Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations
Abstract
:1. Introduction
2. Pathogenesis and Histology—Osteoarthritis as a Whole Joint Disease
2.1. Articular Cartilage
2.2. Subchondral Bone
2.3. Synovium
2.4. Infrapatellar Fat Pad, Menisci, Periarticular Muscles, Ligaments and Tendons
2.5. The Role of Cytokines, Chemokines, Mirna, Gene Expression and Other Molecules
2.5.1. Cytokines Involved in OA Signalization
2.5.2. Adipokines
2.5.3. Genetics and Epigenetics of OA
2.5.4. The Role of miRNAs in Epigenetic Regulation of OA
2.5.5. The Mitochondrial Genetics and Epigenetics in Osteoarthritis
3. State-Of-The-Art Non-Operative Therapeutic Consideration
3.1. Platelet-Rich Plasma
3.2. Bone Marrow Mesenchymal Stem Cells
- Interference with the underlying pathological or inflammatory process via immune modulation [193]. This effect is expressed through the suppression of Th1 and up-regulation of Th2 cells, inhibiting IFN-y production by interaction with NK cells, switching the phenotype macrophages from proinflammatory M1 to M2, and reducing the antibody production of B-lymphocytes [192];
- MiRNA secretion, regulating the gene expression of the surrounding cells [192].
3.3. Intra-articular Application of Autologous Microfragmented Adipose Tissue with Stromal Vascular Fraction
3.4. Extracellular Vesicles
4. Future Strategies for OA Management
4.1. Phenoty** OA
4.2. Human-Recombinant Fibroblast Growth Factor 18 (Sprifermin)
4.3. Bone Morphogenetic Protein 7 (BMP-7)
4.4. Monoclonal Antibodies
4.5. Gene Therapy of OA
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Bortoluzzi, A.; Furini, F.; Scirè, C.A. Osteoarthritis and its management—Epidemiology, nutritional aspects and environmental factors. Autoimmun. Rev. 2018, 17, 1097–1104. [Google Scholar] [CrossRef] [PubMed]
- Mabey, T.; Honsawek, S. Cytokines as biochemical markers for knee osteoarthritis. World J. Orthop. 2015, 6, 95–105. [Google Scholar] [CrossRef] [PubMed]
- Nelson, A.E. Osteoarthritis year in review 2017: Clinical. Osteoarthr. Cartil. 2018, 26, 319–325. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Loeser, R.F.; Goldring, S.R.; Scanzello, C.R.; Goldring, M.B. Osteoarthritis: A disease of the joint as an organ. Arthritis Rheum. 2012, 64, 1697–1707. [Google Scholar] [CrossRef] [Green Version]
- Martel-Pelletier, J.; Barr, A.J.; Cicuttini, F.M.; Conaghan, P.G.; Cooper, C.; Goldring, M.B.; Goldring, S.R.; Jones, G.; Teichtahl, A.J.; Pelletier, J.P. Osteoarthritis. Nat. Rev. Dis. Prim. 2016, 2, 1–18. [Google Scholar] [CrossRef] [Green Version]
- Swingler, T.E.; Niu, L.; Smith, P.; Paddy, P.; Le, L.; Barter, M.J.; Young, D.A.; Clark, I.M. The function of microRNAs in cartilage and osteoarthritis. Clin. Exp. Rheumatol. 2019, 37, 40–47. [Google Scholar]
- Ilas, D.C.; Churchman, S.M.; McGonagle, D.; Jones, E. Targeting subchondral bone mesenchymal stem cell activities for intrinsic joint repair in osteoarthritis. Futur. Sci. OA 2017, 3, FSO228. [Google Scholar] [CrossRef] [Green Version]
- Hunter, D.J.; Bierma-Zeinstra, S. Osteoarthritis. Lancet 2019, 393, 1745–1759. [Google Scholar] [CrossRef]
- Carlson, A.K.; Rawle, R.A.; Wallace, C.W.; Brooks, E.G.; Adams, E.; Greenwood, M.C.; Olmer, M.; Lotz, M.K.; Bothner, B.; June, R.K. Characterization of synovial fluid metabolomic phenotypes of cartilage morphological changes associated with osteoarthritis. Osteoarthr. Cartil. 2019, 27, 1174–1184. [Google Scholar] [CrossRef]
