746
Views
32
CrossRef citations to date
0
Altmetric
Review

An update on the up and coming therapies to treat osteoarthritis, a multifaceted disease

, , , &
Pages 1745-1756 | Received 27 Jan 2016, Accepted 09 Jun 2016, Published online: 04 Jul 2016

References

  • Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ. 2003;81:646–656.
  • Brandt KD, Radin EL, Dieppe PA, et al. Yet more evidence that osteoarthritis is not a cartilage disease. Ann Rheum Dis. 2006;65:1261– 1264.
  • Herrero-Beaumont G, Roman-Blas JA, Castaneda S, et al. Primary osteoarthritis no longer primary: three subsets with distinct etiological, clinical, and therapeutic characteristics. Semin Arthritis Rheum. 2009;39:71–80.
  • Guilak F. Biomechanical factors in osteoarthritis. Best Pract Res Clin Rheumatol. 2011;25:815–823.
  • Williams CJ, Jimenez SA. Skeletal dysplasias and the osteoarthritic phenotype. Best Pract Res Clin Rheumatol. 2003;17:1005–1018.
  • Valdes AM, Spector TD. The contribution of genes to osteoarthritis. Rheum Dis Clin North Am. 2008;34:581–603.
  • Roman-Blas JA, Castaneda S, Largo R, et al. Osteoarthritis associated with estrogen deficiency. Arthritis Res Ther. 2009;11:241.
  • Sniekers YH, Weinans H, Bierma-Zeinstra SM, et al. Animal models for osteoarthritis: the effect of ovariectomy and estrogen treatment – a systematic approach. Osteoarthritis Cartilage. 2008;16:533–541.
  • Bellido M, Lugo L, Roman-Blas JA, et al. Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis. Arthritis Res Ther. 2010;12:R152.
  • Sniekers YH, Weinans H, Van Osch GJ, et al. Oestrogen is important for maintenance of cartilage and subchondral bone in a murine model of knee osteoarthritis. Arthritis Res Ther. 2010;12:R182.
  • Felson DT, Zhang Y, Hannan MT, et al. The incidence and natural history of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthritis Rheum. 1995;38:1500–1505.
  • Srikanth VK, Fryer JL, Zhai G, et al. A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoarthritis Cartilage. 2005;13:769–781.
  • Sowers MR, McConnell D, Jannausch M, et al. Estradiol and its metabolites and their association with knee osteoarthritis. Arthritis Rheum. 2006;54:2481–2487.
  • Spector TD, Nandra D, Hart DJ, et al. Is hormone replacement therapy protective for hand and knee osteoarthritis in women? The Chingford Study. Ann Rheum Dis. 1997;56:432–444.
  • Wluka AE, Davis SR, Bailey M, et al. Users of oestrogen replacement therapy have more knee cartilage than non-users. Ann Rheum Dis. 2001;60:332–336.
  • Carbone LD, Nevitt MC, Wildy K, et al. The relationship of antiresorptive drug use to structural findings and symptoms of knee osteoarthritis. Arthritis Rheum. 2004;50:3516–3525.
  • Loeser RF Jr. Aging cartilage and osteoarthritis—what’s the link? Sci Aging Knowledge Environ. 2004;29:pe31.
  • Loeser RF. Molecular mechanisms of cartilage destruction: mechanics, inflammatory mediators, and aging collide. Arthritis Rheum. 2006;54:1357–1360.
  • Zhuo Q, Yang W, Chen J, et al. Metabolic syndrome meets osteoarthritis. Nat Rev Rheumatol. 2012;8:729–737.
  • Yoshimura N, Muraki S, Oka H, et al. Accumulation of metabolic risk factors such as overweight, hypertension, dyslipidaemia, and impaired glucose tolerance raises the risk of occurrence and progression of knee osteoarthritis: a 3-year follow-up of the ROAD study. Osteoarthritis Cartilage. 2012;20:1217–1226.
  • Gomez R, Villalvilla A, Largo R, et al. TLR4 signalling in osteoarthritis: finding targets for candidate DMOADs. Nat Rev Rheumatol. 2015;11:159–170.
  • Castaneda S, Roman-Blas JA, Largo R, et al. Osteoarthritis: a progressive disease with changing phenotypes. Rheumatology (Oxford). 2014;53:1–3.
  • Glyn-Jones S, Palmer AJ, Agricola R, et al. Osteoarthritis. Lancet. 2015;386:376–387.
