Abstract
Osteoarthritis (OA) of the knee is the most common form of non-traumatic joint disease. Previous studies have shown the involvement of β-NGF and its receptors TrKA and p75NTR in OA-related pain, but their role in its pathogenesis is still unclear. The aim of our study was to investigate the amount of β-NGF and the expression levels of its receptors on cells isolated from synovial fluid and blood from OA patients who had undergone total knee arthroplasty, in order to check any possible correlation with the disease staging. Our results show a progressive stage-related increase of β-NGF and its receptors both in serum and synovial fluid. Furthermore, with respect to control subjects, OA patients show an increased amount of inflammatory monocytes along with an increased expression of β-NGF, TrKA and p75NTR. In conclusion, our study suggests a stage-related modulation of β-NGF and its receptors in the inflammatory process of OA.
Acknowledgments
We are grateful to patients and their family members for their participation in this study. We thank Eva Tikotin for editorial assistance and Dr. Alberto Marco del Pino for statistical analysis support.
Funding: This study was supported by PRIN 2010KL2Y73_002v and by a Surgical and Biomedical Sciences Department grant 2016.
Conflict of interest statement: The authors declare no competing interests.
References
Aida, Y., Maeno, M., Suzuki, N., Shiratsuchi, H., Motohashi, M., and Matsumura, H. (2005). The effect of IL-1β on the expression of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in human chondrocytes. Life Sci. 77, 3210–3221.10.1016/j.lfs.2005.05.052Search in Google Scholar
Aloe, L., Tuveri, M.A., Carcassi, U., and Levi-Montalcini, R. (1992). Nerve growth factor in the synovial fluid of patients with chronic arthritis. Arthritis Rheum. 35, 351–355.10.1142/9789812830319_0034Search in Google Scholar
Altman, R., Asch, E., Bloch, D., Bole, G., Borenstein, D., Brandt, K., Christy, W., Cooke, T.D., Greenwald, R., Hochberg, M., et al. (1986). Development of criteria for the classification and reporting of osteoarthritis of the knee. Arthritis Rheum. 29, 1039–1049.10.1002/art.1780290816Search in Google Scholar
Arevalo, J.C. and Wu, S.H. (2006). Neurotrophin signaling: many exciting surprises! Cell Mol. Life Sci. 63, 1523–1537.10.1007/s00018-006-6010-1Search in Google Scholar
Barthel, C., Yeremenko, N., Jacobs, R., Schmidt, R.E., Bernateck, M., Zeidler, H., Tak, P.P., Baeten, D., and Rihl, M. (2009). Nerve growth factor and receptor expression in rheumatoid arthritis and spondyloarthritis. Arthritis Res. Ther. 11, R82.10.1186/ar2716Search in Google Scholar
Brown, M.T., Murphy, F.T., Radin, D.M., Davignon, I., Smith, M.D., and West, C.R. (2012). Tanezumab reduces osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase III trial. J. Pain 13, 790–798.10.1016/j.jpain.2012.05.006Search in Google Scholar
Caroleo, M.C., Costa, N., Bracci-Laudiero, L., and Aloe, L. (2001). Human monocyte/macrophages activate by exposure to LPS overexpress NGF and NGF receptors. J. Neuroimmunol. 113, 193–201.10.1016/S0165-5728(00)00441-0Search in Google Scholar
Dou, Y.C., Hagströmer, L., Emtestam, L., and Johansson, O. (2006). Increased nerve growth factor and its receptors in atopic dermatitis: an immunohistochemical study. Arch. Dermatol. Res. 298, 31–37.10.1007/s00403-006-0657-1Search in Google Scholar
