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Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis

Nature Reviews Rheumatology volume 8, pages 390–398 (2012)Cite this article

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Abstract

During osteoarthritis (OA), angiogenesis is increased in the synovium, osteophytes and menisci and leads to ossification in osteophytes and the deep layers of articular cartilage. Angiogenic and antiangiogenic factors might both be upregulated in the osteoarthritic joint; however, vascular growth predominates, and the articular cartilage loses its resistance to vascularization. In addition, blood vessel growth is increased at—and disrupts—the osteochondral junction. Angiogenesis in this location is dependent on the creation of channels from subchondral bone spaces into noncalcified articular cartilage. Inflammation drives synovial angiogenesis through macrophage activation. Blood vessel and nerve growth are linked by common pathways that involve the release of proangiogenic factors, such as vascular endothelial growth factor, β-nerve growth factor and neuropeptides. Proangiogenic factors might also stimulate nerve growth, and molecules produced by vascular cells could both stimulate and guide nerve growth. As sensory nerves grow along new blood vessels in osteoarthritic joints, they eventually penetrate noncalcified articular cartilage, osteophytes and the inner regions of menisci. Angiogenesis could, therefore, contribute to structural damage and pain in OA and provide potential targets for new treatments.

Key Points

  • Angiogenesis contributes to synovitis, osteochondral damage, osteophyte formation and meniscal pathology in patients with osteoarthritis (OA)

  • Angiogenesis is intimately linked to sensory nerve growth through shared regulatory pathways

  • Nerve growth along new blood vessels into structures that are normally not innervated could contribute to pain in OA

  • Inhibition of subchondral bone turnover can prevent osteochondral angiogenesis and reduce pain in animal models of OA

  • Inhibition of angiogenesis could potentially be used to treat OA

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Figure 1: Sites of angiogenesis in the osteoarthritic knee.
Figure 2: Histological appearance of regions of neovascularization in human osteoarthritis.
Figure 3: Potential proangiogenic and antiangiogenic effects of β-NGF.

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References

  1. Brown, R. A. & Weiss, J. B. Neovascularisation and its role in the osteoarthritic process. Ann. Rheum. Dis. 47, 881–885 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fransès, R. E., McWilliams, D. F., Mapp., P. I. & Walsh, D. A. Osteochondral angiogenesis and increased protease inhibitor expression in OA. Osteoarthritis Cartilage 18, 563–571 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bonnet, C. S. & Walsh, D. A. Osteoarthritis, angiogenesis and inflammation. Rheumatology (Oxford) 44, 7–16 (2005).

    Article  CAS  Google Scholar 

  4. Ashraf, S. et al. Increased vascular penetration and nerve growth in the meniscus: a potential source of pain in osteoarthritis. Ann. Rheum. Dis. 70, 523–529 (2011).

    Article  PubMed  Google Scholar 

  5. Levick, J. R. & Knight, A. D. Osmotic flows across the blood-joint barrier. Ann. Rheum. Dis. 46, 534–539 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Stevens, C. R., Blake, D. R., Merry, P., Revell, P. A. & Levick, J. R. A comparative study by morphometry of the microvasculature in normal and rheumatoid synovium. Arthritis Rheum. 34, 1508–1513 (1991).

    Article  CAS  PubMed  Google Scholar 

  7. Blake, D. R. et al. Hypoxic-reperfusion injury in the inflamed human joint. Lancet 1, 289–293 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. O'Hara, B. P., Urban, J. P. & Maroudas, A. Influence of cyclic loading on the nutrition of articular cartilage. Ann. Rheum. Dis. 49, 536–539 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Walsh, D. A., Mapp., P. I., Wharton, J., Polak, J. M. & Blake, D. R. Neuropeptide degrading enzymes in normal and inflamed human synovium. Am. J. Pathol. 142, 1610–1621 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Suri, S. et al. Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis. Ann. Rheum. Dis. 66, 1423–1428 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ashraf, S., Mapp., P. I. & Walsh, D. A. Contributions of angiogenesis to inflammation, joint damage, and pain in a rat model of osteoarthritis. Arthritis Rheum. 63, 2700–2710 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Mapp., P. I. et al. Angiogenesis in two animal models of osteoarthritis. Osteoarthritis Cartilage 16, 61–69 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Shibakawa, A. et al. Presence of pannus-like tissue on osteoarthritic cartilage and its histological character. Osteoarthritis Cartilage 11, 133–140 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Smith, M. D., Triantafillou, S., Parker, A., Youssef, P. P. & Coleman, M. Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J. Rheumatol. 24, 365–371 (1997).