- Nguyen, U.-S.D.T.; Zhang, Y.; Zhu, Y.; Niu, J.; Zhang, B.; Felson, D.T. Increasing Prevalence of Knee Pain and Symptomatic Knee Osteoarthritis: Survey and Cohort Data. Ann. Intern. Med. 2011, 155, 725–732. [Google Scholar] [CrossRef]
- Zhang, Y.; Jordan, J.M. Epidemiology of Osteoarthritis. Clin. Geriatr. Med. 2010, 26, 355–369. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- GBD 2015 Disease and Injury Incidence and Prevalence Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016, 388, 1545–1602. [CrossRef] [Green Version]
- Prince, M.J.; Wu, F.; Guo, Y.; Gutierrez Robledo, L.M.; O’Donnell, M.; Sullivan, R.; Yusuf, S. The burden of disease in older people and implications for health policy and practice. Lancet 2015, 385, 549–562. [Google Scholar] [CrossRef]
- Shane Anderson, A.; Loeser, R.F. Why is osteoarthritis an age-related disease? Best Pract. Res. Clin. Rheumatol. 2010, 24, 15–26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Felson, D.T. Osteoarthritis as a disease of mechanics. Osteoarthr. Cartil. 2013, 21, 10–15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vina, E.R.; Kwoh, C.K. Epidemiology of osteoarthritis. Curr. Opin. Rheumatol. 2018, 30, 160–167. [Google Scholar] [CrossRef] [PubMed]
- Harris, E.C.; Coggon, D. HIP osteoarthritis and work. Best Pract. Res. Clin. Rheumatol. 2015, 29, 462–482. [Google Scholar] [CrossRef] [Green Version]
- Ezzat, A.M.; Li, L.C. Occupational Physical Loading Tasks and Knee Osteoarthritis: A Review of the Evidence. Physiother. Can. 2014, 66, 91–107. [Google Scholar] [CrossRef] [Green Version]
- Driban, J.B.; Hootman, J.M.; Sitler, M.R.; Harris, K.P.; Cattano, N.M. Is Participation in Certain Sports Associated With Knee Osteoarthritis? A Systematic Review. J. Athl. Train. 2017, 52, 497–506. [Google Scholar] [CrossRef]
- Berenbaum, F.; Wallace, I.J.; Lieberman, D.E.; Felson, D.T. Modern-day environmental factors in the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 2018, 14, 674–681. [Google Scholar] [CrossRef]
- Hame, S.L.; Alexander, R.A. Knee osteoarthritis in women. Curr. Rev. Musculoskelet. Med. 2013, 6, 182–187. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Long, H.; Zeng, X.; Liu, Q.; Wang, H.; Vos, T.; Hou, Y.; Lin, C.; Qiu, Y.; Wang, K.; ** of a Stromal Vascular Fraction from Microfragmented Lipoaspirate Used in Osteoarthritis Cartilage Treatment and Its Lipoaspirate Counterpart. Genes 2019, 10, 474. [Google Scholar] [CrossRef] [Green Version]
- Borić, I.; Hudetz, D.; Rod, E.; Jeleč, Ž.; Vrdoljak, T.; Skelin, A.; Polašek, O.; Plečko, M.; Trbojević-Akmačić, I.; Lauc, G.; et al. A 24-Month Follow-Up Study of the Effect of Intra-Articular Injection of Autologous Microfragmented Fat Tissue on Proteoglycan Synthesis in Patients with Knee Osteoarthritis. Genes 2019, 10, 1051. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Russo, A.; Screpis, D.; Di Donato, S.L.; Bonetti, S.; Piovan, G.; Zorzi, C. Autologous micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis: An update at 3 year follow-up. J. Exp. Orthop. 2018, 5, 52. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mautner, K.; Bowers, R.; Easley, K.; Fausel, Z.; Robinson, R. Functional Outcomes Following Microfragmented Adipose Tissue Versus Bone Marrow Aspirate Concentrate Injections for Symptomatic Knee Osteoarthritis. Stem Cells Transl. Med. 2019, 8, 1149–1156. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Russo, A.; Condello, V.; Madonna, V.; Guerriero, M.; Zorzi, C. Autologous and micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis. J. Exp. Orthop. 2017, 4, 33. [Google Scholar] [CrossRef] [PubMed]
