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Etiology and Treatment of Osteoarthritis: A Developmental Biology Perspective

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Regenerative Medicine: Laboratory to Clinic

Abstract

Osteoarthritis is a debilitating disorder of the joints during which cartilage lining the articular surface of the bones undergoes progressive, irreversible damage, ultimately resulting in disability in locomotion. The current understanding about the pathogenesis of osteoarthritis is far from complete, and no effective therapy is available to tackle osteoarthritis. Analyzing the pathogenesis of osteoarthritis from the vantage point of a developmental biologist indicates that the molecular and histological changes observed during osteoarthritis closely recapitulate embryonic cartilage differentiation, thereby offering a new paradigm to understand this disease. In order to come up with new strategies for halting disease progression or initiating regeneration, it is important to understand the etiology of osteoarthritis from a molecular perspective afforded by developmental biological studies.

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Abbreviations

ACI:

Autologous chondrocyte implantation

ChM-I:

Chondromodulin-I

CSPCs:

Cartilage stem/progenitor cells

MACI:

Matrix-assisted chondrocyte implantation

NSAIDs:

Nonsteroidal anti-inflammatory drugs

PCL:

Polycaprolactone

PTHrP:

Parathyroid hormone-related peptide

References

  1. Litwic A, Edwards MH, Dennison EM, et al. Epidemiology and burden of osteoarthritis. Br Med Bull. 2013;105:185–99.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2163–96.

    Article  PubMed  Google Scholar 

  3. Bitton R. The economic burden of osteoarthritis. Am J Manag Care. 2009;15:S230–5.

    PubMed  Google Scholar 

  4. Bi W, Deng JM, Zhang Z, et al. Sox9 is required for cartilage formation. Nat Genet. 1999;22:85–9.

    Article  CAS  PubMed  Google Scholar 

  5. Kozhemyakina E, Lassar AB, Zelzer EA. pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. Development. 2015;142:817–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Vortkamp A, Lee K, Lanske B, et al. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science. 1996;273:613–22.

    Article  CAS  PubMed  Google Scholar 

  7. Cooper KL, Oh S, Sung Y, et al. Multiple phases of chondrocyte enlargement underlie differences in skeletal proportions. Nature. 2013;495:375–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bandyopadhyay A, Kubilus JK, Crochiere ML, et al. Identification of unique molecular subdomains in the perichondrium and periosteum and their role in regulating gene expression in the underlying chondrocytes. Dev Biol. 2008;321:162–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mendez-Ferrer S, Michurina TV, Ferraro F, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466:829–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Maes C, Kobayashi T, Selig MK, et al. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell. 2010;19:329–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Park J, Gebhardt M, Golovchenko S, et al. Dual pathways to endochondral osteoblasts: a novel chondrocyte-derived osteoprogenitor cell identified in hypertrophic cartilage. Biol Open. 2015;4:608–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rodda SJ, McMahon AP. Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development. 2006;133:3231–44.

    Article  CAS  PubMed  Google Scholar 

  13. Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell. 2002;2:389–406.

    Article  CAS  PubMed  Google Scholar 

  14. Sophia Fox AJ, Bedi A, Rodeo SA. The basic science of articular cartilage: structure, composition, and function. Sports Health. 2009;1:461–8.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Khan IM, Redman SN, Williams R, et al. The development of synovial joints. Curr Top Dev Biol. 2007;79:1–36.

    Article  CAS  PubMed  Google Scholar 

  16. Koyama E, Shibukawa Y, Nagayama M, et al. A distinct cohort of progenitor cells participates in synovial joint and articular cartilage formation during mouse limb skeletogenesis. Dev Biol. 2008;316:62–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ray A, Singh PN, Sohaskey ML, et al. Precise spatial restriction of BMP signaling is essential for articular cartilage differentiation. Development. 2015;142:1169–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Brunet LJ, McMahon JA, McMahon AP, et al. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science. 1998;280:1455–7.

    Article  CAS  PubMed  Google Scholar 

  19. Yang X, Chen L, Xu X, et al. TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol. 2001;153:35–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Candela ME, Yasuhara R, Iwamoto M, et al. Resident mesenchymal progenitors of articular cartilage. Matrix Biol. 2014;39:44–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jiang Y, Tuan RS. Origin and function of cartilage stem/progenitor cells in osteoarthritis. Nat Rev Rheumatol. 2015;11:206–12.

    Article  PubMed  Google Scholar 

  22. Bhosale AM, Richardson JB. Articular cartilage: structure, injuries and review of management. Br Med Bull. 2008;87:77–95.

    Article  PubMed  Google Scholar 

  23. Pritzker KP, Gay S, Jimenez SA, et al. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthr Cartil. 2006;14:13–29.