    CAS  PubMed  Google Scholar 

  15. Bondeson, J. et al. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum. 62, 647–657 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Haywood, L. et al. Inflammation and angiogenesis in osteoarthritis. Arthritis Rheum. 48, 2173–2177 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Conaghan, P. G. et al. MRI and non-cartilaginous structures in knee osteoarthritis. Osteoarthritis Cartilage 14 (Suppl. A), A87–A94 (2006).

    Article  PubMed  Google Scholar 

  18. Revell, P. A., Mayston, V., Lalor, P. & Mapp., P. The synovial membrane in osteoarthritis: a histological study including the characterisation of the cellular infiltrate present in inflammatory osteoarthritis using monoclonal antibodies. Ann. Rheum. Dis. 47, 300–307 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Walsh, D. A., Wade, M., Mapp., P. I. & Blake, D. R. Focally regulated endothelial proliferation and cell death in human synovium. Am. J. Pathol. 152, 691–702 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Walsh, D. A. et al. Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis. Rheumatology (Oxford) 49, 1852–1861 (2010).

    Article  CAS  Google Scholar 

  21. Petersen, W. & Tillmann, B. Collagenous fibril texture of the human knee joint menisci. Anat. Embryol. (Berl.) 197, 317–324 (1998).

    Article  CAS  Google Scholar 

  22. Aigner, T., Dietz, U., Stöss, H. & von der Mark, K. Differential expression of collagen types I, II, III, and X in human osteophytes. Lab. Invest. 73, 236–243 (1995).

    CAS  PubMed  Google Scholar 

  23. Hashimoto, S. et al. Development and regulation of osteophyte formation during experimental osteoarthritis. Osteoarthritis Cartilage 10, 180–187 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Lainer-Carr, D. & Brahn, E. Angiogenesis inhibition as a therapeutic approach for inflammatory synovitis. Nat. Clin. Pract. Rheumatol. 3, 434–442 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Walsh, D. A. et al. Angiogenesis in the synovium and at the osteochondral junction in osteoarthritis. Osteoarthritis Cartilage 15, 743–751 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Mantovani, A., Sica, A. & Locati, M. Macrophage polarization comes of age. Immunity 23, 344–346 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Aron-Wisnewsky, J. et al. Human adipose tissue macrophages: m1 and m2 cell surface markers in subcutaneous and omental depots and after weight loss. J. Clin. Endocrinol. Metab. 94, 4619–4623 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Hamilton, J. A. & Tak, P. P. The dynamics of macrophage lineage populations in inflammatory and autoimmune diseases. Arthritis Rheum. 60, 1210–1221 (2009).

    Article  PubMed  Google Scholar 

  29. McInnes, I. B. et al. Production of nitric oxide in the synovial membrane of rheumatoid and osteoarthritis patients. J. Exp. Med. 184, 1519–1524 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Wu, W. K., Llewellyn, O. P., Bates, D. O., Nicholson, L. B. & Dick, A. D. IL-10 regulation of macrophage VEGF production is dependent on macrophage polarisation and hypoxia. Immunobiology 215, 796–803 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Pufe, T., Petersen, W., Tillmann, B. & Mentlein, R. The splice variants VEGF121 and VEGF189 of the angiogenic peptide vascular endothelial growth factor are expressed in osteoarthritic cartilage. Arthritis Rheum. 44, 1082–1088 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Pfander, D., Cramer, T., Deuerling, D., Weseloh, G. & Swoboda, B. Expression of thrombospondin-1 and its receptor CD36 in human osteoarthritic cartilage. Ann. Rheum. Dis. 59, 448–454 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Moses, M. A. et al. Troponin I is present in human cartilage and inhibits angiogenesis. Proc. Natl Acad. Sci. USA 96, 2645–2650 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Eisenstein, R., Sorgente, N., Soble, L. W., Miller, A. & Kuettner, K. E. The resistance of certain tissues to invasion: penetrability of explanted tissues by vascularized mesenchyme. Am. J. Pathol. 73, 765–774 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Fenwick, S. A., Gregg, P. J. & Rooney, P. Osteoarthritic cartilage loses its ability to remain avascular. Osteoarthritis Cartilage 7, 441–452 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Walker, G. D., Fischer, M., Gannon, J., Thompson, R. C. Jr & Oegema, T. R. Jr. Expression of type-X collagen in osteoarthritis. J. Orthop. Res. 13, 4–12 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Wilson, A. S., Legg, P. G. & McNeur, J. C. Studies on the innervation of the medial meniscus in the human knee joint. Anat. Rec. 165, 485–491 (1969).