  • Burr DB, Gallant MA. Bone remodelling in osteoarthritis. Nat Rev Rheumatol. 2012;8:665–673.
  • Funck-Brentano T, Cohen-Solal M. Subchondral bone and osteoarthritis. Curr Opin Rheumatol. 2015;27:420–426.
  • Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol. 2010;6:625–635.
  • Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage. 2013;21:16–21.
  • Conaghan PG, Dickson J, Grant RL. Guideline Development Group. Care and management of osteoarthritis in adults: summary of NICE guidance. Bmj. 2008;336:502–503.
  • Alvarez-Soria MA, Largo R, Santillana J, et al. Long term NSAID treatment inhibits COX-2 synthesis in the knee synovial membrane of patients with osteoarthritis: differential proinflammatory cytokine profile between celecoxib and aceclofenac. Ann Rheum Dis. 2006;65:998–1005.
  • Alvarez-Soria MA, Herrero-Beaumont G, Moreno-Rubio J, et al. Long term NSAID treatment directly decreases COX-2 and mPGES-1 production in the articular cartilage of patients with osteoarthritis. Osteoarthritis Cartilage. 2008;16:1484–1493.
  • Jordan KM, Arden NK, Doherty M, et al. Standing committee for international clinical studies including therapeutic trials ESCISIT. EULAR recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a task force of the standing committee for international clinical studies including therapeutic trials (ESCISIT). Ann Rheum Dis. 2003;62:1145–1155.
  • McCarberg B, Tenzer P. Complexities in the pharmacologic management of osteoarthritis pain. Curr Med Res Opin. 2013;29:539–548.
  • Patrignani P, Tacconelli S, Bruno A, et al. Managing the adverse effects of nonsteroidal anti-inflammatory drugs. Expert Rev Clin Pharmacol. 2011;4:605–621.
  • Bhala N, Emberson J, et al.; Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382:769–779.
  • Katz JA. COX-2 inhibition: what we learned–a controversial update on safety data. Pain Med. 2013;14:S29–S34.
  • Hennekens CH, Borzak S, Bjorkman DJ. Cardiovascular risks of cyclooxygenase-2 inhibitors and traditional anti-inflammatory drugs: necessary but not sufficient for clinical decision making. Expert Rev Cardiovasc Ther. 2014;12:291–293.
  • Tehrani M, Aguiar M, Katz JD. Narcotics in rheumatology. Health Serv Insights. 2013;6:39–45.
  • Goodwin JL, Kraemer JJ, Bajwa ZH. The use of opioids in the treatment of osteoarthritis: when, why, and how? Curr Rheumatol Rep. 2009;11:5–14.
  • Avouac J, Gossec L, Dougados M. Efficacy and safety of opioids for osteoarthritis: a meta-analysis of randomized controlled trials. Osteoarthritis Cartilage. 2007;15:957–965.
  • Bruyère O, Cooper C, Pelletier JP, et al. A consensus statement on the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis-From evidence-based medicine to the real-life setting. Semin Arthritis Rheum. 2016;45(4Suppl):S3–S11.
  • Davies PS, Graham SM, MacFarlane RJ, et al. Disease-modifying osteoarthritis drugs: in vitro and in vivo data on the development of DMOADs under investigation. Expert Opin Investig Drugs. 2013;22:423–441.
  • Kongtharvonskul J, Anothaisintawee T, McEvoy M, et al. Efficacy and safety of glucosamine, diacerein, and NSAIDs in osteoarthritis knee: a systematic review and network meta-analysis. Eur J Med Res. 2015;20:24.
  • Hochberg MC, Martel-Pelletier J, Monfort J, et al.; on behalf of the MOVES Investigation Group. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, noninferiority trial versus celecoxib. Ann Rheum Dis. 2016;75:37–44.
  • Roman-Blas JA, Castaneda S, Largo R, et al. An OA phenotype may obtain major benefit from bone-acting agents. Semin Arthritis Rheum. 2014;43:421–428.
  • Tu G, Xu W, Huang H, et al. Progress in the development of matrix metalloproteinase inhibitors. Curr Med Chem. 2008;15:1388–1395.
  • Finckh A, Gabay C. At the horizon of innovative therapy in rheumatology: new biologic agents. Curr Opin Rheumatol. 2008;20:269–275.
  • Bursavich MG, Gilbert AM, Lombardi S, et al. Synthesis and evaluation of aryl thioxothiazolidinone inhibitors of ADAMTS-5 (aggrecanase-2). Bioorg Medicin Chem Lett. 2007;17:1185–1188.