Feldmann, M. (2001). Pathogenesis of arthritis: recent research progress. Nat. Immunol. 2, 771–773.10.1038/ni0901-771Search in Google Scholar
Felson, D.T. (2004). An update on the pathogenesis and epidemiology of osteoarthritis. Radiol. Clin. North Am. 42, 1–9.10.1016/S0033-8389(03)00161-1Search in Google Scholar
Freund-Michel, V. and Frossard, N. (2008). The nerve growth factor and its receptors in airway inflammatory diseases. Pharmacol. Ther. 117, 52–76.10.1016/j.pharmthera.2007.07.003Search in Google Scholar
Haseeb, A. and Haqqi, T.M. (2013). Immunopathogenesis of osteoarthritis. Clin. Immunol. 146, 185–196.10.1016/j.clim.2012.12.011Search in Google Scholar
Hayden, M.S. and Ghosh, S. (2004). Signaling to NF-κB. Genes Dev. 18, 2195–2224.10.1101/gad.1228704Search in Google Scholar
Hirose, M., Kuroda, Y., and Murata, E. (2016). NGF/TrkA Signaling as a therapeutic target for pain. Pain Pract. 16, 175–182.10.1111/papr.12342Search in Google Scholar
Houard, X., Goldring, M.B., and Berenbaum, F. (2013). Homeostatic mechanisms in articular cartilage and role of inflammation in osteoarthritis. Curr. Rheumatol. Rep. 15, 375.10.1007/s11926-013-0375-6Search in Google Scholar
Ji, Q., Xu, X., Zhang, Q., Kang, L., Xu, Y., Zhang, K., Li, L., Liang, Y., Hong, T., Ye, Q., et al. (2016). The IL-1β/AP-1/miR-30a/ADAMTS-5 axis regulates cartilage matrix degradation in human osteoarthritis. Mol. Med. 94, 771–785.10.1007/s00109-016-1418-zSearch in Google Scholar
Kean, W.F., Kean, R., and Buchanan, W.W. (2004). Osteoarthritis: symptoms, signs and source of pain. Inflammopharmacology 12, 3–31.10.1163/156856004773121347Search in Google Scholar
Kellgren, J.H. and Lawrence, J.S. (1957). Radiological assessment of osteo-arthrosis. Ann. Rheum. Dis. 16, 494–502.10.1136/ard.16.4.494Search in Google Scholar
Lambiase, A., Bracci-Laudiero, L., Bonini, S., Bonini, S., Starace, G., D’Elios, M.M., De Carli, M., and Aloe, L. (1997). Human CD4+ T cell clones produce and release nerve growth factor and express high-affinitynerve growth factor receptors. J. Allergy Clin. Immunol. 100, 408–414.10.1016/S0091-6749(97)70256-2Search in Google Scholar
Lambiase, A., Micera, A., Sgrulletta, R., and Bonini, S. (2004). Nerve growth factor and the immune system: old and new concepts in the cross-talk between immune and resident cells during pathophysiological conditions. Curr. Opin. Allergy Clin. Immunol. 4, 425–430.10.1097/00130832-200410000-00015Search in Google Scholar PubMed
Lee, A.S., Ellman, M.B., Yan, D., Kroin, J.S., Cole, B.J., van Wijnen, A.J., and Im, H.J. (2013). A current review of molecular mechanisms regarding osteoarthritis and pain. Gene 527, 440–447.10.1016/j.gene.2013.05.069Search in Google Scholar
Liaskou, E., Zimmermann, H.W., Li, K.K., Oo, Y.H., Suresh, S., Stamataki, Z., Qureshi,O., Lalor, P.F., Shaw, J., Syn, W., et al. (2013). Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 57, 385–398.10.1002/hep.26016Search in Google Scholar
Manni, L., Lundeberg, T., Fiorito, S., Bonini, S., Vigneti, E., and Aloe, L. (2003). Nerve growth factor release by human synovial fibroblasts prior to and following exposure to tumor necrosis factor-alpha, interleukin-1 beta and cholecystokinin-8: the possible role of NGF in the inflammatory response. Clin. Exp. Rheumatol. 21, 617–624.Search in Google Scholar