    Article  CAS  PubMed  Google Scholar 

  24. Heinegard D, Saxne T. The role of the cartilage matrix in osteoarthritis. Nat Rev Rheumatol. 2011;7:50–6.

    Article  PubMed  Google Scholar 

  25. Maldonado M, Nam J. The role of changes in extracellular matrix of cartilage in the presence of inflammation on the pathology of osteoarthritis. Biomed Res Int. 2013;2013:284873.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Billinghurst RC, Dahlberg L, Ionescu M, et al. Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. J Clin Invest. 1997;99:1534–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dahlberg L, Billinghurst RC, Manner P, et al. Selective enhancement of collagenase-mediated cleavage of resident type II collagen in cultured osteoarthritic cartilage and arrest with a synthetic inhibitor that spares collagenase 1 (matrix metalloproteinase 1). Arthritis Rheum. 2000;43:673–82.

    Article  CAS  PubMed  Google Scholar 

  28. Neuhold LA, Killar L, Zhao W, et al. Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest. 2001;107:35–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. CW W, Tchetina EV, Mwale F, et al. Proteolysis involving matrix metalloproteinase 13 (collagenase-3) is required for chondrocyte differentiation that is associated with matrix mineralization. J Bone Miner Res. 2002;17:639–51.

    Article  Google Scholar 

  30. Song RH, Tortorella MD, Malfait AM, et al. Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis Rheum. 2007;56:575–85.

    Article  CAS  PubMed  Google Scholar 

  31. Verma P, Dalal K. ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis. J Cell Biochem. 2011;112:3507–14.

    Article  CAS  PubMed  Google Scholar 

  32. Moses MA, Wiederschain D, Wu I, et al. Troponin I is present in human cartilage and inhibits angiogenesis. Proc Natl Acad Sci U S A. 1999;96:2645–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shukunami C, Oshima Y, Hiraki Y. Chondromodulin-I and tenomodulin: a new class of tissue-specific angiogenesis inhibitors found in hypovascular connective tissues. Biochem Biophys Res Commun. 2005;333:299–307.

    Article  CAS  PubMed  Google Scholar 

  34. Enomoto H, Inoki I, Komiya K, et al. Vascular endothelial growth factor isoforms and their receptors are expressed in human osteoarthritic cartilage. Am J Pathol. 2003;162:171–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pfander D, Kortje D, Zimmermann R, et al. Vascular endothelial growth factor in articular cartilage of healthy and osteoarthritic human knee joints. Ann Rheum Dis. 2001;60:1070–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pufe T, Harde V, Petersen W, et al. Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes. J Pathol. 2004;202:367–74.

    Article  CAS  PubMed  Google Scholar 

  37. Gerber HP, TH V, Ryan AM, et al. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med. 1999;5:623–8.

    Article  CAS  PubMed  Google Scholar 

  38. Maes C, Carmeliet P, Moermans K, et al. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech Dev. 2002;111:61–73.

    Article  CAS  PubMed  Google Scholar 

  39. Felson DT, Gale DR, Elon Gale M, et al. Osteophytes and progression of knee osteoarthritis. Rheumatology (Oxford). 2005;44:100–4.

    Article  CAS  Google Scholar 

  40. Gilbertson EM. Development of periarticular osteophytes in experimentally induced osteoarthritis in the dog. A study using microradiographic, microangiographic, and fluorescent bone-labelling techniques. Ann Rheum Dis. 1975;34:12–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hashimoto S, Creighton-Achermann L, Takahashi K, et al. Development and regulation of osteophyte formation during experimental osteoarthritis. Osteoarthr Cartil. 2002;10:180–7.

    Article  CAS  PubMed  Google Scholar 

  42. Gelse K, Soder S, Eger W, et al. Osteophyte development--molecular characterization of differentiation stages. Osteoarthr Cartil. 2003;11:141–8.

    Article  CAS  PubMed  Google Scholar 

  43. van der Kraan PM, van den Berg WB. Osteophytes: relevance and biology. Osteoarthr Cartil. 2007;15:237–44.

    Article  PubMed  Google Scholar 

  44. He Y, Siebuhr AS, Brandt-Hansen NU, et al. Type X collagen levels are elevated in serum from human osteoarthritis patients and associated with biomarkers of cartilage degradation and inflammation. BMC Musculoskelet Disord. 2014;15:309.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Murata M, Yudoh K, Masuko K. The potential role of vascular endothelial growth factor (VEGF) in cartilage: how the angiogenic factor could be involved in the pathogenesis of osteoarthritis? Osteoarthr Cartil. 2008;16:279–86.

    Article  CAS  PubMed  Google Scholar 

  46. Miosge N, Hartmann M, Maelicke C, et al. Expression of collagen type I and type II in consecutive stages of human osteoarthritis. Histochem Cell Biol. 2004;122:229–36.

    Article  CAS  PubMed  Google Scholar 

  47. Shen J, Li J, Wang B, et al. Deletion of the transforming growth factor beta receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice. Arthritis Rheum. 2013;65:3107–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhen G, Wen C, Jia X, et al. Inhibition of TGF-beta signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med. 2013;19:704–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Guo X, Day TF, Jiang X, et al. Wnt/beta-catenin signaling is sufficient and necessary for synovial joint formation. Genes Dev. 2004;18:2404–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hartmann C, Tabin CJ. Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton. Cell. 2001;104:341–51.