    Article  CAS  PubMed  Google Scholar 

  38. Day, B., Mackenzie, W. G., Shim, S. S. & Leung, G. The vascular and nerve supply of the human meniscus. Arthroscopy 1, 58–62 (1985).

    Article  CAS  PubMed  Google Scholar 

  39. Mapp., P. I. Innervation of the synovium. Ann. Rheum. Dis. 54, 398–403 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lanzetta, A. et al. The nervous structures of anterior cruciate ligament of human knee, healthy and lesioned, studied with confocal scanning laser microscopy. Ital. J. Anat. Embryol. 109, 167–176 (2004).

    PubMed  Google Scholar 

  41. Reimann, I. & Christensen, S. B. A histological demonstration of nerves in subchondral bone. Acta Orthop. Scand. 48, 345–352 (1977).

    Article  CAS  PubMed  Google Scholar 

  42. Mapp., P. I. et al. Substance P-, calcitonin gene-related peptide- and C-flanking peptide of neuropeptide Y-immunoreactive fibres are present in normal synovium but depleted in patients with rheumatoid arthritis. Neuroscience 37, 143–153 (1990).

    Article  CAS  PubMed  Google Scholar 

  43. Walsh, D. A. et al. Innervation and neurokinin receptors during angiogenesis in the rat sponge granuloma. Histochem. J. 28, 759–769 (1996).

    Article  CAS  PubMed  Google Scholar 

  44. Jimenez-Andrade, J. M., Ghilardi, J. R., Castañeda-Corral, G., Kuskowski, M. A. & Mantyh, P. W. Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer pain. Pain 152, 2564–2574 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fan, T. P., Hu, D. E., Guard, S., Gresham, G. A. & Watling, K. J. Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by NK1 or interleukin-1 receptor antagonists. Br. J. Pharmacol. 110, 43–49 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Movafagh, S., Hobson, J. P., Spiegel, S., Kleinman, H. K. & Zukowska, Z. Neuropeptide Y induces migration, proliferation, and tube formation of endothelial cells bimodally via Y1, Y2, and Y5 receptors. FASEB J. 20, 1924–1926 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Seegers, H. C., Hood, V. C., Kidd, B. L., Cruwys, S. C. & Walsh, D. A. Enhancement of angiogenesis by endogenous substance P release and neurokinin-1 receptors during neurogenic inflammation. J. Pharmacol. Exp. Ther. 306, 8–12 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Seegers, H. C., Avery, P. S., McWilliams, D. F., Haywood, L. & Walsh, D. A. Combined effect of bradykinin B2 and neurokinin-1 receptor activation on endothelial cell proliferation in acute synovitis. FASEB J. 18, 762–764 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Mapp., P. I., McWilliams, D. F., Turley, M. J., Hargin, E. & Walsh, D. A. A role for the sensory neuropeptide calcitonin gene-related peptide in endothelial cell proliferation in vivo. Br. J. Pharmacol. 166, 1261–1271 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ashraf, S., Mapp., P. I. & Walsh, D. A. Angiogenesis and the persistence of inflammation in a rat model of proliferative synovitis. Arthritis Rheum. 62, 1890–1898 (2010).

