint Surg. Am., 1981, vol. 63, no. 1, pp. 120-130.

18. Behrens F., Shepard N., Mitchell N. Alterations of rabbit articular cartilage by intra-articular injections of glucocorticoids. J. Bone Joint Surg. Am., 1975, vol. 57, no. 1, pp. 70-76.

19. Chunekamrai S., Krook L.P., Lust G., Maylin G.A. Changes in articular cartilage after intra-articular injections of methylprednisolone acetate in horses. Am. J. Vet. Res., 1989, vol. 50, no. 10, pp. 1733-1741.

20. Mankin H.J., Conger K.A. The acute effects of intra-articular hydrocortisone on articular cartilage in rabbits. J. Bone Joint Surg. Am., 1966, vol. 48, no. 7, pp. 1383-1388.

21. Murray R.C., DeBowes R.M., Gaughan E.M., Zhu C.F., Athanasiou K.A. The effects of intra-articular methylprednisolone and exercise on the mechanical properties of articular cartilage in the horse. Osteoarthritis Cartilage, 1998, vol. 6, no. 2, pp. 106–114. DOI: 10.1053/joca.1997.0100

22. Salter R.B., Gross A., Hall J.H. Hydrocortisone arthropathy – an experimental investigation. Can. Med. Assoc. J., 1967, vol. 97, no. 8, pp. 374-377.

23. Pelletier J.P., Martel-Pelletier J. Protective effects of corticosteroids on cartilage lesions and osteophyte formation in the Pond-Nuki dog model of osteoarthritis. Arthritis Rheum., 1989, vol. 32, no. 2, pp. 181-193. DOI: 10.1002/anr.1780320211

24. Pelletier J.P., Mineau F., Raynauld J.P., Woessner J.F. Jr, Gunja-Smith Z., Martel-Pelletier J. Intraarticular injections with methylprednisolone acetate reduce osteoarthritic lesions in parallel with chondrocyte stromelysin synthesis in experimental osteoarthritis. Arthritis Rheum., 1994, vol. 37, no. 3, pp. 414-423. DOI: 10.1002/art.1780370316

25. Pelletier J.P., DiBattista J.A., Raynauld J.P., Wilhelm S., Martel-Pelletier J. The in vivo effects of intraarticular corticosteroid injections on cartilage lesions, stromelysin, interleukin-1, and oncogene protein synthesis in experimental osteoarthritis. Lab. Invest., 1995, vol. 72, no. 5, pp. 578-586.

26. Huebner K.D., Shrive N.G., Frank C.B. Dexamethasone inhibits inflammation and cartilage damage in a new model of post-traumatic osteoarthritis. J. Orthop. Res., 2014, vol. 32, no. 4, pp. 566-572. DOI: 10.1002/jor.22568

27. Zhang Z., Wei X., Gao J., Zhao Y., Zhao Y., Guo L., Chen C., Duan Z., Li P., Wei L. Intra-articular injection of cross-linked hyaluronic aciddexamethasone hydrogel attenuates osteoarthritis: an experimental study in a rat model of osteoarthritis. Int. J. Mol. Sci., 2016, vol. 17, no. 4, pp. 411. DOI: 10.3390/ijms17040411

28. Lu Y.C., Evans C.H., Grodzinsky A.J. Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines. Arthritis Res. Ther., 2011, vol. 13, no. 5, pp. R142. DOI: 10.1186/ar3456

29. Bodick N., Williamson T., Strand V., Senter B., Kelley S., Boyce R., Lightfoot-Dunn R. Local effects following single and repeat intra-articular injections of triamcinolone acetonide extended-release: results from three nonclinical toxicity studies in dogs. Rheumatol. Ther., 2018, vol. 5, no. 2, pp. 475-498. DOI: 10.1007/s40744-018-0125-3