Marcu, K.B., Otero, M., Olivotto, E., Borzi, R.M., and Goldring, M.B. (2010). NF-κB signaling: multiple angles to target OA. Curr. Drug Targets 11, 599–613.10.2174/138945010791011938Search in Google Scholar
Martel-Pelletier, J., Alaaeddine, N., and Pelletier, J.P. (1999). Cytokines and their role in the pathophysiology of osteoarthritis. Front Biosci. 15, D694–D703.10.2741/MartelSearch in Google Scholar
Ogura, T., Suzuki, M., Sakuma, Y., Yamauchi, K., Orita, O., Miyagi, M., Ishikawa, T., Kamoda, H., Oikawa, Y., Kanisawa, I., et al. (2016). Differences in levels of inflammatory mediators in meniscal and synovial tissue of patients with meniscal lesions. J. Exp. Orthop. 3, 7.10.1186/s40634-016-0041-9Search in Google Scholar
Orita, S., Koshi, T., Mitsuka, T., Miyagi, M., Inoue, G., Arai, G., Ishikawa, T., Hanaoka, E., Yamashita, K., Yamashita, M., et al. (2011). Associations between proinflammatory cytokines in the synovial fluid and radiographic grading and pain-related scores in 47 consecutive patients with osteoarthritis of the knee. BMC Musculoskelet. Disord. 12, 144.10.1186/1471-2474-12-144Search in Google Scholar
Prakash, Y., Thompson, M.A., Meuchel, L., Pabelick, C.M., Mantilla, C.B., Zaidi, S., and Martin, R.J. (2010). Neurotrophins in lung health and disease. Expert. Rev. Respir. Med. 4, 395–411.10.1586/ers.10.29Search in Google Scholar
Pula, G., Pistilli, A., Montagnoli, C., Stabile, A.M., Rambotti, M.G., and Rende, M. (2013). The tricyclic antidepressant amitriptyline is cytotoxic to HTB114 human leiomyosarcoma and induces p75(NTR)-dependent apoptosis. Anticancer Drugs 24, 899–910.10.1097/CAD.0b013e328364312fSearch in Google Scholar
Rahmati, M., Mobasheri, A., and Mozafari, M. (2016). Inflammatory mediators in osteoarthritis: a critical review of the state-of-the-art, current prospects, and future challenges. Bone 85, 81–90.10.1016/j.bone.2016.01.019Search in Google Scholar
Raychaudhuri, S.P. and Raychaudhuri, S.K. (2004). Role of NGF and neurogenic inflammation in the pathogenesis of psoriasis. Prog. Brain Res. 146, 433–437.10.1016/S0079-6123(03)46027-5Search in Google Scholar
Reichardt, L.F. (2006). Neurotrophin-regulated signalling pathways. Philos. Trans. R. Soc. Lond. B Biol. Sci. 361, 1545–1564.10.1098/rstb.2006.1894Search in Google Scholar PubMed PubMed Central
Reinshagen, M., von Boyen, G., Adler, G., and Steinkamp, M. (2002). Role of neurotrophins in inflammation of the gut. Curr. Opin. Investig. Drugs 3, 565–568.Search in Google Scholar
Rende, M., Rambotti, M.G., Stabile, A.M., Pistilli, A., Montagnoli, C., Chiarelli, M.T., and Mearini, E. (2010). Novel localization of low affinity NGF receptor (p75) in the stroma of prostate cancer and possible implication in neoplastic invasion: an immunohistochemical and ultracytochemical study. Prostate 70, 555–561.10.1002/pros.21089Search in Google Scholar PubMed
Rochlitzer, S., Nassenstein, C., and Braun, A. (2006). The contribution of neurotrophins to the pathogenesis of allergic asthma. Biochem. Soc Trans. 34, 594–599.10.1042/BST0340594Search in Google Scholar PubMed
Rost, B., Hanf, G., Ohnemus, U., Otto-Knapp, R., Groneberg, D.A., Kunkel, G., and Noga, O. (2005). Monocytes of allergics and non-allergics produce, store and release the neurotrophins NGF, BDNF and NT-3. Regul. Pept. 124, 19–25.10.1016/j.regpep.2004.06.024Search in Google Scholar PubMed