    Article  CAS  PubMed  Google Scholar 

  51. Yuasa T, Kondo N, Yasuhara R, et al. Transient activation of Wnt/{beta}-catenin signaling induces abnormal growth plate closure and articular cartilage thickening in postnatal mice. Am J Pathol. 2009;175:1993–2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthr Cartil. 2008;16:137–62.

    Article  CAS  PubMed  Google Scholar 

  53. Bellamy N, Campbell J, Robinson V, et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006;2:CD005328.

    Google Scholar 

  54. Rannou F, Poiraudeau S. Non-pharmacological approaches for the treatment of osteoarthritis. Best Pract Res Clin Rheumatol. 2010;24:93–106.

    Article  PubMed  Google Scholar 

  55. Katz JN, Earp BE, Gomoll AH. Surgical management of osteoarthritis. Arthritis Care Res (Hoboken). 2010;62:1220–8.

    Article  Google Scholar 

  56. Felson DT. Arthroscopy as a treatment for knee osteoarthritis. Best Pract Res Clin Rheumatol. 2010;24:47–50.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Moseley JB, O'Malley K, Petersen NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2002;347:81–8.

    Article  PubMed  Google Scholar 

  58. Makris EA, Gomoll AH, Malizos KN, et al. Repair and tissue engineering techniques for articular cartilage. Nat Rev Rheumatol. 2015;11:21–34.

    Article  CAS  PubMed  Google Scholar 

  59. Mithoefer K, McAdams T, Williams RJ, et al. Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis. Am J Sports Med. 2009;37:2053–63.

    Article  PubMed  Google Scholar 

  60. Knutsen G, Drogset JO, Engebretsen L, et al. A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years. J Bone Joint Surg Am. 2007;89:2105–12.

    PubMed  Google Scholar 

  61. Ronn K, Reischl N, Gautier E, et al. Current surgical treatment of knee osteoarthritis. Arthritis. 2011;2011:454873.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Sharma L. Osteoarthritis year in review 2015: clinical. Osteoarthr Cartil. 2016;24:36–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Luyten FP, Vanlauwe J. Tissue engineering approaches for osteoarthritis. Bone. 2012;51:289–96.

    Article  CAS  PubMed  Google Scholar 

  64. Hutmacher DW. Scaffolds in tissue engineering bone and cartilage. Biomaterials. 2000;21:2529–43.

    Article  CAS  PubMed  Google Scholar 

  65. Chan BP, Leong KW. Scaffolding in tissue engineering: general approaches and tissue-specific considerations. Eur Spine J. 2008;17(Suppl 4):467–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pelttari K, Winter A, Steck E, et al. Premature induction of hypertrophy during in vitro chondrogenesis of human mesenchymal stem cells correlates with calcification and vascular invasion after ectopic transplantation in SCID mice. Arthritis Rheum. 2006;54:3254–66.

    Article  CAS  PubMed  Google Scholar 

  67. Kock L, van Donkelaar CC, Ito K. Tissue engineering of functional articular cartilage: the current status. Cell Tissue Res. 2012;347:613–27.

    Article  CAS  PubMed  Google Scholar 

  68. Huey DJ, JC H, Athanasiou KA. Unlike bone, cartilage regeneration remains elusive. Science. 2012;338:917–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hellingman CA, Davidson EN, Koevoet W, et al. Smad signaling determines chondrogenic differentiation of bone-marrow-derived mesenchymal stem cells: inhibition of Smad1/5/8P prevents terminal differentiation and calcification. Tissue Eng Part A. 2011;17:1157–67.

    Article  CAS  PubMed  Google Scholar 

  70. Hellingman CA, Koevoet W, van Osch GJ. Can one generate stable hyaline cartilage from adult mesenchymal stem cells? A developmental approach. J Tissue Eng Regen Med. 2012;6:e1–e11.

    Article  CAS  PubMed  Google Scholar 

  71. Ludin A, Sela JJ, Schroeder A, et al. Injection of vascular endothelial growth factor into knee joints induces osteoarthritis in mice. Osteoarthritis Cartilage. 2013;21:491–7.

    Google Scholar 

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Authors and Affiliations

  1. Biological Sciences and Bioengineering Department, Indian Institute of Technology Kanpur, Kanpur, UP, 208016, India

    Akrit Pran Jaswal & Amitabha Bandyopadhyay Ph.D.

  2. Icahn School of Medicine at Mount Sinai, Gustave L. Levy Place, New York, NY, 10029-5674, USA

    Ayan Ray Ph.D.

Authors
  1. Akrit Pran Jaswal
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  2. Ayan Ray Ph.D.
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  3. Amitabha Bandyopadhyay Ph.D.
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Correspondence to Amitabha Bandyopadhyay Ph.D. .

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Editors and Affiliations

  1. Stem Cell Biology Laboratory, National Institute of Immunology, New Delhi, India

    Asok Mukhopadhyay

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Jaswal, A.P., Ray, A., Bandyopadhyay, A. (2017). Etiology and Treatment of Osteoarthritis: A Developmental Biology Perspective. In: Mukhopadhyay, A. (eds) Regenerative Medicine: Laboratory to Clinic. Springer, Singapore. https://doi.org/10.1007/978-981-10-3701-6_2

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