  • Chevalier X, Eymard F, Richette P. Biologic agents in osteoarthritis: hopes and disappointments. Nat Rev Rheumatol. 2013;9:400–410.
  • Schnitzer TJ, Marks JA. A systematic review of the efficacy and general safety of antibodies to NGF in the treatment of OA of the hip or knee. Osteoarthritis Cartilage 2015;23(Suppl 1):S8–S17.
  • Bannwarth B, Kostine M. Targeting nerve growth factor (NGF) for pain management: what does the future hold for NGF antagonists? Drugs. 2014;74:619–626.
  • Malemud CJ. Biologic basis of osteoarthritis: state of the evidence. Curr Opin Rheumatol. 2015;27:289–294.
  • Chen YJ, Sheu ML, Tsai KS. Advanced glycation end products induce peroxisome proliferator-activated receptor γ down-regulation-related inflammatory signals in human chondrocytes via toll-like receptor-4 and receptor for advanced glycation end products. PLoS ONE. 2013;8:e66611.
  • Vasheghani F, Monemdjou R, Fahmi H, et al. Adult cartilage-specific peroxisome proliferator-activated receptor γ knockout mice exhibit the spontaneous osteoarthritis phenotype. Am J Pathol. 2013;182:1099–1106.
  • Largo R, Diez-Ortego I, Sanchez-Pernaute O, et al. EP2/EP4 signalling inhibits monocyte chemoattractant protein-1 production induced by interleukin 1beta in synovial fibroblasts. Ann Rheum Dis. 2004;63:1197–1204.
  • Wang P, Zhu F, Konstantopoulos K. Interleukin-6 synthesis in human chondrocytes is regulated via the antagonistic actions of prostaglandin (PG)E2 and 15-deoxy-[12,14-PGJ2. PLoS ONE. 2011;6:e27630.
  • Juarranz Y, Gutierrez-Canas I, Arranz A, et al. VIP decreases TLR4 expression induced by LPS and TNF-α treatment in human synovial fibroblasts. Ann NY Acad Sci. 2006;1070:359–364.
  • Hasko G, Linden J, Cronstein B, et al. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov. 2008;7:759–770.
  • Villalvilla A, da Silva JA, Largo R, et al. 6-Shogaol inhibits chondrocytes’ innate immune responses and cathepsin-K activity. Mol Nutr Food Res. 2014;58:256–266.
  • Chevalier X, Goupille P, Beaulieu AD, et al. Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double blind, placebo-controlled study. Arthritis Rheum. 2009;61:344–352.
  • Martel-Pelletier J, Wildi LM, Pelletier JP. Future therapeutics for osteoarthritis. Bone. 2012;51:297–311.
  • Hellio Le Graverand MP, Clemmer RS, Redifer P, et al. A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee. Ann Rheum Dis. 2013;72:187–195.
  • Henrotin Y, Clutterbuck AL, Allaway D, et al. Biological actions of curcumin on articular chondrocytes. Osteoarthritis Cartilage. 2010;18:141–149.
  • Singh R, Ahmed S, Islam N, et al. Epigallocatechin-3-gallate inhibits interleukin-1beta-induced expression of nitric oxide synthase and production of nitric oxide in human chondrocytes: suppression of nuclear factor kappaB activation by degradation of the inhibitor of nuclear factor kappaB. Arthritis Rheum. 2002;46:2079–2086.
  • Kapoor M, Martel-Pelletier J, Lajeunesse D, et al. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7:33–42.
  • Bacconnier L, Jorgensen C, Fabre S. Erosive osteoarthritis of the hand: clinical experience with anakinra. Ann Rheum Dis. 2009;68:1078–1079.
  • Ryu JH, Yang S, Shin Y, et al. Interleukin-6 plays an essential role in hypoxia-inducible factor 2α-induced experimental osteoarthritic cartilage destruction in mice. Arthritis Rheum. 2011;63:2732–2743.
  • Porée B, Kypriotou M, Chadjichristos C, et al. Interleukin-6 (IL-6. and/or soluble IL-6 receptor down-regulation of human type II collagen gene expression in articular chondrocytes requires a decrease of Sp1.Sp3 ratio and of the binding activity of both factors to the COL2A1 promoter. J Biol Chem. 2008;283:4850–4865.