- Peretti, G.M.; Ulivi, M.; De Girolamo, L.; Meroni, V.; Lombardo, M.D.; Mangiavini, L. Evaluation of the use of autologous micro-fragmented adipose tissue in the treatment of knee osteoarthritis: Preliminary results of a randomized controlled trial. J. Biol. Regul. Homeost. Agents 2018, 32, 193–199. [Google Scholar]
- Freitag, J.; Bates, D.; Wickham, J.; Shah, K.; Huguenin, L.; Tenen, A.; Paterson, K.; Boyd, R. Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: A randomized controlled trial. Regen. Med. 2019, 14, 213–230. [Google Scholar] [CrossRef] [Green Version]
- Yun, S.; Ku, S.-K.; Kwon, Y.-S. Adipose-derived mesenchymal stem cells and platelet-rich plasma synergistically ameliorate the surgical-induced osteoarthritis in Beagle dogs. J. Orthop. Surg. Res. 2016, 11, 9. [Google Scholar] [CrossRef] [Green Version]
- Pak, J.; Chang, J.-J.; Lee, J.H.; Lee, S.H. Safety reporting on implantation of autologous adipose tissue-derived stem cells with platelet-rich plasma into human articular joints. BMC Musculoskelet. Disord. 2013, 14, 337. [Google Scholar] [CrossRef] [Green Version]
- Jayaram, P.; Ikpeama, U.; Rothenberg, J.B.; Malanga, G.A. Bone Marrow-Derived and Adipose-Derived Mesenchymal Stem Cell Therapy in Primary Knee Osteoarthritis: A Narrative Review. PM&R 2019, 11, 177–191. [Google Scholar] [CrossRef]
- Shariatzadeh, M.; Song, J.; Wilson, S.L. The efficacy of different sources of mesenchymal stem cells for the treatment of knee osteoarthritis. Cell Tissue Res. 2019, 378, 399–410. [Google Scholar] [CrossRef] [Green Version]
- Wu, X.; Wang, Y.; **ao, Y.; Crawford, R.; Mao, X.; Prasadam, I. Extracellular vesicles: Potential role in osteoarthritis regenerative medicine. J. Orthop. Transl. 2020, 21, 73–80. [Google Scholar] [CrossRef] [PubMed]
- Lener, T.; Gimona, M.; Aigner, L.; Börger, V.; Buzas, E.; Camussi, G.; Chaput, N.; Chatterjee, D.; Court, F.A.; del Portillo, H.A.; et al. Applying extracellular vesicles based therapeutics in clinical trials—An ISEV position paper. J. Extracell. Vesicles 2015, 4, 30087. [Google Scholar] [CrossRef] [PubMed]
- Morrison, T.J.; Jackson, M.V.; Cunningham, E.K.; Kissenpfennig, A.; McAuley, D.F.; O’Kane, C.M.; Krasnodembskaya, A.D. Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer. Am. J. Respir. Crit. Care Med. 2017, 196, 1275–1286. [Google Scholar] [CrossRef]
- Tan, S.S.H.; Tjio, C.K.E.; Wong, J.R.Y.; Wong, K.L.; Chew, J.R.J.; Hui, J.H.P.; Toh, W.S. Mesenchymal Stem Cell Exosomes for Cartilage Regeneration: A Systematic Review of Preclinical In Vivo Studies. Tissue Eng. Part B Rev. 2020, 2019, 0326. [Google Scholar] [CrossRef]
- Sun, Q.; Zhang, Y.; Yang, G.; Chen, X.; Zhang, Y.; Cao, G.; Wang, J.; Sun, Y.; Zhang, P.; Fan, M.; et al. Transforming Growth Factor-Beta-Regulated miR-24 Promotes Skeletal Muscle Differentiation. Nucleic Acids Res. 2008, 36, 2690–2699. [Google Scholar] [CrossRef]
- Fleury, A.; Martinez, M.C.; Le Lay, S. Extracellular Vesicles as Therapeutic Tools in Cardiovascular Diseases. Front. Immunol. 2014, 5, 370. [Google Scholar] [CrossRef] [Green Version]
- Goldie, B.J.; Dun, M.D.; Lin, M.; Smith, N.D.; Verrills, N.M.; Dayas, C.V.; Cairns, M.J. Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons. Nucleic Acids Res. 2014, 42, 9195–9208. [Google Scholar] [CrossRef] [Green Version]
- Dell’Isola, A.; Allan, R.; Smith, S.L.; Marreiros, S.S.P.; Steultjens, M. Identification of clinical phenotypes in knee osteoarthritis: A systematic review of the literature. BMC Musculoskelet. Disord. 2016, 17, 1–12. [Google Scholar] [CrossRef] [Green Version]