    CAS  PubMed  Google Scholar 

  51. Carmeliet, P. & Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 436, 193–200 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Masuda, T. & Shiga, T. Chemorepulsion and cell adhesion molecules in patterning initial trajectories of sensory axons. Neurosci. Res. 51, 337–347 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Miller, L. E. et al. Increased prevalence of semaphorin 3C, a repellent of sympathetic nerve fibers, in the synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum. 50, 1156–1163 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Fassold, A. et al. Soluble neuropilin-2, a nerve repellent receptor, is increased in rheumatoid arthritis synovium and aggravates sympathetic fiber repulsion and arthritis. Arthritis Rheum. 60, 2892–2901 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Seki, T., Selby, J., Haupl, T. & Winchester, R. Use of differential subtraction method to identify genes that characterize the phenotype of cultured rheumatoid arthritis synoviocytes. Arthritis Rheum. 41, 1356–1364 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Ikeda, M., Hosoda, Y., Hirose, S., Okada, Y. & Ikeda, E. Expression of vascular endothelial growth factor isoforms and their receptors Flt-1, KDR, and neuropilin-1 in synovial tissues of rheumatoid arthritis. J. Pathol. 191, 426–433 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Matthies, A. M., Low, Q. E., Lingen, M. W. & DiPietro, L. A. Neuropilin-1 participates in wound angiogenesis. Am. J. Pathol. 160, 289–296 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kigel, B., Varshavsky, A., Kessler, O. & Neufeld, G. Successful inhibition of tumor development by specific class-3 semaphorins is associated with expression of appropriate semaphorin receptors by tumor cells. PLoS ONE 3, e3287 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kong, J. S. et al. Anti-neuropilin-1 peptide inhibition of synoviocyte survival, angiogenesis, and experimental arthritis. Arthritis Rheum. 62, 179–190 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Enomoto, H. et al. Vascular endothelial growth factor isoforms and their receptors are expressed in human osteoarthritic cartilage. Am. J. Pathol. 162, 171–181 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gomez, C. et al. Expression of Semaphorin-3A and its receptors in endochondral ossification: potential role in skeletal development and innervation. Dev. Dyn. 234, 393–403 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Catalano, A. The neuroimmune semaphorin-3A reduces inflammation and progression of experimental autoimmune arthritis. J. Immunol. 185, 6373–6383 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Nico, B., Mangieri, D., Benagiano, V., Crivellato, E. & Ribatti, D. Nerve growth factor as an angiogenic factor. Microvasc. Res. 75, 135–141 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Raychaudhuri, S. K., Raychaudhuri, S. P., Weltman, H. & Farber, E. M. Effect of nerve growth factor on endothelial cell biology: proliferation and adherence molecule expression on human dermal microvascular endothelial cells. Arch. Dermatol. Res. 293, 291–295 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Cantarella, G. et al. Nerve growth factor-endothelial cell interaction leads to angiogenesis in vitro and in vivo. FASEB J. 16, 1307–1309 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Moser, K. V., Reindl, M., Blasig, I. & Humpel, C. Brain capillary endothelial cells proliferate in response to NGF, express NGF receptors and secrete NGF after inflammation. Brain Res. 1017, 53–60 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Steinle, J. J. & Granger, H. J. Nerve growth factor regulates human choroidal, but not retinal, endothelial cell migration and proliferation. Auton. Neurosci. 108, 57–62 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Tanaka, A., Wakita, U., Kambe, N., Iwasaki, T. & Matsuda, H. An autocrine function of nerve growth factor for cell cycle regulation of vascular endothelial cells. Biochem. Biophys. Res. Commun. 313, 1009–1014 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Rahbek, U. L., Dissing, S., Thomassen, C., Hansen, A. J. & Tritsaris, K. Nerve growth factor activates aorta endothelial cells causing PI3K/Akt- and ERK-dependent migration. Pflugers Arch. 450, 355–361 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Park, M. J. et al. Nerve growth factor induces endothelial cell invasion and cord formation by promoting matrix metalloproteinase-2 expression through the phosphatidylinositol 3-kinase/Akt signaling pathway and AP-2 transcription factor. J. Biol. Chem. 282, 30485–30496 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Lazarovici, P., Gazit, A., Staniszewska, I., Marcinkiewicz, C. & Lelkes, P. I. Nerve growth factor (NGF) promotes angiogenesis in the quail chorioallantoic membrane. Endothelium 13, 51–59 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Lazarovici, P., Marcinkiewicz, C. & Lelkes, P. I. Cross talk between the cardiovascular and nervous systems: neurotrophic effects of vascular endothelial growth factor (VEGF) and angiogenic effects of nerve growth factor (NGF)-implications in drug development. Curr. Pharm. Des. 12, 2609–2622 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Seo, K., Choi, J., Park, M. & Rhee, C. Angiogenesis effects of nerve growth factor (NGF) on rat corneas. J. Vet. Sci. 2, 125–130 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Calza, L., Giardino, L., Giuliani, A., Aloe, L. & Levi-Montalcini, R. Nerve growth factor control of neuronal expression of angiogenetic and vasoactive factors. Proc. Natl Acad. Sci. USA 98, 4160–4165 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Santos, P. M., Winterowd, J. G., Allen, G. G., Bothwell, M. A. & Rubel, E. W. Nerve growth factor: increased angiogenesis without improved nerve regeneration. Otolaryngol. Head Neck Surg. 105, 12–25 (1991).