  • Livshits G, Zhai G, Hart DJ, et al. Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: the Chingford Study. Arthritis Rheum. 2009;60:2037–2045.
  • Stannus O, Jones G, Cicuttini F, et al. Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults. Osteoarthritis Cartilage. 2010;18:1441–1447.
  • Sondergaard BC, Schultz N, Madsen SH, et al. MAPKs are essential upstream signaling pathways in proteolytic cartilage degradation—divergence in pathways leading to aggrecanase and MMP-mediated articular cartilage degradation. Osteoarthritis Cartilage. 2010;18:279–288.
  • Loeser RF, Erickson EA, Long DL. Mitogen-activated protein kinases as therapeutic targets in osteoarthritis. Curr Opin Rheumatol. 2008;20:581–586.
  • Mi M, Shi S, Li T, et al. TIMP2 deficient mice develop accelerated osteoarthritis via promotion of angiogenesis upon destabilization of the medial meniscus. Biochem Biophys Res Commun. 2012;423:366–372.
  • Sahebjam S, Khokha R, Mort JS. Increased collagen and aggrecan degradation with age in the joints of TIMP3(-/-) mice. Arthritis Rheum. 2007;56:905–909.
  • Krzeski P, Buckland-Wright C, Balint G, et al. Development of musculoskeletal toxicity without clear benefit after administration of PG 116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12 month, double-blind, placebo-controlled study. Arthritis Res Ther. 2007;9:R109.
  • Brandt KD, Mazzuca SA, Katz BP, et al. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo controlled, double-blind trial. Arthritis Rheum. 2005;52:2015–2025.
  • Chockalingam PS, Sun W, Rivera-Bermudez MA, et al. Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor. Osteoarthritis Cartilage. 2011;19:315–323.
  • Troeberg L, Fushimi K, Khokha R, et al. Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. Faseb J. 2008;22:3515–3524.
  • Hannan MT, Felson DT, Anderson JJ, et al. Estrogen use and radiographic osteoarthritis of the knee in women: the Framingham Osteoarthritis Study. Arthritis Rheum. 1990;33:525–532.
  • Hart DJ, Doyle DV, Spector TD. Incidence and risk factors for radiographic knee osteoarthritis in middle-aged women: the Chingford Study. Arthritis Rheum. 1999;42:17–24.
  • Zhang Y, McAlindon TE, Hannan MT, et al. Estrogen replacement therapy and worsening of radiographic knee osteoarthritis: the Framingham Study. Arthritis Rheum. 1998;41:1867–1873.
  • De Klerk BM, Schiphof D, Groeneveld FP, et al. Limited evidence for a protective effect of unopposed oestrogen therapy for osteoarthritis of the hip: a systematic review. Rheumatology (Oxford). 2009;48:104–112.
  • Maheu E, Dreiser RL, Guillou GB, et al. Hand osteoarthritis patients characteristics according to the existence of a hormone replacement therapy. Osteoarthritis Cartilage. 2000;Suppl A:S33–S37.
  • Lugo L, Villalvilla A, Largo R, et al. Selective estrogen receptor modulators (SERMs): new alternatives for osteoarthritis? Maturitas. 2014;77:380–384.
  • Tsai CL, Liu TK. Inhibition of estradiol-induced early osteoarthritic changes by tamoxifen. Life Sci. 1992;50:1943–1951.
  • Colombo C, Butler M, Hickman L, et al. A new model of osteoarthritis in rabbits II. Evaluation of anti-osteoarthritic effects of selected antirheumatic drugs administered systemically. Arthritis Rheum. 1983;26:1132–1139.
  • Christgau S, Tanko LB, Cloos PA, et al. Suppression of elevated cartilage turnover in postmenopausal women and in ovariectomized rats by estrogen and a selective estrogen-receptor modulator (SERM). Menopause. 2004;11:508–518.
  • Høegh-Andersen P, Tankó LB, Andersen TL, et al. Ovariectomized rats as a model of postmenopausal osteoarthritis: validationand application. Arthritis Res Ther. 2004;6:R169–80.
  • Spector TD, Conaghan PG, Buckland-Wright JC, et al. Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]. Arthritis Res Ther. 2005;7:R625–R633.
  • Bingham CO 3rd, Buckland-Wright JC, Garnero P, 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. 2006;54:3494–3507.
  • Buckland-Wright JC, Messent EA, Bingham CO 3rd, et al. A 2 yr longitudinal radiographic study examining the effect of a bisphosphonate (risedronate) upon subchondral bone loss in osteoarthritic knee patients. Rheumatology (Oxford). 2007;46:257–264.