- Dell’Isola, A.; Steultjens, M.; Dell’Isola, A.; Steultjens, M.; Isola, A.D.; Steultjens, M. Classification of patients with knee osteoarthritis in clinical phenotypes: Data from the osteoarthritis initiative. PLoS ONE 2018, 13, e191045. [Google Scholar] [CrossRef] [PubMed]
- Van Spil, W.E.; Kubassova, O.; Boesen, M.; Bay-Jensen, A.-C.; Mobasheri, A. Osteoarthritis phenotypes and novel therapeutic targets. Biochem. Pharmacol. 2019, 165, 41–48. [Google Scholar] [CrossRef] [PubMed]
- Chen, T.-M.; Chen, Y.-H.; Sun, H.; Tsai, S.-J. Fibroblast growth factors: Potential novel targets for regenerative therapy of osteoarthritis. Chin. J. Physiol. 2019, 62, 2. [Google Scholar] [CrossRef] [PubMed]
- Meloni, G.; Farran, A.; Mohanraj, B.; Guehring, H.; Cocca, R.; Rabut, E.; Mauck, R.; Dodge, G. Recombinant human FGF18 preserves depth-dependent mechanical inhomogeneity in articular cartilage. Eur. Cells Mater. 2019, 38, 23–38. [Google Scholar] [CrossRef]
- Eckstein, F.; Kraines, J.L.; Aydemir, A.; Wirth, W.; Maschek, S.; Hochberg, M.C. Intra-articular sprifermin reduces cartilage loss in addition to increasing cartilage gain independent of location in the femorotibial joint: Post-hoc analysis of a randomised, placebo-controlled phase II clinical trial. Ann. Rheum. Dis. 2020, 79, 525–528. [Google Scholar] [CrossRef]
- Hochberg, M.C.; Guermazi, A.; Guehring, H.; Aydemir, A.; Wax, S.; Fleuranceau-Morel, P.; Reinstrup Bihlet, A.; Byrjalsen, I.; Ragnar Andersen, J.; Eckstein, F. Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis. JAMA 2019, 322, 1360. [Google Scholar] [CrossRef]
- Gigout, A.; Guehring, H.; Froemel, D.; Meurer, A.; Ladel, C.; Reker, D.; Bay-Jensen, A.C.; Karsdal, M.A.; Lindemann, S. Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix. Osteoarthr. Cartil. 2017, 25, 1858–1867. [Google Scholar] [CrossRef] [Green Version]
- Gregori, D.; Giacovelli, G.; Minto, C.; Barbetta, B.; Gualtieri, F.; Azzolina, D.; Vaghi, P.; Rovati, L.C. Association of Pharmacological Treatments With Long-term Pain Control in Patients With Knee Osteoarthritis. JAMA 2018, 320, 2564. [Google Scholar] [CrossRef] [Green Version]
- Stöve, J.; Schneider-Wald, B.; Scharf, H.P.; Schwarz, M.L. Bone morphogenetic protein 7 (bmp-7) stimulates Proteoglycan synthesis in human osteoarthritic chondrocytes in vitro. Biomed. Pharmacother. 2006, 60, 639–643. [Google Scholar] [CrossRef]
- Bone morphogenetic protein 7 inhibits cartilage degradation in a rabbit model of osteoarthritis. Nat. Clin. Pract. Rheumatol. 2009, 5, 4. [CrossRef]
- Hayashi, M.; Muneta, T.; Ju, Y.-J.; Mochizuki, T.; Sekiya, I. Weekly intra-articular injections of bone morphogenetic protein-7 inhibits osteoarthritis progression. Arthritis Res. Ther. 2008, 10, R118. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hunter, D.J.; Pike, M.C.; Jonas, B.L.; Kissin, E.; Krop, J.; McAlindon, T. Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskelet. Disord. 2010, 11, 232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mimpen, J.Y.; Snelling, S.J.B. Chondroprotective Factors in Osteoarthritis: A Joint Affair. Curr. Rheumatol. Rep. 2019, 21, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Oo, W.M.; Yu, S.P.C.; Daniel, M.S.; Hunter, D.J. Disease-modifying drugs in osteoarthritis: Current understanding and future therapeutics. Expert Opin. Emerg. Drugs 2018, 23, 331–347. [Google Scholar] [CrossRef]