Seidel, M.F., Herguijuela, M., Forkert, R., and Otten, U. (2010). Nerve growth factor in rheumatic diseases. Semin. Arthritis Rheum. 40, 109–126.10.1016/j.semarthrit.2009.03.002Search in Google Scholar PubMed
Skaper, S.D. (2012). The neurotrophin family of neurotrophic factors: an overview. Methods Mol. Biol. 846, 1–12.10.1007/978-1-61779-536-7_1Search in Google Scholar PubMed
Stabile, A.M., Montagnoli, C., Pistilli, A., Rambotti, M.G., Pula, G., and Rende, M. (2013). Antiproliferative and pro-apoptotic effects of the Trk-inhibitor GW441756 in human myosarcomas and prostatic carcinoma. Curr. Signal Transduct. Ther. 8, 74–83.10.2174/1574362411308010010Search in Google Scholar
Stabile, A., Pistilli, A., Crispoltoni, L., Montagnoli, C., Tiribuzi, R., Casali, L., and Rende, M. (2016). A role for NGF and its receptors TrKA and p75NTR in the progression of COPD. Biol. Chem. 397, 157–163.10.1515/hsz-2015-0208Search in Google Scholar PubMed
Szczepankiewicz, A., Rachel, M., Sobkowiak, P., Kycler, Z., Wojsyk-Banaszak, I., Schöneich, N., Szczawińska-Popłonyk, A., Bręborowicz, A., Seidel, M.F., Herguijuela, M., et al. (2010). Neurotrophin serum concentrations and polymorphisms of neurotrophins and their receptors in children with asthma. Semin. Arthritis Rheum. 40, 109–126.10.1016/j.rmed.2012.09.024Search in Google Scholar PubMed
Tak, P.P. and Firestein, G.S. (2001). NF-κB: a key role in inflammatory diseases. J. Clin. Invest. 107, 7–11.10.1172/JCI11830Search in Google Scholar PubMed PubMed Central
Takano, S., Uchida, K., Miyagi, M., Inoue, G., Fujimaki, H., Aikawa, J., Iwase, D., Minatani, A., Iwabuchi, K., and Takaso, M. (2016). Nerve growth factor regulation by TNF-α and IL-1β in synovial macrophages and fibroblasts in osteoarthritic mice. J. Immunol. Res. 2016, 5706359.10.1155/2016/5706359Search in Google Scholar PubMed PubMed Central
Vincent, K.R., Conrad, B.P., Fregly, B.J., and Vincent, H.K. (2012). The pathophysiology of osteoarthritis: a mechanical perspective on the knee joint. PM R. 4, 3–9.10.1016/j.pmrj.2012.01.020Search in Google Scholar PubMed PubMed Central
Wojdasiewicz, P., Poniatowski, Ł.A., and Szukiewicz, D. (2014). The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediat. Inflamm. 2014, 561459.10.1155/2014/561459Search in Google Scholar PubMed PubMed Central
Wu, Z., Nagata, K., and Iijima, T. (2000). Immunohistochemical study of NGF and its receptors in the synovial membrane of the ankle joint of adjuvant-induced arthritic rats. Histochem. Cell Biol. 114, 453–459.10.1007/s004180000222Search in Google Scholar PubMed
Yang, J., Zhang, L., Yu, C., Yang, X.F., and Wang, H. (2014). Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark. Res. 7, 7771–7772.10.1186/2050-7771-2-1Search in Google Scholar PubMed PubMed Central
Zhai, G., Doré, J., and Rahman P. (2015). TGF-β signal transduction pathways and osteoarthritis Rheumatol. Int. 35, 1283–1292.Search in Google Scholar
Ziegler-Heitbrock, L., Ancuta, P., Crowe, S., Dalod, M., Grau, V., and Hart, D.N. (2010). Nomenclature of monocytes and dendritic cells in blood. Blood 21, 74–80.10.1182/blood-2010-02-258558Search in Google Scholar PubMed
©2017 Walter de Gruyter GmbH, Berlin/Boston