  • Laslett LL, Dore DA, Quinn SJ, et al. Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial. Ann Rheum Dis. 2012;71:1322–1328.
  • Karsdal MA, Byrjalsen I, Alexandersen P, et al. CSMC021C2301/2 investigators. Treatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials. Osteoarthritis Cartilage. 2015;23:532–543.
  • Bellido M, Lugo L, Roman-Blas JA, et al. Improving subchondral bone integrity reduces progression of cartilage damage in experimental osteoarthritis preceded by osteoporosis. Osteoarthritis Cartilage. 2011;19:1228–1236.
  • Reginster JY, Badurski J, Bellamy N, et al. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann Rheum Dis. 2013;72:179–186.
  • Castaneda S, Roman-Blas JA, Largo R, et al. Subchondral bone as a key target for osteoarthritis treatment. Biochem Pharmacol. 2012;83:315–323.
  • Strand V, McIntyre LF, Beach WR, et al. Safety and efficacy of US approved viscosupplements for knee osteoarthritis: a systematic review and meta-analysis of randomized, saline-controlled trials. J Pain Res. 2015;8:217–228.
  • Maheu E, Rannou F, Reginster JY. Efficacy and safety of hyaluronic acid in the management of osteoarthritis: evidence from real-life setting trials and surveys. Semin Arthritis Rheum. 2016;45(4 Suppl):S28–S33.
  • Campbell KA, Erickson BJ, Saltzman BM, et al. Is local viscosupplementation injection clinically superior to other therapies in the treatment of osteoarthritis of the knee: a systematic review of overlapping meta-analyses. Arthroscopy. 2015;31:2036–2045.
  • Richette P, Chevalier X, Ea HK. Hyaluronan for knee osteoarthritis: an updated meta-analysis of trials with low risk of bias. RMD Open. 2015;1:e000071.
  • Bannuru RR, Natov NS, Dasi UR, et al. Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis–meta-analysis. Osteoarthritis Cartilage. 2011;19:611–619.
  • Bannuru RR, Schmid CH, Kent DM, et al. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015;162:46–54.
  • Hunter DJ. Viscosupplementation for osteoarthritis of the knee. N Engl J Med. 2015;372:1040–1047.
  • Navarro-Sarabia F, Herrero-Beaumont G. Viscosupplementation for osteoarthritis of the knee. Ann Intern Med. 2013;58:74–75.
  • Rutjes AW, Juni P, Da Costa BR, et al. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med. 2012;157:180–191.
  • Jevsevar D, Donnelly P, Brown GA, et al. Viscosupplementation for osteoarthritis of the knee: a systematic review of the evidence. J Bone Joint Surg Am. 2015;97(24):2047–2060.
  • Migliore A, Bizzi E, Herrero-Beaumont G, et al. The discrepancy between recommendations and clinical practice for viscosupplementation in osteoarthritis: mind the gap! Eur Rev Med Pharmacol Sci. 2015;19:1124–1129.
  • Brown GA. AAOS clinical practice guideline: treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg. 2013;21:577–579.
  • Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology. American College of Rheumatology 2012 recommendations for the use of non-pharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64:465–474.
  • McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014;22:363–388.
  • Bruyere O, Cooper C, Pelletier JP, et al. An algorithm recommendation for the management of knee osteoarthritis in Europe and internationally: a report from a task force of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Semin Arthritis Rheum. 2014;44:253–263.
  • Bannuru RR, McAlindon TE, Sullivan MC, et al. Effectiveness and implications of alternative placebo treatments: a systematic review and network meta-analysis of osteoarthritis trials. Ann Intern Med. 2015;163:365–372.
  • Zhang W, Robertson J, Jones AC, et al. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis. 2008;67:1716–1723.
  • Zhang W, Zou K, Doherty M. Placebos for knee osteoarthritis: reaffirmation of “Needle Is Better Than Pill”. Ann Intern Med. 2015;163:392–393.
  • Forogh B, Mianehsaz E, Shoaee S, et al. Effect of single injection of platelet-rich plasma in comparison with corticosteroid on knee osteoarthritis: a double-blind randomized clinical trial. J Sports Med Phys Fitness. 2015. Jul 14. [Epub ahead of print].