- Shepard, H.M.; Phillips, G.L.; Thanos, C.D.; Feldmann, M. Developments in therapy with monoclonal antibodies and related proteins. Clin. Med. J. R. Coll. Physicians Lond. 2017, 17, 220–232. [Google Scholar] [CrossRef]
- Das, V.; Kc, R.; Li, X.; O-Sullivan, I.S.; van Wijnen, A.J.; Kroin, J.S.; Pytowski, B.; Applegate, D.T.; Votta-Velis, G.; Ripper, R.L.; et al. Blockade of vascular endothelial growth factor receptor-1 (Flt-1), reveals a novel analgesic for osteoarthritis-induced joint pain. Gene Rep. 2018, 11, 94–100. [Google Scholar] [CrossRef]
- Kan, S.-L.; Li, Y.; Ning, G.-Z.; Yuan, Z.-F.; Chen, L.-X.; Bi, M.-C.; Sun, J.-C.; Feng, S.-Q. Tanezumab for Patients with Osteoarthritis of the Knee: A Meta-Analysis. PLoS ONE 2016, 11, e0157105. [Google Scholar] [CrossRef]
- Schnitzer, T.J.; Easton, R.; Pang, S.; Levinson, D.J.; Pixton, G.; Viktrup, L.; Davignon, I.; Brown, M.T.; West, C.R.; Verburg, K.M. Effect of Tanezumab on Joint Pain, Physical Function, and Patient Global Assessment of Osteoarthritis among Patients with Osteoarthritis of the Hip or Knee: A Randomized Clinical Trial. JAMA J. Am. Med. Assoc. 2019, 322, 37–48. [Google Scholar] [CrossRef]
- Tiseo, P.J.; Kivitz, A.J.; Ervin, J.E.; Ren, H.; Mellis, S.J. Fasinumab (REGN475), an antibody against nerve growth factor for the treatment of pain: Results from a double-blind, placebo-controlled exploratory study in osteoarthritis of the knee. Pain 2014, 155, 1245–1252. [Google Scholar] [CrossRef]
- Gow, J.M.; Tsuji, W.H.; Williams, G.J.; Mytych, D.; Sciberras, D.; Searle, S.L.; Mant, T.; Gibbs, J.P. Safety, tolerability, pharmacokinetics, and efficacy of AMG 403, a human anti-nerve growth factor monoclonal antibody, in two phase I studies with healthy volunteers and knee osteoarthritis subjects. Arthritis Res. Ther. 2015, 17, 282. [Google Scholar] [CrossRef] [Green Version]
- Miller, R.E.; Tran, P.B.; Ishihara, S.; Larkin, J.; Malfait, A.M. Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis. Osteoarthr. Cartil. 2016, 24, 299–306. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nixon, A.J.; Grol, M.W.; Lang, H.M.; Ruan, M.Z.C.; Stone, A.; Begum, L.; Chen, Y.; Dawson, B.; Gannon, F.; Plutizki, S.; et al. Disease-Modifying Osteoarthritis Treatment With Interleukin-1 Receptor Antagonist Gene Therapy in Small and Large Animal Models. Arthritis Rheumatol. 2018, 70, 1757–1768. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pickar-Oliver, A.; Gersbach, C.A. The next generation of CRISPR–Cas technologies and applications. Nat. Rev. Mol. Cell Biol. 2019, 20, 490–507. [Google Scholar] [CrossRef] [PubMed]
- Zhao, L.; Huang, J.; Fan, Y.; Li, J.; You, T.; He, S.; **ao, G.; Chen, D. Exploration of CRISPR/Cas9-based gene editing as therapy for osteoarthritis. Ann. Rheum. Dis. 2019, 78, 676–682. [Google Scholar] [CrossRef]
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Primorac, D.; Molnar, V.; Rod, E.; Jeleč, Ž.; Čukelj, F.; Matišić, V.; Vrdoljak, T.; Hudetz, D.; Hajsok, H.; Borić, I. Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations. Genes 2020, 11, 854. https://doi.org/10.3390/genes11080854
Primorac D, Molnar V, Rod E, Jeleč Ž, Čukelj F, Matišić V, Vrdoljak T, Hudetz D, Hajsok H, Borić I. Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations. Genes. 2020; 11(8):854. https://doi.org/10.3390/genes11080854
Chicago/Turabian StylePrimorac, Dragan, Vilim Molnar, Eduard Rod, Željko Jeleč, Fabijan Čukelj, Vid Matišić, Trpimir Vrdoljak, Damir Hudetz, Hana Hajsok, and Igor Borić. 2020. "Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations" Genes 11, no. 8: 854. https://doi.org/10.3390/genes11080854