Abstract
Chronic arthritis caused by the Chikungunya virus (CHIKV) represents a serious global health problem, with a significant proportion of patients developing debilitating and persistent arthropathy. This review critically analyzes the biochemical mechanisms underlying the irreversible destruction of the joint extracellular matrix (ECM), going beyond the acute viral inflammatory response. The objective is to describe the current evidence on the biochemical mechanisms, with an emphasis on the MMP/TIMP imbalance, that lead to ECM degradation in chronic CHIKV arthropathy. The main findings highlight that CHIKV, thanks to its tropism for chondrocytes mediated by receptors such as Mxra8 and CD147, triggers a “proteolytic storm.” This involves sustained overexpression of MMPs (especially MMP-1, -9, -13) and a paradoxical imbalance of TIMPs, where elevated levels of TIMP-2 are associated with chronicity. Degradation follows an orderly sequence: initial loss of agrecan by ADAMTS, followed by irreversible lysis of type II collagen. Finally, chondrocyte apoptosis (via IGFBP-3) and the generation of matrikines (such as the 32-mer fragment of aggrecan) that activate nociceptors via TLR2 explain chondropenia and chronic pain. It is concluded that CHIKV arthropathy is essentially a disease of the ECM, where biochemical degradation and pain signaling are mutually perpetuated.
References
1. Costa ACS, dos Santos AF, Albuquerque GCL, da Rosa MM, Taniele‐Silva J, Duarte ALBP, et al. TIMP‐2 as a Potential Indicator of Persistent Arthralgia in Chikungunya: Evidence From a Brazilian Cohort Study. J Med Virol. 2025;97(10):e70635. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12519943/
2. Bhandari T. WashU Medicine. 2018. Why chikungunya, other arthritis-causing viruses target joints. Disponible en: https://medicine.washu.edu/news/why-chikungunya-other-arthritis-causing-viruses-target-the-joints/
3. Hasan A, Sharma G, Majumder N, Chaudhary S, Mehta D, Vaishya R, et al. Global Proteome Analysis of a Three-Dimensional Human Chondrocyte Cell Culture System Infected with Chikungunya Virus (CHIKV) Reveals Distinct Immune and Inflammatory Signatures. ACS Omega.;10(37):42480-93. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12461325/
4. Legros V, Belarbi E, Jeannin P, Geolier V, Kümmerer BM, Hardy D, et al. Use of Recombinant Chikungunya Virus expressing Nanoluciferase to Identify Chondrocytes as Target Cells in an Immunocompetent Mouse Model. The Journal of Infectious Diseases. 2025;232(2):e223-33. Disponible en: https://doi.org/10.1093/infdis/jiaf232
5. McAllister NM. Chikungunya virus binds sulfated glycosaminoglycans as attachment factors using specific residues in the E2 glycoprotein [Internet] [Doctor of Philosophy]. [Pensilvania, Estados Unidos]: University of Pittsburgh; 2021. Disponible en: http://d-scholarship.pitt.edu/40828/1/McAllister_ETDfinal_2021.pdf
6. Hakim MS, Aman AT. Understanding the Biology and Immune Pathogenesis of Chikungunya Virus Infection for Diagnostic and Vaccine Development. Viruses. 2022;15(1):48. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9863735/
7. De Caluwé L, Coppens S, Vereecken K, Daled S, Dhaenens M, Van Ostade X, et al. The CD147 Protein Complex Is Involved in Entry of Chikungunya Virus and Related Alphaviruses in Human Cells. Front Microbiol. 2021;12:615165.
8. Grass GD, Toole BP. How, with whom and when: an overview of CD147-mediated regulatory networks influencing matrix metalloproteinase activity. Biosci Rep. 2016;36(1):e00283. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718507/
9. Stojanovic SK, Stamenkovic BN, Cvetkovic JM, Zivkovic VG, Apostolovic MRA. Matrix Metalloproteinase-9 Level in Synovial Fluid—Association with Joint Destruction in Early Rheumatoid Arthritis. Medicina. 2023;59(1):167. Disponible en: https://www.mdpi.com/1648-9144/59/1/167
10. Freppel W, Silva LA, Stapleford KA, Herrero LJ. Pathogenicity and virulence of chikungunya virus. Virulence. 2024; Disponible en: https://www.tandfonline.com/doi/abs/10.1080/21505594.2024.2396484
11. Coates-Park S, Rich JA, Stetler-Stevenson WG, Peeney D. The TIMP protein family: diverse roles in pathophysiology. American Journal of Physiology-Cell Physiology. 2024;326(3):C917-34. Disponible en: https://journals.physiology.org/doi/full/10.1152/ajpcell.00699.2023
12. Giannelli G, Erriquez R, Iannone F, Marinosci F, Lapadula G, Antonaci S. MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in patients with rheumatoid arthritis and psoriatic arthritis. Clin Exp Rheumatol. 2004;22(3):335-8.
13. Shahin A, Elsawaf A, Ramadan S, Shaker O, Amin M, Taha M. Serum Levels of Tissue Inhibitors of Metalloproteinase 2 in Patients With Systemic Sclerosis With Duration More Than 2 Years: Correlation With Cardiac and Pulmonary Abnormalities. Mediators Inflamm. 2006;2006(6):38458. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1775032/
14. Lokireddy S, Vemula S, Vadde R. Connective tissue metabolism in chikungunya patients. Virol J. 27 de febrero de 2008;5:31.
15. Mosyak L, Georgiadis K, Shane T, Svenson K, Hebert T, McDonagh T, et al. Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5. Protein Sci. 2008;17(1):16-21. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2144589/
16. Lim EXY, Supramaniam A, Lui H, Coles P, Lee WS, Liu X, et al. Chondrocytes Contribute to Alphaviral Disease Pathogenesis as a Source of Virus Replication and Soluble Factor Production. Viruses. 2018;10(2):86. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850393/
17. Hasan A, Sharma G, Majumder N, Chaudhary S, Mehta D, Vaishya R, et al. Global Proteome Analysis of a Three-Dimensional Human Chondrocyte Cell Culture System Infected with Chikungunya Virus (CHIKV) Reveals Distinct Immune and Inflammatory Signatures. ACS Omega. 2025;10(37):42480-93. Disponible en: https://doi.org/10.1021/acsomega.5c02832
18. Silveira-Freitas JEP, Campagnolo ML, dos Santos Cortez M, de Melo FF, Zarpelon-Schutz AC, Teixeira KN. Long chikungunya? An overview to immunopathology of persistent arthralgia. World J Virol. 2024;13(2):89985. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11229846/
19. Sun W, Shi S, Liao S, Zhai M. Chikungunya fever: pathogenesis and mechanisms underlying pain symptoms. Front Immunol. 2025;16:1679385. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12643972/
20. Miller RE, Ishihara S, Tran PB, Golub SB, Last K, Miller RJ, et al. An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2. JCI Insight. 2018;3(6). Disponible en: https://insight.jci.org/articles/view/95704
This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright (c) 2026 Gisselle Diaz Breto, Marla González Martínez (Author)