Cell sources of inflammatory mediators present in bone marrow areas inside the meniscus

Autoři: Francisco Airton Castro Rocha aff001;  Virgínia Claudia Carneiro Girão aff002;  Rodolfo de Melo Nunes aff001;  Ana Carolina Matias Dinelly Pinto aff001;  Bruno Vidal aff003;  João Eurico Fonseca aff003
Působiště autorů: Departmento de Morfologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, Ceará, Brasil aff001;  Department of Internal Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil aff002;  Serviço de Reumatologia e Doenças Ósseas Metabólicas, Hospital de Santa Maria, CHULN, Lisboa, Portugal aff003;  Unidade de Investigação em Reumatologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Centro Académico de Medicina de Lisboa, Portugal aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0226986



To demonstrate the production of inflammatory mediators by cells located in bone marrow spaces inside rodent menisci.


Mice subjected to transection of the medial collateral and anterior cruciate ligaments and meniscotomy (osteoarthritis model) or to a sham procedure, as well as non-operated (naive) mice and rats, had knee joints excised. Tissues were stained with hematoxylin-eosin and tartrate-resistant acid phosphatase (TRAP). CD68+ cells, inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, and tumor necrosis factor (TNF) expression were detected using immunohistochemistry.


Lamellar ossified areas, bone-entrapped osteocytes and bone marrow spaces were found inside menisci of one week up to 6 months-old naïve mice, regardless of gender. Menisci from naive rats also showed the same pattern with bone marrow areas. CD68+ cells were identified in bone marrow areas inside the meniscus of mice. TRAP+ osteoclasts, and hematogenous precursors expressing IL-1β, TNF, and iNOS were identified inside bone marrow areas in meniscal samples from both naïve and sham operated mice. Quantitative immunoexpression of IL-1 β, TNF and iNOS was more intense, P = 0.0194, 0.0293, 0.0124, respectively, in mouse knees from mice sacrificed 49 days after being subjected to an osteoarthritis (OA) model as compared to sham operated animals.


We provide novel data showing that rodent menisci display bone marrow areas with cells able to produce inflammatory mediators. Immunoexpression of inflammatory mediators in those bone marrow areas is significantly more pronounced in mice subjected to experimental OA

Klíčová slova:

Bone marrow – Bone marrow cells – Cell staining – Cytokines – Inflammation – Knee joints – Osteoarthritis – Skeletal joints


1. Englund M, Roemer FW, Hayashi D, Crema MD, Guermazi A. Meniscus pathology, osteoarthritis and the treatment controversy. Nat Rev Rheumatol. 2012; 8:412–9. doi: 10.1038/nrrheum.2012.69 22614907

2. Englund M, Haugen IK, Guermazi A, Roemer FW, Niu J, Neogi T, et al. Evidence that meniscus damage may be a component of osteoarthritis: the Framingham study. Osteoarthritis Cartilage. 2016; 24:270–3. doi: 10.1016/j.joca.2015.08.005 26318660

3. Roemer FW, Kwoh CK, Hannon MJ, Hunter DJ, Eckstein F, Fujii T, et al. What comes first? Multitissue involvement leading to radiographic osteoarthritis: magnetic resonance imaging-based trajectory analysis over four years in the osteoarthritis initiative. Arthritis Rheumatol. 2015; 67:2085–96. doi: 10.1002/art.39176 25940308

4. McAlindon TE. Toward a new paradigm of knee osteoarthritis. Arthritis Rheumatol. 2015; 67:1987–9. doi: 10.1002/art.39177 25940432

5. Makris EA, Hadidi P, Athanasiou KA. The knee meniscus: structure-function, pathophysiology, current repair techniques, and prospects for regeneration. Biomaterials. 2011; 32:7411–31. doi: 10.1016/j.biomaterials.2011.06.037 21764438

6. Verdonk PC, Forsyth RG, Wang J, Almqvist KF, Verdonk R, Veys EM, et al. Characterisation of human knee meniscus cell phenotype. Osteoarthritis Cartilage. 2005;13;548–60. doi: 10.1016/j.joca.2005.01.010 15979007