  • Raeissadat SA, Rayegani SM, Hassanabadi H, et al. Knee osteoarthritis injection choices: platelet- rich plasma (PRP) versus hyaluronic acid (A one year randomized clinical trial). Clin Med Insights Arthritis Musculoskelet Disord. 2015;8:1–8.
  • Meheux CJ, McCulloch PC, Lintner DM, et al. Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: a systematic review. Arthroscopy. 2015. pii: S0749-8063(15)00659-3.
  • Rabago D, Patterson JJ, Mundt M, et al. Dextrose and morrhuate sodium injections (prolotherapy) for knee osteoarthritis: a prospective open label trial. J Altern Complement Med. 2014;20:383–391.
  • Yang KG, Raijmakers NJ, van Arkel ER, et al. Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial. Osteoarthr Cartil. 2008;16:498–505.
  • Baltzer AW, Moser C, Jansen SA, et al. Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Cartilage. 2009;17:152–160.
  • Baltzer AW, Ostapczuk MS, Stosch D, et al. A new treatment for hip osteoarthritis: clinical evidence for the efficacy of autologous conditioned serum. Orthop Rev (Pavia). 2013;5:59–64.
  • Hunter DJ, Pike MC, Jonas BL, et al. Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskelet Disord. 2010;11:232.
  • Ellsworth JL, Berry J, Bukowski T, et al. Fibroblast growth factor-18 is a trophic factor for mature chondrocytes and their progenitors. Osteoarthritis Cartilage. 2002;10:308–320.
  • Lohmander LS, Hellot S, Dreher D, et al. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2014;66:1820–1831.
  • Diekman BO, Guilak F. Stem cell-based therapies for osteoarthritis: challenges and opportunities. Curr Opin Rheumatol. 2013;25:119–126.
  • Jo CH, Lee YG, Shin WH, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. 2014;32:1254–1266.
  • Bandara G, Mueller GM, Galea-Lauri J, et al. Intraarticular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer. Proc Natl Acad Sci USA. 1993;90:0764–8.
  • Fernandes J, Tardif G, Martel-Pelletier J, et al. In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: prevention of osteoarthritis progression. Am J Pathol. 1999;154:1159–1169.
  • Zhang X, Yu C, Xushi ZC, et al. Direct chitosan-mediated gene delivery to the rabbit knee joints in vitro and in vivo. Biochem Biophys Res Commun. 2006;341:202–208.
  • Chen B, Qin J, Wang H, et al. Effects of adenovirus-mediated bFGF, IL-1Ra and IGF-1 gene transfer on human osteoarthritic chondrocytes and osteoarthritis in rabbits. Exp Mol Med. 2010;42:684–695.
  • Watson RS, Broome TA, Levings PP, et al. scAAV-mediated gene transfer of interleukin-1-receptor antagonist to synovium and articular cartilage in large mammalian joints. Gene Ther. 2013;20:670–677.
  • Ha CW, Noh MJ, Choi KB, et al. Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients. Cytotherapy. 2012;14:247–256.
  • Ha CW, Cho JJ, Elmallah RK, et al. A multicenter, single-blind, phase iia clinical trial to evaluate the efficacy and safety of a cell-mediated gene therapy in degenerative knee arthritis patients. Hum Gene Ther Clin Dev. 2015;26:125–130.
  • Lawrence A, Xu X, Bible MD, et al. Synthesis and characterization of a lubricin mimic (mLub) to reduce friction and adhesion on the articular cartilage surface. Biomaterials. 2015;73:42–50.
  • Iqbal SM, Leonard C, Regmi CS, et al. Lubricin/Proteoglycan 4 binds to and regulates the activity of toll-like receptors in vitro. Sci Rep. 2016;6:18910.
  • Ludwig TE, McAllister JR, Lun V, et al. Diminished cartilage-lubricating ability of human osteoarthritic synovial fluid deficient in proteoglycan 4: restoration through proteoglycan 4 supplementation. Arthritis Rheum. 2012;64:3963–3971.
  • Elsaid KA, Zhang L, Waller K, et al. The impact of forced joint exercise on lubricin biosynthesis from articular cartilage following ACL transection and intra-articular lubricin’s effect in exercised joints following ACL transection. Osteoarthritis Cartilage. 2012;20:940–948.
  • Herrero-Beaumont G, Guerrero R, Sánchez-Pernaute O, et al. Cartilage and bone biological markers in the synovial fluid of osteoarthritic patients after hyaluronan injections in the knee. Clin Chim Acta. 2001;308:107–115.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.