    Article  CAS  PubMed  Google Scholar 

  76. Graiani, G. et al. Nerve growth factor promotes reparative angiogenesis and inhibits endothelial apoptosis in cutaneous wounds of type 1 diabetic mice. Diabetologia 47, 1047–1054 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Liu, X. et al. Neuronal-driven angiogenesis: role of NGF in retinal neovascularization in an oxygen-induced retinopathy model. Invest. Ophthalmol. Vis. Sci. 51, 3749–3757 (2010).

    Article  PubMed  Google Scholar 

  78. Emanueli, C. et al. Nerve growth factor promotes angiogenesis and arteriogenesis in ischemic hindlimbs. Circulation 106, 2257–2262 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Adriaenssens, E. et al. Nerve growth factor is a potential therapeutic target in breast cancer. Cancer Res. 68, 346–351 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. US National Library of Medicine. Phase III Study of docetaxel and ramucirumab or placebo in breast cancer. ClinicalTrials.gov [online], (2012).

  81. US National Library of Medicine. A study of paclitaxel with or without ramucirumab in metastatic gastric adenocarcinoma (RAINBOW). ClinicalTrials.gov [online] (2011).

  82. US National Library of Medicine. A study of chemotherapy and ramucirumab vs. chemotherapy alone in second line non-small cell lung cancer patients who received prior first line platinum based chemotherapy ClinicalTrials.gov [online] (2012).

  83. Strassle, B. W. et al. Inhibition of osteoclasts prevents cartilage loss and pain in a rat model of degenerative joint disease. Osteoarthritis Cartilage 18, 1319–1328 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Mapp., P. I., Walsh, D. A., Bowyer, J. & Maciewicz, R. A. Effects of a metalloproteinase inhibitor on osteochondral angiogenesis, chondropathy and pain behavior in a rat model of osteoarthritis. Osteoarthritis Cartilage 18, 593–600 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Moreau, M. et al. Tiludronate treatment improves structural changes and symptoms of osteoarthritis in the canine anterior cruciate ligament model. Arthritis Res. Ther. 13, R98 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Agnello, K. A., Trumble, T. N., Chambers, J. N., Seewald, W. & Budsberg, S. C. Effects of zoledronate on markers of bone metabolism and subchondral bone mineral density in dogs with experimentally induced cruciate-deficient osteoarthritis. Am. J. Vet. Res. 66, 1487–1495 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Jones, M. D. et al. In vivo microfocal computed tomography and micro-magnetic resonance imaging evaluation of antiresorptive and antiinflammatory drugs as preventive treatments of osteoarthritis in the rat. Arthritis Rheum. 62, 2726–2735 (2010).

    Article  PubMed  Google Scholar 

  88. Spector, T. D. et al. Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]. Arthritis Res. Ther. 7, R625–R633 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bingham, C. O. 3rd et al. Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study. Arthritis Rheum. 54, 3494–3507 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Laslett, L. et al. Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2011-200970

  91. Lane, N. E. et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N. Engl. J. Med. 363, 1521–1531 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Dixon, W. & Felson, D. T. Is anti-TNF therapy safer than previously thought? JAMA 306, 2380–2381 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Jeng, L., Olsen, B. R. & Spector, M. Engineering endostatin-producing cartilaginous constructs for cartilage repair using nonviral transfection of chondrocyte-seeded and mesenchymal-stem-cell-seeded collagen scaffolds. Tissue Eng. Part A 16, 3011–3021 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

H. I. Walsh created the original artwork for Figure 1. S. Ashraf, R. Hill, D. F. McWilliams, C. I. Pearson and A. Starling prepared the histological samples shown in Figure 2.

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  1. Arthritis Research UK Pain Centre, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, UK

    Paul I. Mapp & David A. Walsh

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Both authors contributed equally to researching data for the article and writing, editing and reviewing the manuscript.

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Correspondence to David A. Walsh.

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D. A. Walsh declares that he has acted as a consultant for Pfizer. P. I. Mapp declares no competing interests.

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Mapp, P., Walsh, D. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat Rev Rheumatol 8, 390–398 (2012). https://doi.org/10.1038/nrrheum.2012.80

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