7. Fuhrmann IK, Steinhagen J, Rüther W, Schumacher U. Comparative immunohistochemical evaluation of the zonal distribution of extracellular matrix and inflammation markers in human meniscus in osteoarthritis and rheumatoid arthritis. Acta Histochem. 2015; 117:243–54. doi: 10.1016/j.acthis.2014.12.009 25827912

8. Stone AV, Loeser RF, Vanderman KS, Long DL, Clark SC, Ferguson CM. Pro-inflammatory stimulation of meniscus cells increases production of matrix metalloproteinases and additional catabolic factors involved in osteoarthritis pathogenesis. Osteoarthritis Cartilage. 2014; 22:264–74. doi: 10.1016/j.joca.2013.11.002 24315792

9. Gupta T, Zielinska B, McHenry J, Kadmiel M, Haut Donahue TL. IL-1 and iNOS gene expression and NO synthesis in the superior region of meniscal explants are dependent on the magnitude of compressive strains.Osteoarthritis Cartilage. 2008; 16:1213–9. doi: 10.1016/j.joca.2008.02.019 18439846

10. Gamer LW, Xiang L, Rosen V. Formation and maturation of the murine meniscus. J Orthop Res. 2016 Sep 24. doi: 10.1002/jor.23446 27664939

11. de Melo Leite AC, Teotonio MA, Girão VC, de Lima Pompeu MM, de Melo Nunes R, Cunha TM, et al. Meniscal transection rather than excision increases pain behavior and structural damage in experimental osteoarthritis in mice. Osteoarthritis Cartilage. 2014;22;1878–85. doi: 10.1016/j.joca.2014.07.019 25086402

12. Kapadia RD, Badger AM, Levin JM, Swift B, Bhattacharyya A, Dodds RA, et al. Meniscal ossification in spontaneous osteoarthritis in the guinea-pig. Osteoarthritis Cartilage. 2000; 8:374–7. doi: 10.1053/joca.1999.0312 10966844

13. Kato Y, Oshida M, Saito A, Ryu J. Meniscal ossicles. J Orthop Sci. 2007; 12:375–80. doi: 10.1007/s00776-007-1140-3 17657558

14. Weischenfeldt J, Porse B. Bone Marrow-Derived Macrophages (BMM): Isolation and Applications. B. CSH Protoc. 2008 Dec 1; 2008:pdb.prot5080.

15. Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage. 2013; 21:16–21. doi: 10.1016/j.joca.2012.11.012 23194896

16. Abramson SB. Osteoarthritis and nitric oxide. Osteoarthritis Cartilage 2008. 16 Suppl 2:S15–20.

17. Del Carlo M Jr, Loeser RF. Cell death in osteoarthritis. Curr Rheumatol Rep. 2008; 10:37–42. doi: 10.1007/s11926-008-0007-8 18457610

18. da Rocha FA, de Brum-Fernandes AJ. Evidence that peroxynitrite affects human osteoblast proliferation and differentiation. J Bone Miner Res. 2002;17:434–42. doi: 10.1359/jbmr.2002.17.3.434 11874235

19. Mathiessen A, Conaghan PG. Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis Res Ther. 2017; 19:18. doi: 10.1186/s13075-017-1229-9 28148295

20. McInnes IB, Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet. 2017; 389:2328–37. doi: 10.1016/S0140-6736(17)31472-1 28612747

21. Poole R, Blake S, Buschmann M, Goldring S, Laverty S, Lockwood S et al. Recommendations for the use of preclinical models in the study and treatment of osteoarthritis. Osteoarthritis Cartilage. 2010;18:S10–16. doi: 10.1016/j.joca.2010.05.027 20864015

22. Lebel B, Tardieu C, Locker B, Hulet C. Ontogeny-Phylogeny. In: The Meniscus, Beaufils P & Verdonk R. Ed. Springer-Verlag Berlin Heidelberg 2010:3–9.

23. Little CB, Zaki S. What constitutes an "animal model of osteoarthritis"—the need for consensus? Osteoarthritis Cartilage. 2012; 20:261–7. doi: 10.1016/j.joca.2012.01.017 22321719

Článek vyšel v časopise


2019 Číslo 12
Nejčtenější tento týden